John R. Lake

Recurrent and acquired hepatitis C viral infection in liver transplant recipients

To examine the postliver transplant recurrence of hepatitis C virus (HCV) infection in patients with pretransplant infection, as well as its acquisition in patients without prior infection, we used the polymerase chain reaction to amplify HCV RNA in serum and/or liver samples of 89 patients with alcoholic and cryptogenic cirrhosis undergoing liver transplantation. Results were correlated with histologic findings from posttransplant liver biopsies. Ninety-five percent of patients with pretransplant infection had posttransplant viremia. In contrast, 35% of patients without pretransplant infection acquired the virus (P less than 0.0001). Pretransplant HCV infection predisposed patients to hepatitis in the new graft. HCV RNA was present in serum of 96% of patients with posttransplant hepatitis. Fifty-six percent of patients with posttransplant HCV infection had no evidence of liver damage at least 1 year posttransplant. However, of those patients with histologic hepatitis, chronic active hepatitis was common. It is concluded that although HCV infection recurs posttransplant in almost all infected patients, acquisition of the HCV infection with transplant is common. Pretransplant HCV infection is an independent risk factor for the development of posttransplant hepatitis. HCV infection accounts for the majority of posttransplant hepatitis not due to cytomegalovirus, and although many patients with posttransplant viremia have little evidence of histologic hepatitis, significant hepatic damage may occur.

Functional analysis of grafts from living donors. Implications for the treatment of older recipients.

OBJECTIVE Living-related liver transplantation (LRLT) has established efficacy in children. In a larger recipient, LRLT requires the use of a small graft because of limits on the donor hepatectomy. SUMMARY BACKGROUND DATA The minimum graft weight required for successful transplantation has not been well established, although a characteristic pattern of graft dysfunction has been observed in our patients who receive small grafts. The authors present a clinicopathologic study of small liver grafts obtained from living donors. METHODS Clinical and histologic data were reviewed for 25 patients receiving LRLT. In five older recipients (small group), the graft represented 50% or less of expected liver weight, whereas in 20 others (large group), the graft represented at least 60% of expected liver weight. A retrospective analysis of graft function was conducted by analyzing clinical parameters and histology. RESULTS In the small group, 2 of 5 grafts (40%) were lost due to poor function, leading to one patient death (20% mortality), whereas in the large group, 2 of 20 grafts (10%) were lost due to arterial thrombosis without patient mortality. Early ischemic damage related to transplant was comparable with aspartate aminotransferase 203 +/- 23 (small group) and 290 +/- 120 (large group) at 24 hours (p = not significant). Early function was significantly decreased in the small group, with prothrombin time 18.2 +/- 2.2 seconds versus 14.8 +/- 1.6 seconds (large group) on day 3 (p = 0.034). All small group patients developed cholestasis with significantly increased total bilirubin levels at day 7 (16 +/- 5.2 mg% vs. 3.7 +/- 2.7 mg%; p = 0.021) and day 14 (12.0 +/- 7.4 vs. 1.8 +/- 0.7; p = 0.021) compared with the large group. Protocol biopsies in the small group revealed a diffuse ischemic pattern with cellular ballooning on day 7, which progressed to cholestasis in subsequent biopsies. Large group biopsies showed minimal ischemic changes. Three small group patients recovered with normal liver function by 12 weeks. CONCLUSIONS Clinical recovery after a small-for-size transplant is characterized by significant functional impairment associated with paradoxical histologic changes typical of ischemia. These changes apparently are due to graft injury, which can only be the result of small graft size. These findings have significant implications for the extension of LRLT to adults.

Two-year outcome following transjugular intrahepatic portosystemic shunt for variceal bleeding: Results in 90 patients

BACKGROUND/AIMS Transjugular intrahepatic portosystemic shunt (TIPS) is a new therapy for variceal bleeding. Immediate technical and short-term clinical results have been reported. This study was undertaken to evaluate mid-term outcome after TIPS in patients who successfully underwent the procedure for variceal bleeding. METHODS Ninety patients were followed up prospectively by clinical examination and radiological shunt evaluation including Doppler sonography and transjugular portal venography. RESULTS The average follow-up in surviving patients was 2.2 years. The cumulative survival rate was 60% at 1 year and 51% at 2 years. The rate of cumulative rebleeding was 26% at 1 year and 32% at 2 years. A shunt abnormality was noted in all rebleeding patients. Rebleeding was successfully controlled in all but 1 of the patients who underwent shunt revision. Cumulative detection of stenosis or occlusion was 31% at 1 year and 47% at 2 years. Thirty-eight percent of shunt abnormalities were detected by routine surveillance. Percutaneous shunt revision was attempted in 22 patients and was successful in 21 (95%). CONCLUSIONS Although mid-term primary patency is limited in many patients by the development of a shunt stenosis or occlusion, shunt function can be maintained in most patients by careful surveillance and periodic percutaneous intervention.

Endoscopic Sclerotherapy Compared with Percutaneous Transjugular Intrahepatic Portosystemic Shunt after Initial Sclerotherapy in Patients with Acute Variceal Hemorrhage: A Randomized, Controlled Trial

During the past 15 years, endoscopic sclerotherapy and, more recently, band ligation and such pharmacologic agents as octreotide have eclipsed surgical shunting as the preferred method for controlling acute variceal hemorrhage. The status of sclerotherapy for the long-term management of patients with bleeding varices, however, remains controversial. In a previous controlled clinical trial comparing endoscopic sclerotherapy with surgical portacaval shunting [1], we enrolled 64 adult patients with Child class C cirrhosis and active hemorrhage from esophageal varices. At the index hospitalization, patients randomly assigned to sclerotherapy required less blood transfusion and fewer days of hospitalization than did those randomly assigned to shunt surgery. During the initial follow-up period, which extended for a mean of 530 days after randomization, 75% of the patients treated with sclerotherapy were hospitalized for recurrent variceal hemorrhage but none of the patients who had had shunt surgery were rehospitalized [1]. Although patients treated with sclerotherapy had longer hospital stays and received more blood transfusions during short-term follow-up, a longer follow-up study [2] showed no difference in survival or overall health care costs between patients treated with sclerotherapy and those treated with surgical shunt. The transjugular intrahepatic portosystemic shunt (TIPS) procedure is a nonsurgical procedure in which an expandable metal prosthesis is used to connect an intrahepatic portal vein with an adjacent hepatic vein [3, 4]. In our initial report on 100 patients having this procedure [3], TIPS stent placement was technically successful in 96 patients and variceal hemorrhage was controlled in 88 of 94 patients [3]. Furthermore, the 30-day mortality rate was only 13% in patients treated with TIPS. These data, as well as those of other researchers who used radiographically placed portosystemic stents, suggest that TIPS might be more cost-effective than sclerotherapy; however, data comparing the two procedures are limited [5-10]. Therefore, we did a randomized, controlled trial in patients with massive acute variceal hemorrhage in an effort to compare the two therapies for the prevention of recurrent variceal hemorrhage. Methods From November 1991 through December 1995, we enrolled 49 adults who had cirrhosis and endoscopically documented bleeding from esophageal varices. We excluded an estimated additional 250 patients with bleeding varices whom we had seen during the study period (vide infra). Our study protocol was approved by the Committee on Human Research of the University of California, San Francisco. Patients who were admitted to San Francisco General Hospital, University of California Medical Center, and Veterans Affairs Medical Center (all located in San Francisco, California) with massive or submassive acute gastrointestinal tract hemorrhage from large esophageal varices were approached for consent and randomization within 24 hours of admission. Massive hemorrhage was defined as bleeding associated with shock (systolic blood pressure < 80 mm Hg). Submassive hemorrhage was defined as hemorrhage associated with postural vital sign changes (upright pulse rate increased by 20 beats per minute compared with supine pulse rate; upright systolic blood pressure decreased by 20 mm Hg compared with supine blood pressure). The 250 excluded patients were excluded for the following reasons: They were prisoners; they were younger than 18 or older than 75 years of age; they had had a cerebrovascular accident within 3 months before the onset of bleeding; they refused to accept blood products; or they had gastric variceal hemorrhage, electrocardiographic changes compatible with acute myocardial infarction, a Po 2 less than 70 mm Hg or an arterial pH of 7.20 or less on room air at the time of evaluation for eligibility, a serum creatinine level of 221 mol/L or more, a prothrombin time at least 5 seconds longer than control (despite the use of fresh frozen plasma), a platelet count less than 50 109/L, stage IV hepatic encephalopathy, cancer other than skin cancer, the acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex, sepsis, pneumonia, peritonitis, clinical evidence of alcoholic hepatitis, a serum bilirubin concentration of 7 mg/dL or more, thrombosis of the portal vein, thrombosis of the hepatic veins, or thrombosis of the inferior vena cava as determined by Doppler ultrasonography. All patients received endoscopic sclerotherapy at the time of the initial endoscopic procedure that established the source of hemorrhage as esophageal varices. Patients were deemed eligible for participation if they presented with hemodynamically submassive or massive hemorrhage and were found to have large (>1 cm across) distal esophageal varices with cherry red spots, hematocystic spots, or red wale signs. Before randomization, all patients had patency of the portal venous system (main, right, and left portal veins and the splenic vein) and hepatic veins determined by real-time color and pulse-wave Doppler ultrasonography. After we obtained informed consent, we used serially numbered, sealed, opaque envelopes to randomly assign patients either to repeated sclerotherapy or to TIPS. If neither the patient nor the patients next of kin was able to give informed consent, a patient advocate was designated to consider the invitation to participate. Patients randomly assigned to sclerotherapy received treatment every 2 to 7 days during the initial hospitalization; treatment consisted of 0.5- to 2.0-mL injections of ethanolamine oleate solution per varix. Repeated endoscopy and sclerotherapy treatments were done weekly after discharge from the initial hospitalization. As much as 30 mL of ethanolamine oleate solution was used per treatment session. All visible varices were injected within the distal 7 to 10 cm of the esophagus. In patients who developed sclerotherapy-associated ulcers, repeated endoscopy was scheduled to be done 2 to 7 days after the notation of ulcers to assess interval healing. Patients assigned to the TIPS group had the procedure within 48 hours of randomization; the procedure was performed by one of six radiologists skilled in this procedure, as described elsewhere [3]. Catheterization of the hepatic vein was done through the right internal jugular vein. A tract between a suitable hepatic vein and a suitable portal vein was established by needle set (Ring TIPS set, Cook, Inc., Bloomington, Indiana), dilated with a balloon over a guidewire, and then maintained by one or more expandable metal mesh stents (Wallstent, Schneider, Inc., Minneapolis, Minnesota). The adequacy of the portosystemic shunt was documented by contrast injection and manometric measurement at the time of the initial procedure. A target portal vein-to-hepatic vein pressure gradient of 12 mm Hg or less was achieved in all cases. Persistent varices opacified at portal venography after adequate stenting were occluded by using embolization coils. Preprocedural data recorded prospectively included sex, age, vital signs at admission, physical examination findings at admission (including presence of encephalopathy and ascites), nutritional status, results of laboratory tests, and Child-Pugh score [11]. Prospectively identified outcome variables after randomization included death, rebleeding, liver transplantation, total transfusion requirements, onset and presence of encephalopathy, cost of managing variceal hemorrhage after randomization, total duration of hospitalization for variceal hemorrhage and any related encephalopathy, and complications of therapy. Nutritional status was defined as malnourished if the patient had gross muscle wasting, had cachexia, or had lost at least 10% of body weight during the previous 6 months. Bleeding after randomization was defined as bloody or coffee grounds emesis (hemetemesis, melenemesis) or liquid black stools (melena) with a decrease in hematocrit sufficient to warrant transfusion. Hepatic encephalopathy was defined clinically by the presence of asterixis, gross disorientation or agitation, or frank somnolence or coma in the absence of another identifiable cause. Presence of ascites was determined by both ultrasonography and clinical assessment (shifting dullness, fluid wave, gross distention) for all patients initially and for patients in the TIPS group having follow-up Doppler ultrasonography. For patients assigned to sclerotherapy, presence of ascites was subsequently determined by clinical criteria alone. Follow-up information was obtained through face-to-face interviews, telephone interviews, or chart reviews and was obtained from the patient, family, physician, or all three sources. The total cost of health care per patient was calculated as the sum of all real costs for inpatient and outpatient hospital care, including hospital expenditures and costs for professional services from the day of randomization until death or the last follow-up visit. In addition, all outpatient costs for endoscopic sclerotherapy, Doppler ultrasonography, and stent revision during the follow-up period were included. We used the actual cost to the hospital or medical staff, or both, of providing a service or procedure (rather than billing charges or collections). For example, the cost of an endoscopic sclerotherapy session was determined by summating the following: 1 hour of a gastroenterologists time plus benefits (derived from personnel pay records); 2 hours of a registered nurses time plus benefits; the invoice cost of disposable sclerotherapy catheters, bite blocks, and intravenous tubing; the pharmacy costs of all drugs, including the sclerosant agent; the estimated depreciation of an Olympus GIT-IT100 videoendoscope (Lake Success, New York); endoscopic processing costs; 1 hour of recovery room personnel time; and costs of recovery supplies. Outcome variables were compared, using the intention-to-tre

Early allograft dysfunction after liver transplantation: A definition and predictors of outcome

BACKGROUND Poor graft function early after liver transplantation is an important cause of morbidity and mortality. We defined early allograft dysfunction (EAD) using readily available indices of function and identified donor, graft, and pretransplant recipient factors associated with this outcome. METHODS This study examined 710 adult recipients of a first, single-organ liver transplantation for non-fulminant liver disease at three United States centers. EAD was defined by the presence of at least one of the following between 2 and 7 days after liver transplantation: serum bilirubin >10 mg/dl, prothrombin time (PT) > or =17 sec, and hepatic encephalopathy. RESULTS EAD incidence was 23%. Median intensive care unit (ICU) and hospital stays were longer for recipients with EAD than those without (4 days vs. 3 days, P = 0.0001; 24 vs. 15 days, P = 0.0001, respectively). Three-year recipient and graft survival were worse in those with EAD than in those without (68% vs. 83%, P = .0001; 61% vs. 79%, P = 0.0001). A logistic regression model combining donor, graft, and recipient factors predicted EAD better than models examining these factors in isolation. Pretransplant recipient elevations in PT and bilirubin, awaiting a graft in hospital or ICU, donor age > or =50 years, donor hospital stay >3 days, preprocurement acidosis, and cold ischemia time > or =15 hr were independently associated with EAD. CONCLUSION Recipients who develop EAD have longer ICU and hospital stays and greater mortality than those without. Donor, graft, and recipient risk factors all contribute to the development of EAD. Results of these analyses identify factors that, if modified, may alter the risk of EAD.

Outcome of patients with renal insufficiency undergoing liver or liver-kidney transplantation.

Renal insufficiency (RI) is a common finding with end-stage liver disease. RI is generally not regarded as a contraindication to liver transplantation. However, the impact of RI on outcome following transplantation and the role of combined liver-kidney transplant are not well understood. The effect of RI on patients with fulminant hepatic failure (FHF) or chronic liver disease (cirrhosis) was investigated using the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Transplantation Database. Patients were analyzed based on the presence of RI, defined as creatinine >1.6 mg/dl, or on dialysis. Patients undergoing liver-kidney transplantation were analyzed separately. For patients with FHF, the RI group had a lower patient survival rate at 1 year (50% vs. 83%, P=0.04) and tended to have a lower graft survival rate (50% vs. 71%). Stay in the intensive care unit (ICU) was prolonged in the RI group but hospital stay was not. Among patients with cirrhosis, RI did not affect patient survival, except for patients on dialysis or those with liver-kidney transplants. One-year patient and graft survival rates were 65% and 60% for the dialysis group, 74% and 70% for the liver-kidney transplant group, 89% and 86% for RI patients not on dialysis, and 89 and 84% for non-RI patients. ICU and hospital stays were prolonged for all of the RI groups compared with the non-RI patients. Patients with RI had higher rates of posttransplant dialysis; however, the differences tended to equalize after 4 weeks. We conclude that RI in FHF and RI requiring dialysis or liver-kidney transplantation in cirrhosis predict lower posttransplant patient and graft survival rates. Patients with RI have longer hospital and ICU stays and an increased need for dialysis, which likely increases the cost of transplantation. Whether liver-kidney transplantation improves outcome and thus represents an appropriate use of cadaver kidneys requires further study.

Hepatitis B virus and apparent fulminant non-A, non-B hepatitis

While there is evidence that hepatitis C virus (HCV) does not cause fulminant non-A, non-B hepatitis, the causal agent remains unknown. To evaluate the role of hepatitis B virus (HBV) in this disease, we used a two-step polymerase chain reaction (PCR) to amplify the surface and core regions of HBV DNA in serum and liver samples taken prospectively from twenty-six patients (mean age 36 years, range 1 to 64) with acute hepatic failure undergoing liver transplantation. HBV DNA was absent from the serum of all patients before transplantation. Seventeen patients were diagnosed as having non-A, non-B hepatitis because they lacked serological evidence of hepatitis A virus or HBV infection. Liver samples were taken from twelve of these patients, and six samples were positive for HBV DNA. By contrast HBV DNA was not detected in liver from three patients with acute liver failure caused by hepatitis A or toxins. HCV RNA was not found in pretransplant samples by PCR. Four of the six patients with detectable HBV DNA in liver and presumptive non-A, non-B hepatitis had detectable HBV DNA in serum after transplantation. One additional patient who did not donate pretransplant liver had HBV DNA in a post-transplant serum sample. Thus, HBV DNA was present before or after transplantation in seven of seventeen patients with apparent non-A, non-B hepatitis. Three of five patients with detectable post-transplant serum HBV DNA were serologically positive for HBV surface antigen. These findings indicate that HBV may be a common cause of fulminant hepatic failure in patients lacking serological evidence of HBV infection.

Age and liver transplantation: A report of the liver transplantation database

BACKGROUND The average age of liver transplant recipients has increased steadily during the last decade. The effects of recipient age on outcome of liver transplantation were evaluated in a large prospective database. METHODS A total of 735 adult recipients of single-organ liver transplants for nonfulminant liver disease enrolled in a large prospective database between 1990 and 1994 were analyzed for associations of patient age with outcomes. Patients were categorized into two groups: younger being <60 and older being > or = 60 years of age. RESULTS Older liver transplant recipients were more likely to be female, white, and have the diagnoses of primary biliary cirrhosis or cryptogenic cirrhosis than younger recipients, who were more likely to have the diagnosis of alcoholic liver disease. Disease severity was similar between the two groups. After transplantation, the durations of stay in the intensive care unit and hospital were longer for older than for younger transplant recipients, but episodes of acute rejection were less frequent. The quality of life at 1 year was similar among older and younger recipients. Patient survival was lower for older than for younger recipients (81% vs. 90% at 1 year; P=0.004), whereas graft survival was not different (80% vs. 85% at 1 year; P=0.163). The excess mortality among older recipients was largely due to nonhepatic causes, including infectious, cardiac, and neurological diseases occurring within 6 months after transplantation. CONCLUSIONS Although patient survival was significantly lower among liver transplant recipients above the age of 60 years, the excess mortality was due to nonhepatic, largely age-related problems. The overall success of liver transplantation and improvement in quality of life for older recipients is excellent.

Hepatitis C - Its prevalence in end-stage renal failure patients and clinical course after kidney transplantation

There is a high incidence of chronic liver disease in end-stage renal failure patients on dialysis. Hepatitis C virus appears responsible for 80% of post-transfusion hepatitis, and up to 80% of sporadic hepatitis and cryptogenic cirrhosis. Anti-HCV antibodies correlate highly with the presence of active infection. The clinical implications of HCV infection in patients undergoing renal transplantation is unknown. Part I: We undertook a descriptive crosssectional study of all renal failure patients admitted for kidney transplant between 1/84 and 12/88. Pretransplant sera were assayed for anti-HCV using an ELISA. Patients were divided into anti-HCV-positive (study group) and anti-HCV-negative (controls). Part II: A cohort study was performed with both groups followed from the time of transplantation to the present. Comparisons were made by t tests, chi-square analysis with Yates correction, Mann Whitney test for nonparametric results and multiple regression analysis. Part I: Anti-HCV was present in 76 of 716 sera assayed. There were no differences in sex, age, number of previous transplants, and underlying renal disease. Four variables predicted the presence of anti-HCV: number of blood transfusions; duration on dialysis; i.v. drug abuse, and nonwhite race. Part II: A group of 596 patients was further analyzed. The mean duration of follow-up was not different between the two groups. There were no differences in graft survival, overall mortality, or mortality secondary to liver disease or sepsis. Based on these results, the presence of anti-HCV should not be a contraindication for kidney transplantation.

Intragraft cytokine profile during human liver allograft rejection.

Forty-three human liver allograft biopsies and normal liver were directly analyzed for inflammatory and immunoregulatory cytokine gene expression by polymerase chain reaction (PCR). IL-5 gene expression was predominantly present in biopsies from liver allografts with histopathological evidence of acute rejection. IL-2 gene expression was rarely observed in rejecting allografts or allografts without evidence of rejection. In contrast, IL-4 message was readily detectable in the majority of liver allografts regardless of clinical status. The inflammatory mediators IL-1 beta, TNF-alpha, and IL-6 were detected with similar frequency in rejecting allografts and allografts without evidence of rejection. These findings suggest that inflammatory and immunoregulatory cytokines are produced within the allograft. Moreover, IL-5 may play a role in the local mechanisms of liver allograft rejection.