Successful combined liver-heart transplantation in adults: report of three patients and review of the literature.

BACKGROUND: Three patients received liver/heart transplantation, and we report their successful outcome. METHODS: Two patients had alcoholic cirrhosis and dilated cardiomyopathy; one had cryptogenic liver disease and idiopathic cardiomyopathy. RESULTS: All patients had evidence of portal hypertension and coagulopathy. The cardiac transplants were performed first. Cardiopulmonary bypass was discontinued in favor of venovenous bypass, and liver transplantation was then performed. All patients developed acute tubular necrosis; two required a brief period of hemodialysis. There was only one episode of acute cellular rejection of the liver. Protocol endomyocardial biopsies in all three patients revealed no evidence of rejection. All patients are currently using low doses of immunosuppressive medications and have normal liver chemistry tests and cardiac function; two patients have mild renal insufficiency. CONCLUSION: In selected patients with severe cardiac dysfunction and advanced liver disease, liver/heart transplantation can be successfully performed even in the face of portal hypertension and coagulopathy.

Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy.

In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and HBeAg status was maintained in all. Four of the patients with HBeAg responses lost HBsAg at least once. In 10 (43%) of 23 patients tested, we identified HBV polymerase YMDD mutations, 3 with detectable HBV DNA (2 with ALT elevations) and 7 without virological/biochemical breakthrough. In conclusion, up to 18 months of lamivudine therapy was well tolerated, suppressed HBV replication consistently, and tripled the frequency of HBeAg losses observed during brief-duration therapy; HBeAg loss/seroconversion remained durable posttreatment. The emergence of YMDD-variant HBV was relatively common but occurred typically without reappearance of detectable HBV DNA or ALT elevation. Our observations suggest that lamivudine can be stopped after confirmed HBeAg loss or seroconversion.

Rapidly progressive liver injury and fatal alcoholic hepatitis occurring after liver transplantation in alcoholic patients.

Alcohol-related liver disease (ALD) is a common indication for orthotopic liver transplantation (OLT) in adults. Although return to 'heavy drinking' post-OLT is believed to be uncommon, the prevalence and severity of alcohol-related liver injury in such patients is not well characterized. We retrospectively reviewed the records of 68 adult patients who underwent OLT for ALD to determine the incidence of return to heavy drinking and to assess their clinical outcome. Follow-up ranged from 8-99 months (mean 42) post-OLT; 54 patients were followed for > or = 12 months. Ten patients (15%) had evidence of coexisting viral hepatitis (hepatitis C in 9 and hepatitis B in 1) before OLT. Six of 68 patients (8%) returned to heavy drinking post-OLT, and three of those died of alcoholic hepatitis at nine months, 2.5 and 3.5 years after OLT. In two of these three patients, premortem liver biopsy showed histologic features of alcoholic hepatitis in addition to bridging fibrosis or cirrhosis. None of the three patients who died of ALD had coexisting viral hepatitis. Of the 57 patients surviving for > or = 3 months post-OLT, 4 of 8 patients (50%) with steatosis and Mallory bodies in their native livers returned to heavy drinking compared to only 2/49 (4%) without these histologic findings (P<0.05). In conclusion, the incidence of heavy drinking post-OLT was uncommon, however, it was associated with fatal alcoholic hepatitis in 50% of patients. Rapidly progressive alcohol-related liver injury was seen even in the absence of coexisting viral hepatitis. The presence of steatosis and Mallory bodies in the native liver, which suggests recent or ongoing alcohol-related liver injury, predicted a return to heavy drinking post-OLT.

Fulminant hepatic failure secondary to malignant melanoma: case report and review of the literature.

Malignant melanoma has a propensity to metastasize widely to many organs, involving the liver in up to one-third of cases. Fulminant hepatic failure is an unusual presentation of hepatic neoplasms, whether primary or metastatic. We describe a case of malignant melanoma with liver metastases that rapidly progressed to fulminant hepatic failure and death. Striking elevations of liver tests, particularly lactate dehydrogenase, were seen. Liver biopsy showed diffuse intrasinusoidal infiltration with melanoma cells. In patients with malignant melanoma, raised serum lactate dehydrogenase levels may suggest hepatic involvement, with extreme elevations possibly predictive of liver failure.

Night blindness secondary to vitamin A deficiency in a patient with bile duct strictures after liver transplantation.

Vitamin A deficiency and resulting night blindness have previously been reported in patients with chronic liver disease before undergoing liver transplantation. Because early identification of patients with vitamin A deficiency can lead to the relief of symptoms and the prevention of irreversible retinal degeneration, vitamin A deficiency should always be considered in the differential diagnosis of visual disturbances in patients with liver disease. We describe a case of night blindness due to vitamin A deficiency resulting from bile duct strictures in a post-orthotopic liver transplant patient and its successful resolution with vitamin A supplementation.

Clinical course and management of inflammatory bowel disease after liver transplantation.

BACKGROUND: Previous reports investigating the clinical course and management of inflammatory bowel disease (IBD) after orthotopic liver transplant (OLT) have revealed conflicting results. METHODS: To determine the natural history and course of therapy for liver transplant patients with IBD, we reviewed the records of 35 patients, who underwent OLT between 1985 and 1996 and who had a history of either IBD (29 patients) or primary sclerosing cholangitis (PSC) without evidence of IBD before OLT (6 patients). Of 29 patients with IBD before OLT, 25 had a history of ulcerative colitis (UC) and 4 had Crohn's disease. Six patients had undergone total colectomy, one subtotal colectomy, and three partial colectomy before OLT. Mean follow-up after OLT was 37+/-6.4 months. Immunosuppression included cyclosporine, prednisone, and azathioprine in 34 patients and tacrolimus and prednisone in 1 patient. RESULTS: After OLT, 17 patients (49%) had quiescent disease and were receiving no additional medications other than standard immunosuppression to prevent organ rejection. Five patients (14%) had mild flares controlled with initiation of 5'-aminosalicylates (5'-ASA), and two patients (6%) required an increase in oral prednisone. Only one patient with PSC, without evidence of IBD before OLT, developed IBD after OLT. No patients required intravenous steroids or surgical intervention for active IBD. CONCLUSIONS: (1) Standard postOLT immunosuppressive agents in patients undergoing OLT with IBD were able to adequately control disease activity after OLT in the majority of patients. (2) IBD flares after OLT were generally well controlled with aminosalicylates or oral steroids. (3) Aminosalicylates were helpful in the clinical management of IBD, even when patients were taking standard doses of steroids, azathioprine, and cyclosporine.

Incidence and outcome of infection by vancomycin-resistant Enterococcus following orthotopic liver transplantation.

Vancomycin-resistant Enterococcus (VRE) has become a significant nosocomial pathogen. For this study, the records of 325 patients who underwent orthotopic liver transplantation (OLT) were reviewed. Thirty-four patients were infected by VRE (incidence of 10.5%, 14% in adults vs. 5% in children, P < 0.01). Common features of patients who developed infections with VRE included previous antibiotic use (25 patients, 15 of whom received vancomycin), co-infection by other pathogens (28 patients), and relaparotomy following OLT (20 patients). Pulmonary and/or renal failure preceded infection by VRE in 11 and 4 adult patients, respectively. Biliary complications were exceedingly common in patients infected by VRE (28 patients) and significantly increased the risk of infection by VRE (21.5% vs. 3.1% for patients without biliary complications, P < 0.0001). Mortality associated with VRE infections was high (56% vs. 19% for patients not infected by VRE, P < 0.0005). The most frequent cause of death was sepsis (16 of 19 patient deaths), often polymicrobial. The high incidence of infection by VRE following OLT, the lack of effective antibiotics for the treatment of VRE, and the association of VRE with patient mortality emphasizes the need to define the risk factors associated with VRE infection. We suggest early surgical intervention to treat complications that may predispose patients to infection by VRE.

Vitamin A trafficking in Caco-2 cells stably transfected with cellular retinol binding proteins.

During intestinal vitamin A absorption, retinol is esterified by long-chain fatty acids and secreted in chylomicron particles. Stable transfectants of the human intestinal Caco-2 cell line overexpressing cellular retinol binding protein II (CRBP II) or coexpressing CRBP II and CRBP were established to study their role in intestinal vitamin A trafficking. Compared with control cell lines, retinol uptake increased up to twofold by overexpression of CRBP II and up to 2.9-fold by coexpression of CRBP and CRBP II. Retinyl ester synthesis was increased proportionate to the increase in retinol absorption in all cell lines. Retinyl ester secretion was directly correlated with retinyl ester synthesis in control and CRBP II-transfected cell lines. However, transfection with CRBP increased the proportion secreted. Expression of CRBP and CRBP II also affected the polarity of retinyl ester secretion by increasing the proportion secreted basolaterally. Thus these studies provide evidence that intestinal retinol uptake, retinyl ester synthesis, and retinyl ester secretion are correlated with levels of CRBP and CRBP II and that the effects of CRBP on retinyl ester secretion can be distinguished from those of CRBP II.

1,25-Dihydroxyvitamin D3 activates Raf kinase and Raf perinuclear translocation via a protein kinase C-dependent pathway.

1,25-Dihydroxyvitamin D3's (D3) potential mitogenic mechanism of action was pursued in cultured rat hepatic Ito cells, a fibrogenic effector cell which proliferates in vivo during liver injury and fibrogenesis. D3 stimulated Ito cell DNA synthesis and potentiated platelet-derived growth factor-induced mitogenesis. D3's enhancement of [3H]thymidine incorporation was associated with nuclear Egr expression. Recent studies have causally linked the activated proto-oncogene c-Raf with downstream Egr induction. The serine-threonine kinase Raf protein is phosphorylation-activated by a large array of agonists including plasma membrane and cytoplasmic tyrosine kinases but has not previously been associated with the steroid superfamily of mediators. To consider potential prenuclear acute pathways of D3-induced stimulation, the activation of Raf was examined following D3 exposure. D3 induced Raf activation as assessed via (a) enhanced Raf phosphorylation following in vivo 32P labeling, (b) enhanced kinase function utilizing exogenous histone 1 protein as substrate, and (c) the shift in Raf physical localization changing from a diffuse cytoplasmic distribution to a perinuclear domain. A similar activation of Raf kinase was found in 3T3 cells exposed to D3 with enhanced histone phosphorylation detectable within 1 min following stimulation. The proximal cascade leading to Raf kinase activation may involve a protein kinase activity was severely attenuated by stimulated kinase activity was severely attenuated by previous phorbol ester treatment for 20 h or staurosporine pretreatment.

Posttranslational inhibition of Ito cell type I collagen production by triiodothyronine.

Increased Ito cell collagen production occurs during in vivo liver fibrogenesis. Regulation of the overproduction of collagen was studied in cultured rat hepatic Ito cells, which resemble the myofibroblast associated with liver fibrosis. Previous studies suggest that the steroid hormones, retinoic acid, and glucocorticoids may have antifibrogenic properties in vitro and in vivo when used at pharmacological doses. Their potential roles at physiological levels are not well understood. The current study examined the potential regulation of the overproduction of type I collagen in cultured rat hepatic Ito cells by another steroid hormone, 3,5,3'-triiodo-L-thyronine (T3). T3 induced a 3.4-fold reduction in type I collagen production. The effect was dose dependent and was maximal with physiological levels of T3 (10(-9) M). The effect of T3 was independent of any suppression in total protein synthesis. The mechanism of the suppressive effect of T3 on collagen production was explored and was found to be at a posttranslational level. This study suggests that the inhibitory effects of T3 on type I collagen production are likely caused by enhanced intracellular turnover of type I collagen.

Anorexia and weight loss as the solitary symptoms of choledocholithiasis.

Two patients are described who presented symptoms of anorexia and weight loss. Further investigation revealed choledocholithiasis in both cases, though neither patient had the classic symptoms of biliary colic, jaundice, cholangitis, or pancreatitis. The associated weight loss and anorexia resolved completely after successful bile duct surgery. These cases emphasize the need to exclude benign causes of common bile duct obstruction in patients with anorexia, weight loss, and abnormal results of liver function tests, mimicking a possible underlying malignancy.

Pathogenesis of hepatic fibrosis and the role of cytokines.

No definitive therapy exists for the treatment of hepatic fibrosis and cirrhosis. Recent evidence suggests that hepatic lipocytes (Ito cells, fat storage cells, or stellate cells of the liver) are responsible for much of the collagen hypersecretion and nodule formation that occurs during hepatic fibrosis and cirrhosis. This review describes the cellular mechanisms of hepatic fibrogenesis emphasizing new experimental data about cytokines or growth factors to suggest potential avenues of future therapeutic design.