Retrospective evaluation of the risk of hepatitis B virus reactivation after transplantation.

Numerous case reports describe patients with previously documented immunity developing active hepatitis B virus (HBV) infection after transplantation. However, the risk of reactivation of HBV under long-term immunosuppression in hepatitis B core antibody (HBcAb)-positive, hepatitis B surface antigen (HBsAg)-negative transplant recipients has not been clearly described. Herein, we present a long-term follow-up for 49 HBcAb-positive, HBsAg-negative recipients (27 liver, 18 kidney, 4 pancreas) transplanted between June 1996 and April 2001. Among these, 37 recipients (76%) were HBsAb positive at transplantation. Immunosuppression consisted of various antibody induction regimens in 20 (41%) of the recipients with either tacrolimus (33 [67%])- or cyclosporine (16 [33%])-based maintenance immunosuppression. The incidence and duration of HBV prophylaxis was not significant. No patient received hepatitis B immunoglobulin (HBIG) before or after transplantation. Additionally, only two patients received lamivudine, which was started post transplant without clinical indication. The mean length of follow-up was 3.1+/-1.4 years. At the last follow-up, overall patient and graft survival were 98% and 96%, respectively. Patient survival was 96% in liver, 100% in kidney, and 100% in pancreas transplant recipients. The graft survival for each organ type was 93% in liver, 100% in kidney, and 75% in pancreas transplant recipients at the end of follow-up. There was no incidence of HBV reactivation defined as recurrence of HBsAg and/or HBV DNA positivity. These data suggest that the risk of reactivation of HBV in HBcAb-positive, HBsAg-negative transplant recipients under immunosuppression is negligible, regardless of immunosuppressive regimen, lamivudine prophylaxis, or HBsAb status. These patients should have access to transplantation as they enjoy excellent patient and graft survival rates.

Liver disease in cystic fibrosis.

Because of improved survival in the past two decades, liver disease has assumed greater importance in patients with cystic fibrosis. Clinical detection has been difficult thus far. In recent years, advances in our understanding of pathogenesis as well as increasing experience in therapeutic modalities have been accomplished. For these reasons, it is relevant to review this topic.

Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a common but poorly understood liver disease. Our aim was to study a large group of patients referred for Hepatology consultation to further characterize this disorder, in particular its demographics and range of severity. We also sought to better understand its etiology and its relationship to the insulin resistance syndrome, known as the metabolic syndrome or syndrome X. METHODS: Retrospective review of 90 patients seen over a 4-yr period. RESULTS: Ninety patients aged 14-70 with NASH seen at the Liver Clinics at either the University of Tennessee or the Medical University of South Carolina. Eleven had complications of portal hypertension and seven of these had undergone or were awaiting transplantation. NASH was seen in nine families either in siblings or in subsequent generations. Diabetes or insulin resistance were present in almost all in this cohort of patients with NASH. Diabetes, hyperlipidemia, hypertension, and atherosclerotic disease, the components of syndrome X, were common in this population. CONCLUSION: NASH affects males and females equally, and presents over a wide age range. Despite its usually benign course, 28% of patients had cirrhosis and almost half of those had complications of portal hypertension, necessitating liver transplantation. Obesity was common in affected patients and cirrhosis was more common in the morbidly obese. Familial clustering was common, with 18% of patients having a similarly affected first degree relative. The clinical features that define syndrome X (diabetes, hypertension, hyperlipidemia, and atherosclerotic disease) are common in affected patients. Studies of glucose tolerance demonstrated unsuspected diabetes in six, and insulin resistance (the hallmark of syndrome X) in 85% of those tested. We hypothesize that NASH is a disorder of genetic etiology and is the hepatic manifestation of syndrome X, the insulin resistance syndrome.

Contraception and pregnancy after liver transplantation.

1. Libido returns promptly after liver transplantation; patients should be counseled on contraception and avoidance of sexually transmitted diseases. 2. Women after liver transplantation are at increased risk for cancer and should have regularly scheduled screening for cervical and breast cancer. 3. Immunosuppression during pregnancy is not teratogenic and does not lead to congenital anomalies. 4. Pregnancy after liver transplantation is often successful, but must be regarded as high risk, associated with an increased risk for hypertension and preeclampsia, intrauterine growth retardation, and prematurity. It is best delayed until 1 to 2 years after grafting. 5. Close monitoring of immunosuppressant levels in the blood is crucial during pregnancy to avoid inappropriately low levels of immunosuppression.

Hepatitis C infection among survivors of childhood cancer.

Preliminary reports have suggested that survivors of childhood cancer and aplastic anemia who are infected with the hepatitis C virus (HCV) have a low risk for progression to significant liver disease. Among our surviving patients who were transfused between 1961 and March 1992, 77 (6.6% of surviving patients tested thus far) have evidence of HCV infection, whereas 4 surviving patients who were transfused after March 1992 are HCV-infected. One patient chronically infected with HCV died of liver failure, and 2 patients died of hepatocellular carcinoma. To characterize the risk for these and other complications, 65 patients are enrolled in a longitudinal study of HCV infection, of whom 58 (89.2%) had circulating HCV RNA at the time of protocol enrollment, with genotypes 1A and 1B most commonly isolated. Most enrolled patients have few or no symptoms, carry out normal activities, and have normal liver function. To date, 35 patients have undergone liver biopsy for abnormal liver function since the diagnosis of primary malignancy; central pathology review shows 28 (80%) have chronic active hepatitis, 25 (71%) have fibrosis, and 3 (9%) have cirrhosis. These preliminary data suggest that though most survivors of childhood cancer who are infected with HCV are clinically well, some are at risk for clinically significant liver disease. Identification of other HCV-infected patients and prospective monitoring of this cohort are ongoing to determine the risk for, and to identify factors associated with the progression of, liver disease.

Eighteen years of experience with adult and pediatric liver transplantation at the University of Tennessee, Memphis.

1. Since its inception, the liver program at UT Memphis has been striving to serve its population by stressing access, technical innovation, and by its focus on quality of life. The results for both adult and pediatric transplants over the past 18 years demonstrate that small and medium-sized programs can function efficiently and are valuable for their local communities. 2. Patient and graft survival rates exceeded 85% in the pediatric population in the first year with the 5-, 10-, and 15-year results above 75%. 3. Patient and graft survival rates in adults were 83% at one year, 68% at 5 years, and 60% at 10 years. 4. Innovative techniques in liver transplantation have had a dramatic impact on accessibility of pediatric recipients to liver transplantation and recently are becoming crucial for select populations of adults requiring expedited transplantation.

A fistula from the portal vein to the bile duct: an unusual complication of transjugular intrahepatic portosystemic shunt.

We describe a case of a portal vein bile duct fistula as a complication of transjugular intrahepatic portosystemic shunt (TIPS) placement. The patient's course was complicated by endocarditis, hemobilia, recurrent episodes of fever, and bacteremia, followed by liver transplant. The findings of fever, bacteremia (especially with Gram-negative organisms), and a decreased hematocrit after shunt placement should raise the suspicion of an infected shunt with a possible fistula.

Serious hepatitis A: an analysis of patients hospitalized during an urban epidemic in the United States.

BACKGROUND: Memphis and Shelby County, Tennessee, experienced an epidemic of hepatitis A in 1994 and 1995. More than 1700 cases were reported. OBJECTIVE: To characterize the clinical features of patients hospitalized during a large urban epidemic of hepatitis A. DESIGN: Retrospective chart review. SETTING: 15 acute care hospitals in Shelby County, Tennessee. PATIENTS: 256 patients hospitalized with acute hepatitis A. MEASUREMENTS: Laboratory findings (such as prothrombin time and bilirubin level), complications, and mortality. RESULTS: The median patient age was 26 years. Thirty-nine complications occurred in 35 patients. Twenty patients (8%) had extrahepatic complications, and 5 (2%) died. Patients 40 years of age and older were more likely to have serious complications, including death (P = 0.014). Sixty-seven patients (26%) presented with coagulopathy (prothrombin time > or = 3 seconds prolonged). Fifty-four patients (21%) had a bilirubin level greater than 170 micromol/L (10 mg/dL). CONCLUSIONS: During this epidemic, hepatitis A caused serious illness and death. Complications were more frequent in patients 40 years of age and older, but young, healthy persons were also at risk for severe complications.

Prevention of hepatitis B recurrence with indefinite hepatitis B immune globulin (HBIG) prophylaxis after liver transplantation.

Liver transplantation for hepatitis B is followed by a high rate of recurrence some time after transplantation, resulting in poor outcome compared to liver recipients transplanted for other indications. Passive immunoprophylaxis with HBIG has been shown to decrease the rate of recurrence to 25-50%, but the intensity and length of treatment is still controversial. We studied 17 HBsAg positive patients who were transplanted for hepatitis B. Four did not receive immunoprophylaxis and they all reoccurred within 3 months. The remaining 13 have received indefinite, high dose HBIG (10,000 mu or 40,000 mu/dose depending on HBV DNA status pretransplant). Ten of 13 patients (77%) remain HBsAg negative after a mean follow-up of 16.7 months with six of these ten patients being HBV DNA positive pretransplant. Of the three who have experienced recurrence, two received extensive additional immunosuppression beyond that normally administered to transplant patients (chemotherapy, multiple antirejection treatment). The last patient received 110,000 u of HBIG during the first 3 months, which produced an anti-HBs titer level of 225 IU/L, but the following month he was HBsAg positive with an anti-HBs titer of 13 IU/L. We conclude that HBsAg positive patients can be safely transplanted using indefinite, high-dose HBIG prophylaxis, and that with adequate HBIG it is possible to prevent recurrence in HBV DNA positive patients as well.

Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

BACKGROUND: The similarity of the hepatic pathology in acute fatty liver of pregnancy (AFLP) to that seen in children with inherited disorders of intramitochondrial fatty acid oxidation (FAO) suggests that there may be a genetic basis for some cases of AFLP. OBJECTIVE: The purpose of this study was to examine patients with AFLP and their offspring to determine if there were women with AFLP who were heterozygous for the FAO defect, long chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency. METHODS: We evaluated 12 women previously diagnosed with AFLP. Provocative fasting studies and skin biopsies for examination of their cultured skin fibroblasts were performed to search for a generalized defect in FAO both in vivo and in vitro. Cultured skin fibroblasts from AFLP patients, their children, and their husbands were also examined specifically for LCHAD activity. RESULTS: Of 12 women with a previous episode of AFLP, eight had reduced LCHAD activity consistent with being heterozygous for LCHAD deficiency. The eight heterozygotes had a total of nine pregnancies complicated by AFLP. In seven of those nine pregnancies, the women developed severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. Of the nine offspring delivered from these pregnancies, four were confirmed to be affected with homozygous LCHAD deficiency. Three other deceased infants were presumed to be LCHAD-deficient based on clinical findings, postmortem examination, and confirmed heterozygote parents. The remaining two infants delivered after pregnancies complicated by AFLP had LCHAD activity in the heterozygous range and are healthy at 18 and 24 months of age. Consistent with the known autosomal recessive nature of this defect, five tested husbands of LCHAD heterozygous women with a history of AFLP and affected infants also showed reduced LCHAD activity. CONCLUSIONS: These studies indicate that a significant subgroup of women with AFLP are heterozygous for LCHAD deficiency and that careful observation of their offspring for signs of this disorder is warranted. Severe preeclampsia appears to increase the risk of AFLP in LCHAD heterozygous women.

Management of pediatric liver tumors.

Historically, children with liver tumors were uniformly considered to have a poor prognosis and were approached warily by pediatric surgeons and oncologists. Over the last decade, however, advances in diagnostic imaging technology, discovery of effective chemotherapy, and improved surgical techniques have greatly facilitated the management of children with hepatic tumors. Although orthotopic liver transplantation has emerged as a viable treatment option in the management of hepatic malignancies, including hepatoblastoma and hepatocellular carcinoma, its use is still controversial.

Inherited liver diseases in adults.

Important inherited disorders causing acute and chronic liver disease include hemochromatosis, Wilson's disease, alpha 1-antiprotease (antitrypsin) deficiency, and cystic fibrosis. The detection of an index case has implications for screening family members. A normal life span can be expected with treatment in asymptomatic patients with Wilson's disease and hemochromatosis. We present a clinical approach to disease recognition, investigation, and screening.

Hepatic disease in pregnancy.

Liver disease occurring in pregnancy can be categorized into three groups. The first group includes diseases unique to pregnancy and caused by it. Among these are hyperemesis gravidarum, cholestasis of pregnancy, and disorders associated with preeclampsia. Liver involvement may be expected in 50% of patients with hyperemesis gravidarum. Preeclampsia has been associated with both the HELLP syndrome (hemolysis, elevated liver tests, and low platelets), which includes hepatic infarction and rupture, and with acute fatty liver of pregnancy (AFLP). In patients with HELLP syndrome, liver test abnormalities do not correlate with liver injury. Therefore, this and other disorders associated with preeclampsia require aggressive treatment, primarily with delivery. The second group of liver diseases are those exacerbated by pregnancy. Viral infections involving the liver that are usually benign, such as hepatitis E and herpes simplex, are more likely to be exacerbated in pregnant women and are more likely to lead to fulminant hepatic failure. Cholelithiasis and Budd-Chiari syndrome are more prevalent in pregnant women. The third group is comprised of liver diseases that are preexisting in the pregnant patient and includes autoimmune chronic active hepatitis and Wilson's disease. The number of patients in the last group is small, as chronic liver disease is rare in women who are able to bear children.

Primary autoimmune cholangitis. An alternative to antimitochondrial antibody-negative primary biliary cirrhosis.

The authors report the clinical and liver biopsy features of nine patients with primary autoimmune cholangitis, a unique form of chronic nonsuppurative destructive cholangitis associated with high-titer serum antinuclear antibodies, including eight women and one man; their median age was 51 years. All patients showed cholestatic hepatic enzyme profiles (median gamma glutamyl transferase and alkaline phosphatase, 800 U/L and 700 U/L, respectively). The median antinuclear antibody titer was 1:1,280 (range, 1:640-1:2,560). All patients' sera were negative for antimitochondrial antibodies; six were also nonreactive for anti-M2 mitochondrial autoantigens. Liver biopsies showed marked paucity of interlobular bile ducts (median percentage of portal tracts containing bile ducts, 11%; range, 0-50%). Granulomatous cholangitis was present in two cases; five livers showed the pattern of bile ductular proliferative piecemeal necrosis. Seven patients were treated with prednisone and azathioprine without clinical benefit. During follow-up of 1 to 5 years, disease has progressed in seven patients, including four who have developed other autoimmune conditions. Although clinically, biochemically, and histopathologically comparable to primary biliary cirrhosis, autoimmune cholangitis abdicates antimitochondrial antibodies in favor of antinuclear antibodies. It represents a distinctive subset of antimitochondrial antibody-negative adult ductopenic disorders, for which conventional immunosuppressive therapy does not appear warranted.