Chronic Hepatitis E Virus Manifesting as Elevated Transaminases in a Heart Transplant Patient.

Hepatitis E virus (HEV) is a common cause of viral hepatitis worldwide. Genotypes 1 and 2 cause acute hepatitis in endemic regions (Asia and Africa), whereas genotypes 3 and 4 (America and Europe) result in sporadic acute or chronic hepatitis, specifically in certain groups. HEV infections are rising because of increased transplantation rates and immunosuppression. We report a 75-year-old heart transplant patient with nonspecific symptoms, diagnosed with HEV chronic hepatitis. Despite ribavirin-induced hemolytic anemia, the patient achieved sustained virological response and normalization of liver enzymes.

Rifaximin treatment in hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. RESULTS: Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P<0.001). A breakthrough episode of hepatic encephalopathy occurred in 22.1% of patients in the rifaximin group, as compared with 45.9% of patients in the placebo group. A total of 13.6% of the patients in the rifaximin group had a hospitalization involving hepatic encephalopathy, as compared with 22.6% of patients in the placebo group, for a hazard ratio of 0.50 (95% CI, 0.29 to 0.87; P=0.01). More than 90% of patients received concomitant lactulose therapy. The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. CONCLUSIONS: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.)

Factors associated with hepatic fibrosis in patients with chronic hepatitis C: a retrospective study of a large cohort of U.S. patients.

GOALS: To determine the risk factors for stage 3 and 4 fibrosis in a large cohort of U.S. patients with chronic hepatitis C (CHC). BACKGROUND: Multiple host and viral factors affect the outcomes of CHC. Further defining the pathogenic roles of these factors in CHC progression will lead to improving management of this disease. STUDY: Retrospective study of a large cohort of US patients with CHC. RESULTS: Of the 460 patients, 331 were males and 129 were females with mean age of 48.4+/-8.0 years, and 191 (41.7%) had stage 3 and 4 fibrosis. Clinically, a multivariate analysis revealed that age of > or =60 years at presentation, the estimated duration of hepatitis C virus (HCV) infection > or =25 years, a body mass index > or =30 kg/m, and a history of diabetes mellitus were independently associated with stage 3 and 4 fibrosis, after adjusting for history of alcohol use. Laboratorially, a multivariate analysis revealed that aspartate aminotransferase (AST) > or =2 x upper limit of normal (ULN), alpha fetoprotein > or =15 microg/L, and presence of grade 2 and 3 steatosis were independently associated with stage 3 and 4 fibrosis, after adjusting for alanine aminotransferase > or =2 x upper limit of normal, AST/alanine aminotransferase ratio > or =1, HCV genotyping, transferrin saturation, and a histology activity index score > or =7. CONCLUSIONS: The present study indicated that elderly, longer duration of HCV infection, obesity, and history of diabetes mellitus are independent clinical parameters associated with advanced fibrosis, whereas elevated AST, alpha fetoprotein, and presence of grade 2 and 3 steatosis are independent laboratorial parameters associated with stage 3 and 4 fibrosis in patients with CHC.

Comparison of esophageal capsule endoscopy and esophagogastroduodenoscopy for diagnosis of esophageal varices.

AIM: To investigate the utility of esophageal capsule endoscopy in the diagnosis and grading of esophageal varices. METHODS: Cirrhotic patients who were undergoing esophagogastroduodenoscopy (EGD) for variceal screening or surveillance underwent capsule endoscopy. Two separate blinded investigators read each capsule endoscopy for the following results: variceal grade, need for treatment with variceal banding or prophylaxis with beta-blocker therapy, degree of portal hypertensive gastropathy, and gastric varices. RESULTS: Fifty patients underwent both capsule and EGD. Forty-eight patients had both procedures on the same day, and 2 patients had capsule endoscopy within 72 h of EGD. The accuracy of capsule endoscopy to decide on the need for prophylaxis was 74%, with sensitivity of 63% and specificity of 82%. Inter-rater agreement was moderate (kappa = 0.56). Agreement between EGD and capsule endoscopy on grade of varices was 0.53 (moderate). Inter-rater reliability was good (kappa = 0.77). In diagnosis of portal hypertensive gastropathy, accuracy was 57%, with sensitivity of 96% and specificity of 17%. Two patients had gastric varices seen on EGD, one of which was seen on capsule endoscopy. There were no complications from capsule endoscopy. CONCLUSION: We conclude that capsule endoscopy has a limited role in deciding which patients would benefit from EGD with banding or beta-blocker therapy. More data is needed to assess accuracy for staging esophageal varices, PHG, and the detection of gastric varices.

Hepatic intra-arterial infusion of yttrium-90 microspheres in the treatment of recurrent hepatocellular carcinoma after liver transplantation: a case report.

Hepatocellular carcinoma (HCC) recurs with a reported frequency of 12%-18% after liver transplantation. Recurrence is associated with a mortality rate exceeding 75%. Approximately one-third of recurrences develop in the transplanted liver and are therefore amenable to local therapy. A variety of treatment modalities have been reported including resection, transarterial chemo-embolization (TACE), radiofrequency ablation (RFA), ethanol ablation, cryoablation, and external beam irradiation. Goals of treatment are tumor control and the minimization of toxic effect to functional parenchyma. Efficacy of treatment is mitigated by the need for ongoing immunosuppression. Yttrium-90 microspheres have been used as a treatment modality both for primary HCC and for pre-transplant management of HCC with promising results. Twenty-two months after liver transplantation for hepatitis C cirrhosis complicated by HCC, a 42-year old man developed recurrence of HCC in his transplant allograft. Treatment of multiple right lobe lesions with anatomic resection and adjuvant chemotherapy was unsuccessful. Multifocal recurrence in the remaining liver allograft was treated with hepatic intra-arterial infusion of yttrium-90 microspheres (SIR-Spheres, Sirtex Medical Inc., Lake Forest, IL, USA). Efficacy was demonstrated by tumor necrosis on imaging and a decrease in alpha-fetoprotein (AFP) level. There were no adverse consequences of initial treatment.

Formal heparin anticoagulation protocol improves safety of charcoal-based liver-assist treatments.

Extracorporeal devices have had limited effectiveness in liver failure due to consequences of inadequate anticoagulation. The purpose of this study was to evaluate an anticoagulation protocol developed for Liver Dialysis Unit (LDU) treatments. Twelve patients underwent 19 LDU treatments for acetaminophen overdose (n = 1), subacute liver failure (n = 1), and refractory encephalopathy in cirrhosis (n = 10). The initial 6 patients (group 1) were treated according to the manufacturer's recommendations. The subsequent 6 patients (group 2) were treated using a formal heparin anticoagulation protocol that included 2000 units in prime solution and 30 units/kg induction, activated clotting time (ACT) measurements, and heparin administered by dose-response curve to maintain 300-second ACT. Protamine reversal was used. Treatments were well tolerated and equally effective in both groups. Adequate (ACT > or = 250 seconds) and therapeutic (ACT 250-350 seconds) anticoagulation was maintained more consistently in group 2 (90.9% vs 50.0%, p < 0.0001; and 77.4% vs 45.8%, p < 0.001). There was less consumption of fibrinogen (12.1% vs 43.3%, p < 0.005) and platelets (13.8% vs 29.9%, p < 0.05) and a trend for less blood product used (8.3 vs 15.8 units/patient, p = 0.13) and fewer complications (16.7% vs 66.7%, p = 0.15) in group 2. Anticoagulation using ACT monitoring, heparin dose-response curves, and a target ACT of 300 seconds improves the safety of LDU treatments.

Inhibited proliferation of cyclooxygenase-2 expressing human hepatoma cells by NS-398, a selective COX-2 inhibitor.

Hepatocellular carcinoma (HCC) is a growing human health problem worldwide. Limited treatment and poor prognosis of this disease emphasize the importance in developing an effective chemoprevention. Overexpression of cyclooxygenase-2 (COX-2) has been associated with hepatocarcinogenesis. Although COX-2 inhibitors have been tested for chemoprevention of colon cancer, it remains unknown whether these agents possess anti-HCC effects as well. The present study assessed the effects of a selective COX-2 inhibitor, NS-398, on proliferation of human hepatoma cells in association with COX-2 expression, and the possible mechanisms. In four tested human hepatoma cell lines, overexpression of COX-2 was confirmed in HepG2, HuH7, and Chang liver cells, but not in PLC/PRF/5 cells. Addition of 50 micro M NS-398 resulted in both dose-dependent and time-course inhibition of HepG2 proliferation. In contrast, addition of 50 micro M NS-398 to COX-2 non-expressing PLC/PRF/5 cells resulted in only a mild reduction of cell proliferation. Consistent with this, a 48-h culture of HepG2 cells with 50 micro M NS-398 caused a significant decrease of prostaglandin E2 (PGE2) production. While, the same NS-398 treatment showed only a mild suppression of PGE2 production in COX-2 non-expressing PLC/PRF/5 cells. These findings indicate that NS-398-induced suppression of HepG2 proliferation appears mediated by decreased COX-2/prostaglandin (PG) production. We also found that NS-398-induced inhibition of HepG2 proliferation was associated with decreased 5-bromo-2'-deoxyuridine (BrdU) uptake, suggesting a reduced cell cycle progression in G1-S transition. NS-398 treatment also enhanced the apoptotic rate in COX-2 expressing HepG2 cells, but not in COX-2 non-expressing PLC/PRF/5 cells. Our findings confirmed an effective inhibitory effect of NS-398 on proliferation of COX-2 expressing human hepatoma cells through a decreased COX-2/PG activity that is associated with altered cell cycle progression and apoptotic rate.

Nitric oxide in ascitic fluid is an independent predictor of the development of renal impairment in patients with cirrhosis and spontaneous bacterial peritonitis.

BACKGROUND/AIMS: Cirrhotic patients with spontaneous bacterial peritonitis show a marked activation of the cytokine cascade, and cytokines induce the synthesis of nitric oxide in vitro. Our aim was to assess whether patients with ascitic fluid infection show increased levels of nitric oxide, and whether this is related to the development of renal impairment. METHODS: Retrospective analysis of prospectively collected specimens from 168 patients with cirrhosis and presence of sterile or infected ascitic fluid. Routine biochemical data together with nitric oxide metabolites, tumour necrosis factor and interleukin-6 were measured. Univariate and multivariate analyses were performed to identify factors related to the development of renal impairment. RESULTS: Patients with infected ascites showed increased serum and ascitic-fluid levels of nitric oxide metabolites and cytokines compared with patients with sterile ascites. A significant direct correlation was observed between serum and ascitic fluid nitric oxide metabolite levels. Multivariate analysis identified ascitic-fluid nitric oxide metabolites as an independent predictor of renal impairment. CONCLUSIONS: The increased serum and ascitic fluid nitric oxide found in patients with infected ascites might induce a deterioration of the increased peripheral vasodilation found in this setting, leading to the development of renal impairment in a series of patients with spontaneous bacterial peritonitis.

Clinical presentation of chronic hepatitis C in patients with end-stage renal disease and on hemodialysis versus those with normal renal function.

BACKGROUND: The natural history of chronic hepatitis C (CHC) remains to be defined in patients with end-stage renal disease (ESRD). AIMS: To determine the clinical presentation of CHC and the factors associated with stage III-IV fibrosis in patients with CHC and ESRD. METHODS: The study included patients with CHC and ESRD (n = 91) or normal renal function (NRF, n = 159). Both groups were matched for mean age, gender, history of alcohol use, and estimated duration of hepatitis C virus (HCV) infection. RESULTS: Presentation of CHC and ESRD was independently associated with non-Caucasian ethnicity (OR = 3.24, p= 0.0003), a history of diabetes mellitus (DM, OR = 7.911, p < 0.0001), and lower frequencies of being obese (OR = 0.457, p= 0.035), of having hepatic steatosis (OR = 0.372, p= 0.003), and stage III-IV fibrosis (OR = 0.403, p= 0.016). After adjusting for serum levels of alpha-fetoprotein (AFP) and HCV RNA, CHC, and ESRD were independently associated with lower frequencies of elevated alanine aminotransferase (ALT, OR = 0.175, p= 0.02) and aspartate aminotransferase (AST, OR = 0.169, p= 0.04), but higher frequencies of AST/ALT ratio >1 (OR = 7.173, p= 0.002) and hypoalbuminemia (OR = 9.567, p= 0.0007). Compared to patients with NRF and stage III-IV fibrosis, those with ESRD and stage III-IV fibrosis had a significantly higher frequency of a history of DM (OR = 8.014, p= 0.0031) and lower frequency of elevated AST (OR = 0.054, p= 0.004), which were independent of the frequencies of lower levels of ALT and albumin, and AST/ALT ratio >1. In patients with CHC and ESRD, the presence of stage III-IV fibrosis was significantly associated with hepatic steatosis (OR = 4.523, p= 0.012) and thrombocytopenia (OR = 4.884, p= 0.044), which were independent of the frequencies of a history of DM, splenomegaly, and a higher level of AST. CONCLUSIONS: CHC and ESRD are independently associated with a higher frequency of a history of DM, but lower frequencies of being obese, and having hepatic steatosis, stage III-IV fibrosis, and elevated transaminases. In patients with CHC and ESRD, stage III-IV fibrosis is not associated with a history of DM, but is independently associated with hepatic steatosis and thrombocytopenia.

Spontaneous Bacterial Peritonitis.

Spontaneous bacterial peritonitis (SBP) is the prototypical ascitic fluid infection occurring in patients with advanced liver disease and ascites. The key to successful treatment of SBP is a knowledge of appropriate antibiotic regimens and an understanding of the setting in which infection develops, particularly those individuals at high risk for infection. A high index of suspicion should lead to early diagnostic paracentesis and ascitic fluid analysis. Treatment of SBP involves the use of non-nephrotoxic broad-spectrum antibiotics expected to cover the typical bacterial flora associated with SBP. SBP typically involves infection with a single organism, with Escherichia coli, Klebsiella spp, and Streptococcus spp responsible for nearly three fourths of cases. The treatment of choice is cefotaxime 2 g given intravenously every 8 hours for a total of 5 days. The antibiotic regimen is adjusted based on the results of ascitic fluid cultures. Other antibiotic regimens for SBP are less well studied. Given the significant morbidity and mortality rates associated with SBP, efforts to prevent its development and recurrence with antibiotic prophylaxis are warranted. The most extensively studied form of prophylaxis involves selective intestinal decontamination (SID) with the oral fluoroquinolone norfloxacin. Individuals with low-protein ascites (ascitic fluid total protein < 1g/dL) benefit from SID with norfloxacin 400 mg daily during times of hospitalization. Long-term primary prophylaxis during outpatient management of individuals awaiting liver transplantation with severe ascites and advanced liver failure should also be considered. Patients with cirrhosis and upper gastrointestinal bleeding should receive norfloxacin 400 mg twice daily for 1 week following their bleed. Those individuals surviving an episode of SBP should be treated with norfloxacin 400 mg daily until the risk of SBP is removed by definitive resolution of the ascites or liver transplantation surgery. Although the infection-related mortality associated with SBP has decreased to less than 10%, hospitalization-related mortality remains as high as 30% as a result of the severe underlying liver disease in which the infection arises and the marked generation of cytokines and nitric oxide resulting from the infection. Recently, the simultaneous administration of intravenous albumin and antibiotics for SBP has been shown to result in the decreased development of azotemia and hospitalization-related mortality. Further improvement in the outcomes of SBP will require treatments targeting this cytokine cascade rather than the development of more potent antibiotics.

High-dose proton beam radiotherapy of hepatocellular carcinoma: preliminary results of a phase II trial.

This phase II trial was undertaken to determine the efficacy and toxicity of proton beam radiotherapy for patients with locally unresectable hepatocellular carcinoma. Cirrhotic patients were eligible if they had a Child-Pugh score of 10 or less. Eligible patients included those with T 1 -T 3 hepatocellular carcinoma; selected T 4 patients also were eligible. Patients with lymph node or distant metastases were ineligible. Daily proton beam radiotherapy was directed to the liver tumor with an additional 1-2 cm margin. The total dose was 63 cobalt Gray equivalents, administered in 15 divided fractions over 3 weeks. Thirty-four patients have completed treatment and have been followed up for a minimum of 6 months, with a median follow-up period of 20 months. The mean age was 65 years, and average tumor size was 5.7 cm. Posttreatment toxicity included a small but significant decline in albumin levels and increased total bilirubin; 3 experienced duodenal or colonic bleeding when bowel was immediately adjacent to the treated tumor. Two-year actuarial data showed a 75% local tumor control rate and an overall survival rate of 55%. Of patients with an elevated pretreatment alpha-fetoprotein, 85% were found to have declining alpha-fetoprotein levels from a pretreatment mean of 1405 to 35 at 6 months after treatment. Six patients underwent liver transplantation between 6 and 16 months after completion of radiotherapy with 2 showing no evidence of residual carcinoma within the explanted liver. Overall the majority of patients responded to treatment, and the therapy was well tolerated.

Charcoal-based hemodiabsorption liver support for episodic type C hepatic encephalopathy.

OBJECTIVES: Episodic (acute) type C hepatic encephalopathy (AHE) fails to respond to 5 days of medical therapy in 10-30% of patients and carries a 10-30% mortality rate. We prospectively studied extracorporeal liver support for AHE failing to respond to medical therapy to assess its safety and efficacy and the role of anticoagulation. METHODS: A series of patients with cirrhosis and AHE failing to respond to at least 24 h of medical therapy underwent a maximum of three 6-h charcoal-based hemodiabsorption (Liver Dialysis Unit) treatments. A standard anticoagulation protocol, with heparin dosing based on activated clotting time (ACT) determinations, heparin dose-response curve, and target ACT of 275-300 s, was developed. Therapy was terminated if patients met a predetermined clinical response, deteriorated, or underwent transplantation. RESULTS: Eighteen patients with grade 2-4 AHE despite 5.9 +/- 3.9 days of medical therapy underwent a mean of 1.6 treatments. In 2.6 +/- 1.9 days, 16 patients (88.9%) improved to less than grade 2 HE or achieved at least a 50% hepatic encephalopathy index (HEI) reduction. Median mental status (grade 2 vs 1, p < 0.05) and HEI (0.634 +/- 0.194 vs 0.363 +/- 0.263, p < 0.005) improved significantly. Survival was 94.4% and 72.2% at 5 and 30 days, respectively. Use of our developed anticoagulation protocol resulted in less platelet (14.2% +/- 2.8% vs 32.5% +/- 5.8%, p < 0.005) and fibrinogen consumption (12.1% +/- 3.5% vs 43.3% +/- 8.6%, p < 0.0005) and blood product use (6.2 +/- 1.8 vs 19.0 +/- 5.6 units, p < 0.05) compared with treatments according to manufacturer's guidelines. CONCLUSIONS: Charcoal-based hemodiabsorption treatments in which a standardized anticoagulation protocol is used is safe and effective treatment for AHE not responding to standard medical therapy.

Fatal spontaneous gallbladder variceal bleeding in a patient with alcoholic cirrhosis.

Gallbladder varices are unusual ectopic varices that may develop in patients with portal hypertension, particularly in those with portal vein occlusion. In rare instances, these varices may cause hemobilia, life-threatening bleeding, or even rupture of the gallbladder. We report the first case of a 41-year-old man with alcoholic cirrhosis and patent portal vein who developed massive hemoperitoneum from spontaneous rupture of varices in the gallbladder fossa. The diagnosis of gallbladder varices eluded conventional imaging and was made only at autopsy. Gallbladder variceal hemorrhage is a rare, but potentially catastrophic complication of cirrhosis.

Clinical significance of elevated alpha-fetoprotein (AFP) in patients with chronic hepatitis C, but not hepatocellular carcinoma.

BACKGROUND: Although elevated serum alpha-fetoprotein (AFP) is often seen in patients with chronic hepatitis C (CHC), its prevalence, risk factors, and clinical significance remain to be determined. AIMS: The present study assessed the frequency of, the risk factors for, and the clinical significance of elevated AFP in patients with CHC, but not hepatocellular carcinoma. METHODS: This retrospective study utilized systematic chart review and statistical analyses to investigate 357 U.S. patients with CHC from a university medical center and a regional veteran administration medical center. RESULTS: The prevalence of elevated serum AFP (i.e., >/=10.0 microg/L) was 23.0%, including 15.3% (28/183), 24.5% (25/102), and 42.0% (29/69) in patients with chronic hepatitis C and stage 0-II, III, and IV hepatic fibrosis, respectively. After adjusting for age, HCV load, and hepatic steatosis, stage III/IV fibrosis, elevated aspartate aminotransferase (AST), and prolonged prothrombin time as measured by international normalized ratio (INR) remained independently associated with elevated serum AFP in these patients. A serum AFP level of 15.0 microg/L was 22.8% sensitive and 94.5% specific for stage III/IV fibrosis. CONCLUSIONS: In patients with chronic hepatitis C, 23.0% had elevated serum AFP that is independently associated with stage III/IV hepatic fibrosis, elevated level of AST, and prolonged INR.

Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States.

BACKGROUND: Hepatic steatosis has been associated with chronic hepatitis C (CHC), but its prevalence, risk factors, and clinical significance remain to be determined. AIMS: The present study determined the frequency of, and risk factors for hepatic steatosis and its association with activity and progression of CHC in a large cohort of U.S. patients. METHODS: This is a retrospective study that utilized systematic chart review and statistical analyzes to investigate 324 U.S. patients with CHC from a university medical center and a regional VA medical center. RESULTS: The frequency of hepatic steatosis was 66.0%. We demonstrated that not only being obese, but also overweight (i.e. body mass index > or =25 kg/m(2)) was independently associated with hepatic steatosis. In our cohort of patients with CHC, hepatic steatosis, especially grade II/III steatosis, was significantly associated with elevated aspartate aminotransferase at entry, persistently elevated alanine aminotransferase, and stage III/IV fibrosis. Grade II/III steatosis, was significantly associated with a higher histology activity index as well. Multivariate analysis indicated that steatosis, especially grade II/III steatosis, was independently associated with stage III/IV fibrosis. CONCLUSIONS: Being overweight/obese serves as an independent risk factor for hepatic steatosis in U.S. patients with CHC. Steatosis accelerates activity and progression of CHC, and is independently associated with stage III/IV hepatic fibrosis in these patients.

Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis.

Nephrogenic fibrosing dermopathy (NFD) is a recently described cutaneous fibrosing disorder associated with renal dysfunction. It appears similar to scleromyxedema but with some notable exceptions, including the lack of involvement of the face and absence of plasma cells on histology, systemic involvement, and paraproteinemia. Patients can present with thickened or edematous skin with indurated papules and plaques involving the extremities and the trunk. We report the first three cases of NFD after liver transplantation successfully treated with plasmapheresis. Two patients underwent liver transplantation for hepatitis C virus-induced cirrhosis and one for hepatitis B virus-induced cirrhosis. All the patients had encephalopathy, refractory ascites, and malnutrition prior to transplantation. Like those patients with NFD, all three of our patients had renal dysfunction and required hemodialysis before and after transplantation. Two were not dependent on dialysis at the time of diagnosis, however. These patients had excellent liver allograft function, but the other patient had allograft failure secondary to recurrent hepatitis C. Immunosuppression therapy consisted of basiliximab, mycophenolate mofetil, calcineurin inhibitor, and prednisone. The patients developed "woody" skin induration of the distal extremities, erythematous papules, and contractures at 1, 2, and 120 months after transplantation. Skin biopsies resembled NFD. No paraproteinemia was evident. One to three 5-day courses of plasmapheresis resulted in moderate to marked clinical improvement. The improvement of the kidney function in two of our patients did not appear to correlate with that of the skin disorder, because the kidney function was improving at the time the diagnosis of NFD was made. In conclusion, we report the first three cases of NFD after liver transplantation. Plasmapheresis was moderately successful in resolving the skin-indurated papules, severe skin induration, and associated joint contractures. Preliminary studies (unpublished data) show that decreasing plasma levels of transforming growth factor-beta1 after plasmapheresis appear to correlate with the amelioration of this clinical condition.