Cytomegalovirus viremia: risk factor for allograft cirrhosis after liver transplantation for hepatitis C.

BACKGROUND: Despite recent advances in diagnosis and treatment, cytomegalovirus (CMV) infection continues to be a common cause of morbidity in liver transplant (LT) recipients. Because CMV infection suppresses cell-mediated immunity, which seems to be important in neutralizing hepatitis C virus (HCV) infection, we assessed the impact of CMV infection on histopathological HCV recurrence after LT. METHODS: The study group was comprised of 43 consecutive LT recipients with at least 6 months of histologic follow-up. Group 1 consisted of the 8 patients who developed CMV viremia after LT; group 2 comprised the 35 patients without CMV viremia. There was no significant difference with regard to age, initial immunosuppression, incidence of rejection, distribution of HCV genotypes, or mean follow-up between the groups. Semiquantitative histopathologic assessment of allograft hepatitis was performed using the Knodell's score. RESULTS: The mean total Knodell score of the final allograft biopsy was significantly greater in group 1 patients (P=0.016), with most of the difference due to periportal/bridging necrosis (P=0.009) and lobular activity subitem (P=0.01) scores. Half of the CMV viremic patients eventually developed allograft cirrhosis as compared with 11% of the CMV-negative patients (P=0.027). Accordingly, the cirrhosis-free actuarial survival by Kaplan-Meier estimates was significantly diminished in the CMV viremic patients. Glycoprotein B genotype analysis of CMV isolates revealed no significant differences between patients who did and those who did not develop allograft cirrhosis. CONCLUSIONS: After LT for chronic HCV, patients who develop CMV viremia incur a significantly greater risk of severe HCV recurrence.

Timing and severity of initial hepatitis C recurrence as predictors of long-term liver allograft injury.

BACKGROUND: The majority of patients infected with hepatitis C virus (HCV) undergoing liver transplantation develop evidence of histologic recurrence, and multiple mechanisms are likely poised to affect long-term allograft injury. The purpose of this analysis was to study the hypothesis that histologic and biochemical features at the onset of HCV recurrence predict the long-term evolution of allograft hepatitis. METHODS: We studied 34 consecutive liver transplant recipients with evidence of histologic HCV recurrence and with a minimal histologic follow-up of 1 year (up to 6.2 years; mean: 696+/-83.2 days). Two-hundred and seventy-eight serial allograft biopsies (mean: 6.85+/-0.62 per patient, range: 4-21) were analyzed. The hepatic activity index was utilized to quantitate piecemeal necrosis, intralobular degeneration, portal inflammation, and hepatic fibrosis. The presence of hepatocyte ballooning degeneration and cholestasis was also assessed. RESULTS: Although there was no significant difference with regard to initial hepatic activity index scores between patients who ultimately developed allograft cirrhosis (group 1; n=8) versus those with milder hepatitis (group 2; n=26), the finding of ballooning degeneration/cholestasis was more frequent in the former group (P=0.04). The distribution of HCV genotypes, the mean follow-up after orthotopic liver transplantation, the mean number of allograft biopsy specimens per patient, basal immunosuppression, and incidence of rejection were comparable in both groups. Patients who ultimately developed allograft cirrhosis had significantly higher initial total bilirubin at the onset of histologic recurrence and peak total bilirubin (pT. Bili, the highest value in the ensuing month). Actuarial rates of moderate-to-severe allograft hepatitis were significantly greater in patients with pT. Bili > or = 3.5 mg/dl (P=0.004). Multiple regression analysis identified pT. Bili as the only independent predictor of allograft cirrhosis. CONCLUSIONS: Features at the onset of histologic HCV recurrence predict the natural history of allograft injury; specifically, marked, transient hyperbilirubinemia is associated with the subsequent development of allograft cirrhosis.

Biliary tract complications of side-to-side without T tube versus end-to-end with or without T tube choledochocholedochostomy in liver transplant recipients.

BACKGROUND: Biliary anastomotic complications remain a major cause of morbidity in liver transplant recipients, ranging between 10% and 50% in large clinical series. An end-to-end choledochocholedochostomy with or without T tube (CDCD EE with T tube and CDCD EE w/o T tube) and a Roux-en Y choledochojejunostomy have been standard methods for biliary drainage. METHODS: The objectives of this retrospective study were to: (1) evaluate the incidence of biliary tract complications using a new method of side-to-side choledochocholedochostomy without T tube (CDCD SS w/o T tube) and (2) compare the results of CDCD SS w/o T tube with those of CDCD EE with T tube and CDCD EE w/o T tube. From September 1991 through June 1996, 279 orthotopic liver transplants were performed in 268 patients and followed through December 1996 (minimum of 6 months' follow-up). A total of 227 CDCD anastomoses in 220 patients were studied (7 retransplants > 30 days): CDCD EE with T tube (n=124), CDCD EE w/o T tube (n=44), and CDCD SS w/o T tube (n=59). RESULTS: Sixty-nine biliary complications were observed in 220 patients (30%). Anastomotic and/or T-tube leaks were seen in 43 patients (19%), and anastomotic strictures were found in 26 patients (12%). Forty patients (18%) required percutaneous or endoscopic stent placement (6%) or surgical interventions (12%). CDCD EE with T tube had the highest incidence of biliary leak requiring rehospitalization but the lowest anastomotic stricture and intervention rate and the lowest 6-month mortality rate. CONCLUSIONS: CDCD EE with T tube was superior to CDCD EE or CDCD SS w/o T tube despite the increased number of rehospitalizations. CDCD SS w/o T tube did not offer significant advantages over conventional biliary anastomotic techniques.

Liver disease in cystic fibrosis.

CF is a common hereditary disorder of ion transport, with increasing numbers of patients surviving beyond childhood and developing manifestations of hepatobiliary involvement. Inspissated secretions within the biliary tree result in obstruction and periductular inflammation that eventually progresses to focal and then multilobular cirrhosis. Fatty infiltration of the liver and hepatomegaly is common. Variceal hemorrhage and other findings of portal hypertension may be the initial presentation. At present, therapy with high-dose ursodeoxycholic acid should be considered standard, as it has been shown repeatedly to reduce the injurious effects of the cholestasis. Liver transplantation has been successfully performed on those with advanced disease and adequate pulmonary function. Innovative therapies for CF, including gene transfer, appear promising in preliminary studies, offering hope that earlier intervention in the course of hepatobiliary CF may soon be possible.

Association of fungal infection and increased mortality in liver transplant recipients.

BACKGROUND: Invasive fungal infection is associated with increased morbidity and mortality following orthotopic liver transplantation (OLTx). Understanding the risk factors associated with fungal infection may facilitate identification of high-risk patients and guide appropriate initiation of antifungal therapy. OBJECTIVES: The aim of this study was to determine the incidence of fungal infections, identify the most common fungal pathogens, and determine the risk factors associated with fungal infections and mortality in OLTx recipients. METHODS: Medical records from 96 consecutive OLTx in 90 American veterans (88 males, 2 females; mean age 48 years, range 32 to 67) performed from January 1994 to December 1997 were retrospectively reviewed for fungal infection in the first 120 days after transplantation. Infection was defined by positive cultures from either blood, urine (<105 CFU/mL), cerebrospinal or peritoneal fluid, and/or deep tissue specimens. Superficial fungal infection and asymptomatic colonization were excluded from study. All patients received cyclosporine, azathioprine, and prednisone as maintenance immunosuppressive therapy. Fungal prophylaxis consisted of oral clotrimazole (10 mg) troches, five times per day during the study period. RESULTS: Thirty-five patients (38%) had documented infection with one or more fungal pathogens, including Candida albicans (25 of 35; 71%), C torulopsis (7 of 35; 20%), C tropicalis (2 of 35; 6%), non-C albicans (2 of 35; 6%), Aspergillus fumigatus (4 of 35; 11%), and Cryptococcus neoformans (1 of 35; 3%). The crude survival for cases with or without fungal infection was 68% and 87%, respectively (P <0.0001). The median intensive care unit stay and overall duration of hospitalization were significantly longer for patients with fungal infection (P <0.01). The mean time interval from transplantation to the development of fungal infection was 15 days (range 4 to 77) with a mean survival time from fungal infection to death of 21 days (range 3 to 64). Fungal infections occurred significantly more often in patients with renal insufficiency (serum creatinine >2.5 mg/dL), biliary/vascular complications, and retransplantation. CONCLUSIONS: Fungal infections were associated with increased morbidity and mortality following OLTx, with Candida albicans being the most common pathogen. Treatment strategies involving antifungal prophylaxis for high-risk patients and earlier initiation of antifungal therapy in cases of presumed infection are warranted.

Management of biliary complications after liver transplantation.

Biliary tract complications after liver transplantation are common, and the evaluation of newer treatment options compared with standard surgical treatment is important. In 62 liver transplants performed in 55 adult patients, the biliary tract was reconstructed with choledochocholedochostomy (CC) in 52 (84%) and Roux-en-Y choledochojejunostomy (RYCJ) in 10 (16%). Seventeen biliary tract complications occurred in 16 patients (29%). The incidence of complications was the same after CC and RYCJ. Eight complications (47%) occurred within the first month and nine (53%) thereafter. Only 6 of 17 (35%) biliary tract complications required operation. One patient died of a biliary tract complication. No other allografts were lost due to biliary tract complications. Four patients transplanted at other centers were also treated, for a total of 21 biliary tract complications. Overall, there were nine bile leaks, eight bile duct strictures, two Roux loop hemorrhages, one choledocholithiasis, and one ampullary dyskinesia. Temporary or permanent stents were used successfully in seven of eight strictures. Five bile leaks were managed without operation. Nonsurgical management is appropriate for a selected majority of patients with late bile leaks, biliary tract strictures, or choledocholithiasis after liver transplantation.

Vancomycin-resistant Enterococcus in liver transplant patients.

BACKGROUND: Vancomycin-resistant Enterococcus (VRE) infection is emerging in the transplant population, and there is no effective antibiotic therapy available. The aims of this retrospective review were to (1) investigate the outcome of and (2) identify common characteristics associated with VRE infection and colonization in orthotopic liver transplant (OLTx) candidates. METHODS: From October 1994 through September 1998, 126 isolates of VRE were identified in 42 of 234 OLTx recipients and 5 OLTx candidates who did not proceed to transplantation. Data were collected by patient chart review or from a computerized hospital database. RESULTS: The 1-year mortality rate with VRE infection was 82%, and with VRE colonization, 7%. This mortality rate contrasts with a 14% 1-year mortality for non-VRE transplant patients (P <0.01, infected patients and colonized patients). Characteristics of VRE colonized and infected patients included recent prior vancomycin (87%), coinfection by other microbial pathogens (74%), recent prior susceptible enterococcal infection (72%), concurrent fungal infection (62%), additional post-OLTx laparotomies (47%), and renal failure (Cr >2.5 mg/dL or need for dialysis; 43%). Biliary complications were seen in 52% of post-OLTx VRE-infected or VRE-colonized patients (versus 22% in non-VRE transplant patients, P <0.05). CONCLUSION: VRE infection is associated with a very high mortality rate after liver transplantation. The incidence of biliary complications prior to VRE isolation is very high in VRE-infected and VRE-colonized patients. The most common characteristics of VRE patients were recent prior vancomycin use, recent prior susceptible enterococcal infection, coinfection with other microbial pathogens, and concurrent fungal infection. With no proven effective antimicrobial therapy for VRE, stringent infection control measures, including strict and limited use of vancomycin, must be practiced.

Initial two-year results of the Oregon Liver Transplantation Program.

During the first 24 months of the Oregon Liver Transplantation Program, which began in October 1988, 94 patients were formally evaluated and 47 adults underwent 54 liver transplantations. Thirty-four percent of patients were veterans. The recipient operation lasted a mean of 7.4 hours (range: 4 to 16 hours). Veno-venous bypass was used routinely at first but selectively later (7 of the last 26 cases), resulting in reduced operating time. Hepatic artery reconstruction was end-to-end anastomosis in 52 cases and iliac conduit in 2. No arterial thrombosis occurred. Biliary reconstruction was choledochocholedochostomy in 83% and choledochojejunostomy in 17%. Biliary complications occurred in 28%. Operative mortality was 2%, and 1-year actual survival was 80%. Patients with hepatitis B fared worse, with four of six dying at a mean of 7.6 months. Overall, the median hospital stay was 30 days. Patients surviving more than 3 months had a mean Karnofsky score of 82%. No significant difference in outcome was noted in patients receiving prophylactic OKT3 monoclonal antibody (used in 45%) versus conventional immunosuppressive therapy. Overall, allograft rejection occurred in 55% of patients. Retransplantation was required in seven patients, three for primary graft nonfunction, two for uncontrolled rejection during induction therapy with OKT3, and two for graft failure secondary to recurrent hepatitis B.

Liver transplantation for severe Amanita phalloides mushroom poisoning.

Amanita phalloides mushroom poisoning is an increasingly common and potentially lethal problem for which liver transplantation offers definitive therapy in selected patients. When significant liver dysfunction appears, early transfer to a liver transplant center is important to identify appropriate candidates and to begin the search for a donor organ. The clinical course of five severely poisoned patients, four of whom underwent liver transplantation, is reviewed. Indications for transplantation included primarily a markedly prolonged prothrombin time that was only partially correctable and a constellation of findings including metabolic acidosis, hypoglycemia, hypofibrinogenemia, and increased serum ammonia, following a marked elevation in serum aminotransferase levels. Unlike viral fulminant hepatic failure, grade III or IV hepatic encephalopathy, marked elevation of the serum bilirubin level, and azotemia were not indications for transplantation. Resected livers demonstrated hepatocyte viability of 0% to 30%. Manifestations of Amanita poisoning complicating preoperative and/or postoperative care included severe diarrhea, gastrointestinal hemorrhage, hypophosphatemia, bowel edema, and marrow suppression with lymphopenia, thrombocytopenia, and neutropenia. All five patients are well 1 year later. This largest experience with liver transplantation for Amanita poisoning further defines the early clinical and laboratory indications for, and the unique complicating features of, transplantation in this setting.

Hepatic allograft abscess with hepatic arterial thrombosis.

BACKGROUND: Intrahepatic abscess (IA) is an uncommon complication after liver transplantation (OLTx) usually found in the setting of hepatic arterial thrombosis (HAT) often with associated biliary tree necrosis and/or stricture. Conventional treatment of IA in this setting has required retransplantation. METHODS: A retrospective review of 274 patients (287 OLTx) from September 1991 through September 1996 was performed. Median follow-up was 3.6 years. Diagnosis of HAT was confirmed by arteriography and IA was documented by computerized tomography. Percutaneous drainage of the abscess and stenting of biliary strictures, if present, was achieved using conventional interventional radiology techniques. RESULTS: The diagnosis of hepatic artery complication was made in 14 patients (5.1%), 2 of whom required retransplantation. Hepatic artery thrombosis associated with solitary IA was found in 3 patients (1%) who were transplanted in our center and in 1 additional patient followed up at our center but transplanted elsewhere. All 4 patients had complete resolution of IA using this approach. Three of the 4 patients are alive and well, with the fourth patient succumbing to recurrent hepatitis B infection resulting in allograft failure. CONCLUSIONS: Solitary hepatic allograft abscesses associated with HAT respond to percutaneous drainage and antibiotics, obviating the need for retransplantation in this setting.

The differential effect of eicosapentaenoic acid and oleic acid on lipid synthesis and VLDL secretion in rabbit hepatocytes.

The suppression of plasma very low density lipoprotein (VLDL) triglyceride levels by dietary fish oils rich in polyunsaturated n-3 fatty acids has been attributed to decreased hepatic VLDL secretion. To investigate the effect of n-3 fatty acids on lipid metabolism and VLDL secretion in a tissue culture system, we incubated rabbit hepatocytes with oleic acid and eicosapentaenoic acid (EPA) and examined [3H]glycerol and [14C]fatty acid incorporation into hepatocyte triglyceride and phospholipid and into media VLDL. Glycerol incorporation studies showed that EPA failed to stimulate VLDL triglyceride secretion from hepatocytes as occurred with oleic acid (P less than 0.05). Oleic acid preferentially enhanced hepatocyte triglyceride synthesis while EPA stimulated significantly phospholipid synthesis (P less than 0.01). Varying the relative concentrations of oleic acid and EPA at a constant total fatty acid concentration corroborated preferential triglyceride synthesis from oleic acid. Synthesis shifted predominantly to phospholipids with increasing concentrations of EPA and lower levels of oleic acid. Incorporation of the [14C]fatty acids (800 microM) followed similar patterns: 87% of [14C]oleic acid was incorporated into hepatocyte triglyceride and 44% of [14C]EPA was assimilated in hepatocyte phospholipid (p less than 0.001). Fatty acids at trace concentrations (53 nM) showed a more divergent pattern of lipid incorporation: 60% of [14C]oleic acid was incorporated into triglyceride while 91% of [14C]EPA was incorporated into phospholipid (p less than 0.001). We conclude that in primary rabbit hepatocyte culture, which appears to be a useful model to study lipid metabolism and VLDL secretion, EPA is avidly incorporated into phospholipid while oleic acid predominantly becomes esterified in triglyceride.(ABSTRACT TRUNCATED AT 250 WORDS)

Emphysematous gastritis secondary to gastric infarction.

We report a 72-yr-old female hospitalized for an upper gastrointestinal hemorrhage who developed emphysematous gastritis and gas in the portal vein. Endoscopy of the stomach revealed severe circumferential erythema, erosions, exudates, and friability of irregularly thickened proximal gastric folds. The patient became septic on the third day of hospitalization and deteriorated rapidly. Computerized tomographic scan of the abdomen revealed extensive collections of gas within the gastric wall and in the intrahepatic portal veins. Autopsy revealed severe atherosclerotic disease and a stenosis with thrombus at the origin of the celiac artery. Clostridium welchii was isolated in blood cultures prior to the patient's death. Postmortem review of endoscopic biopsies of the stomach revealed changes of incipient gastric infarction.

Protein-losing enteropathy in systemic lupus erythematosus. Diagnosis and monitoring immunosuppressive therapy by alpha-1-antitrypsin clearance in stool.

Enteric protein loss resulting in profound hypoalbuminemia and anasarca is an uncommon manifestation of systemic lupus erythematosus and only rarely is the initial presentation of disease. A few patients with SLE and protein-losing enteropathy in the absence of increased central venous pressure or intestinal lymphangiectasia have been reported. We describe the utility alpha-1-antitrypsin clearance in stool for diagnosing and monitoring enteric protein loss during successful immunosuppressive drug therapy in a patient who presented with massive enteric protein loss as the initial manifestation of systemic lupus erythematosus.

Isolated metastasis to small bowel from anaplastic thyroid carcinoma. With a review of extra-abdominal malignancies that spread to the bowel.

Symptomatic involvement of the small bowel by isolated metastasis from an extra-abdominal primary malignancy is rare, most commonly resulting from malignant melanoma and lung cancer. A few other extra-abdominal tumors, not including thyroid cancer, have been documented on rare occasions to present with small-bowel involvement as the first evidence of metastasis. We report a case of anaplastic thyroid carcinoma with isolated symptomatic metastasis to the small intestine. We review the literature regarding the frequency and origin of extra-abdominal malignancies developing small-bowel metastases and the spectrum of clinical manifestations resulting from this syndrome.

Aggressive angiographic diagnosis in acute lower gastrointestinal hemorrhage.

To assess the value of recently developed aggressive pharmacologic angiographic techniques for the diagnosis of acute lower gastrointestinal hemorrhage, we reviewed our experience with 63 consecutive patients referred for angiography. Hemorrhage was severe as indicated by a mean blood transfusion requirement of 9.4 units. Extravasation of contrast (46%), or an obvious vascular abnormality suggestive of a bleeding site (32%), was identified in 78% of patients. Extravasation was seen more frequently in patients with greater than or equal to 3 units of transfusion (66%) than in those with less than 3 units of transfusion (17%, P less than 0.001). After the introduction of pharmacologic techniques using heparin, tolazoline, streptokinase, and indwelling arterial catheters, the percentage of studies with extravasation of contrast increased from 32 to 65% (P less than 0.01). Application of aggressive angiographic techniques increases the diagnostic yield of angiography in acute severe lower gastrointestinal hemorrhage while exposing the patient to modest increased procedure-related risks which can be accepted in selected patients.

Colonic lymphoma in the transplant patient.

A 64-year-old male renal transplant recipient developed rectal bleeding caused by a primary lymphoma of the colon, an unusual site for initial disease involvement. Renal transplant recipients may be at increased risk for the development of primary colonic lymphoma, a diagnosis that should be considered in transplant patients who develop abdominal pain, rectal bleeding, or intestinal perforation. The unique clinical features and special management considerations of colonic lymphoma in the renal transplant recipient are discussed.

Clinical outcome after percutaneous transhepatic obliteration of esophageal varices.

A 4.5-yr experience with percutaneous transhepatic obliteration of gastroesophageal varices in 49 patients is reviewed with respect to technical success, control of active hemorrhage, rebleeding frequency, survival, and complications to better define clinical guidelines regarding its application. The procedure was successfully completed in 94% (46 of 49) of patients, and complete obliteration of all variceal feeder vessels was achieved in approximately one-half (52%). Variceal hemorrhage was controlled in three-quarters (76%) of actively bleeding patients, and recurrent hemorrhage occurred in 65% of patients at mean follow-up of 33 wk. Complete obliteration of all variceal feeder vessels was found not to be necessary from a technical standpoint, because the frequency of control of active hemorrhage and rebleeding were not significantly different in those patients having partial as compared with complete obliteration. In comparison with the reported outcome following standard medical therapy of bleeding varices, survival after variceal obliteration appears similar, but death from hemorrhage may be reduced. The interval to rebleeding is longer in patients having elective variceal obliteration after medical control of hemorrhage than in actively bleeding patients undergoing urgent obliteration of varices. The complication rate of obliteration was acceptable, but Child's class C patients with uncontrolled hemorrhage were a subgroup that experienced high mortality and derived little benefit from obliteration. Variceal obliteration is most appropriate in the bleeding but medically stabilized patient or the inoperable patient with recurrent bleeding. Active bleeding is most often controlled and recurrent bleeding may be prevented for several months, thus allowing consideration of elective shunt surgery.

Expandable venous stents for treatment of the Budd-Chiari syndrome.

The goals of treatment of the Budd-Chiari syndrome are relief of portal hypertension, relief of inferior vena cava syndrome, if present, and preservation of hepatic function. This study presents a patient with clinical resolution of the Budd-Chiari syndrome after placement of expandable metallic stents in the inferior vena cava and hepatic veins. A 26-year-old man with severe ascites and lower extremity edema but with relatively preserved hepatic function had a small gradient across a suprahepatic caval web, large gradients across an intrahepatic caval stenosis and the left hepatic vein, and an occluded right hepatic vein. Under angiographic control, web and caval stenosis were balloon-dilated, and modified Gianturco expandable metallic stents were placed in the intrahepatic vena cava. The left hepatic vein was dilated twice and a stent was placed. All gradients were completely eliminated. There were no complications and after 1 year, the stents have fully expanded without migration, edema and ascites have resolved, hepatic function has normalized, and the patient has returned to work. This new technique provides a simple, safe, effective, relatively inexpensive, and potentially long-lasting treatment for selected patients with the Budd-Chiari syndrome.