A consolidated biovigilance system for blood, tissue and organs: one size does not fit all.

Biovigilance systems to assess and analyze risks for disease transmission through the transfer of organs, tissue, cells and blood between people is part of administrative oversight and has impact upon clinical practice and policy. In 2009, a formal recommendation by the Public Health Service requested that Health and Human Services fund and support efforts to consolidate national biovigilance efforts. There are differences in the biovigilance issues involved in organ and tissue donation/transplantation. If disease avoidance is made the dominant principle guiding organ donor testing, an unintended consequence may be an increase in deaths on the waiting list. We propose that overall benefit for the organ transplant recipient, tempered by patient informed awareness of limited organ availability and assessment processes, should be the guiding principle of such a system.

Characterization of HCV-specific CD4+Th17 immunity in recurrent hepatitis C-induced liver allograft fibrosis.

Hepatitis C virus (HCV) recurrence with accelerated fibrosis following orthotopic liver transplantation (OLT) is a universal phenomenon. To evaluate mechanisms contributing to HCV induced allograft fibrosis/cirrhosis, we investigated HCV-specific CD4+Th17 cells and their induction in OLT recipients with recurrence utilizing 51 HCV+ OLT recipients, 15 healthy controls and 9 HCV- OLT recipients. Frequency of HCV specific CD4+ Tcells secreting IFN-γ, IL-17 and IL-10 was analyzed by ELISpot. Serum cytokines and chemokines were analyzed by LUMINEX. Recipients with recurrent HCV induced allograft inflammation and fibrosis/cirrhosis demonstrated a significant increase in frequency of HCV specific CD4+Th17 cells. Increased pro-inflammatory mediators (IL-17, IL-1ß, IL-6, IL-8 and MCP-1), decreased IFN-γ, and increased IL-4, IL-5 and IL-10 levels were identified. OLT recipients with allograft inflammation and fibrosis/cirrhosis demonstrated increased frequency of Foxp3+ regulatory T cells (Tregs) that inhibited HCV specific CD4+Th1 but not Th17 cells. This suggests that recurrent HCV infection in OLT recipients induces an inflammatory milieu characterized by increased IL-6, IL-1ß and decreased IFN-γ which facilitates induction of HCV specific CD4+Th17 cells. These cells are resistant to suppression by Tregs and may mediate an inflammatory cascade leading to cirrhosis in OLT recipients following HCV recurrence.

Recurrent primary sclerosing cholangitis after orthotopic liver transplantation: is chronic rejection part of the disease process?

BACKGROUND: The possibility of primary sclerosing cholangitis (PSC) recurrence after liver transplantation has been debated. The aim of this study is to examine whether recurrent PSC and chronic rejection (CR) are different expressions of the same disease process. METHODS: One hundred consecutive patients receiving 118 grafts for the diagnosis of PSC were reviewed and placed into three groups: group A, recurrent disease, as evidenced by cholangiographic and pathologic findings with radiographic arterial flow to the liver (n=18; 15.7%); group B, those who developed CR (n=15; 13.0%); and group C, all others (n=82; 71.3%). Cholangiograms and histopathologic specimens were examined in a blinded fashion. RESULTS: Demographic factors were similar, except for age, with a significantly younger age and more episodes of rejection in groups A and B (P<0.03). Group A had a higher incidence of cytomegalovirus hepatitis (P=0.008). Five-year graft survivals for A, B, and C were 64.6%, 33.3%, and 76.1%, respectively (P=0.0001), 5-year patient survivals were 76.2%, 66.7%, and 89.1%, respectively (P=0.0001), and repeat transplantation rates were 27.8%, 46.7%, and 8.5%, respectively (P=0.005). Radiographically, 90% of cholangiograms in patients with recurrent disease showed at least multiple intrahepatic strictures. Histopathologically, patients with recurrent disease and CR shared many features. CONCLUSIONS: We have described a high incidence of recurrent PSC and CR in patients who received transplants for PSC. Histopathologic analysis suggests that CR and recurrent PSC could represent a spectrum of indistinguishable disease. However, the distinct difference in clinical outcome, as evidenced by an increased repeat transplantation rate and lower graft and patient survival in the CR group, clearly suggests that they are two distinct entities that require very different treatment strategies.

Review article: interferon and hepatitis C--factors predicting therapeutic outcome.

Hepatitis C chronically infects approximately 1.5% of Americans and is the most common clinical problem facing hepatologists. Since the virus was initially described in 1989, development of an effective therapy has been challenging. Although several different therapeutic agents have been used, no therapy has been shown to reliably eradicate the virus. Interferon-alpha, a cytokine with immunostimulatory and anti-viral properties, has become the therapy of choice for patients with chronic hepatitis C infection. Trials assessing the efficacy of interferon-alpha have characterized host and viral factors predictive of responses to treatment. A thorough understanding of these predictive factors is requisite to providing cost-effective therapeutic decisions for the patient with chronic hepatitis C infection.

Bone disease after liver transplantation.

1. Bone disease is a common problem in patients with chronic liver disease and liver transplants. 2. The cause of bone disease in these patients is multifactorial. 3. Bone disease worsens initially after liver transplantation, with subsequent improvement over time. However, bone disease in liver transplant recipients is common with long-term follow-up. 4. Evaluation of these patients should include metabolic and hormonal evaluations in conjunction with dual energy x-ray absorptiometry or bone mineral density evaluation. 5. Treatment with calcium, vitamin D, and hormonal supplements should be considered when appropriate for patients awaiting and after liver transplantation. The use of bisphosphanates and calcitonin also should be considered, although published studies in these populations are few in number.

Liver transplantation for cholestatic liver disease: screening and assessment of risk factors.

Orthotopic liver transplantation for primary biliary cirrhosis and primary sclerosing cholangitis is a well-accepted therapy for complications of end-stage liver disease and is associated with an excellent outcome in the majority of cases. However, transplant centers are striving to improve on these outcomes by studying ways to optimize the timing of transplantation. Several natural history and prognostic models for both primary biliary cirrhosis and primary sclerosing cholangitis have been derived from the study of large populations of patients in an attempt to predict long-term rates of survival. In addition, models exist to predict resource utilization after liver transplantation. Other factors besides complications of end-stage liver disease may also be indications for transplantation, including refractory pruritus, recurrent bacterial cholangitis in patients with primary sclerosing cholangitis, hepatic osteodystrophy, and a poor quality of life.

Acetaminophen hepatotoxicity: potentiation by isoniazid.

Potentiation of acetaminophen hepatotoxicity has previously been associated with a history of alcohol abuse. Presented here is the case of a 21-yr-old Philippino female with rapidly deteriorating hepatic functions. She had been on isoniazid, 300 mg daily, as prophylaxis against tuberculosis due to a positive tuberculin skin test. She took 3.25 g of acetaminophen for abdominal cramping and subsequently had rapid deterioration of liver function manifested by prolongation of the prothrombin time, elevated ammonia, marked elevation of transaminases, and hyperbilirubinemia. Over the course of 1 wk, these values essentially normalized and she was discharged. Isoniazid induces the cytochrome P-450 system, resulting in increased metabolism of acetaminophen, formation of toxic metabolites, depletion of glutathione stores, and subsequent hepatocellular injury. Patients on isoniazid should use caution when taking acetaminophen since the potentially hepatotoxic effects may be amplified due to induction of the cytochrome P-450 system.

An unrecognized etiology for pyogenic hepatic abscesses in normal hosts: dental disease.

Cryptogenic pyogenic hepatic abscesses are a diagnosis of exclusion. We have identified two patients with severe dental disease at the time of the diagnosis of their liver abscess. In both cases, oral flora was cultured from the abscess. Unlike a previous report, both patients were immunocompetent. When compared with a group of patients with liver abscesses and diverticulitis, two differences were found. In contrast to the single abscesses seen in 10 of 10 patients with diverticulitis, the patients with dental disease had multiple abscesses (p < 0.02). In addition, Fusobacterium nucleatum was cultured from both dental disease associated abscesses but only one of the diverticulitis associated liver abscesses (p < 0.05). If a liver abscess is thought to be cryptogenic, a thorough dental exam is recommended.

Gastritis secondary to herpes simplex virus.

Gastric infection with herpes simplex virus is rare, with only two cases previously reported. At the time of the previous reports, the virus could not be cultured, and the diagnosis was based on histological findings. Two cases of culture positive herpes simplex virus gastritis are presented, emphasizing the importance of routine gastric biopsies and viral cultures in immunodeficient patients with dyspeptic symptoms.

Increased intracranial pressure and hepatic encephalopathy in chronic liver disease.

Increased intracranial pressure is present in more than 80% of patients with fulminant hepatic failure. However, patients with encephalopathy secondary to chronic liver disease are thought not to develop elevated intracranial pressure. We report two patients with chronic liver disease in hepatic coma with raised intracranial pressure documented by an epidural intracranial pressure monitor. One patient rapidly deteriorated to coma over a period of 4 h. The other patient progressively worsened following intravenous sedation administered during upper endoscopy. Both patients had generalized tonic-clonic seizures, and one demonstrated decerebrate posturing and papilledema. Although all metabolic and structural abnormalities should be excluded in patients with hepatic encephalopathy, if the etiology remains in question, the possibility of increased intracranial pressure should be considered in patients with chronic liver disease.

End stage liver disease in a 13-year old secondary to hepatitis C and hemochromatosis.

Hepatic parenchymal iron deposition is a well-known complication of chronic hepatic inflammatory states. This can make the differential between chronic hepatitis and hereditary hemochromatosis difficult, however. The case of a 13-yr-old male with chronic hepatitis C and hereditary hemochromatosis resulting in end stage liver disease and the need for orthotopic liver transplantation is described. There has been no previously described case of the coexistence of these two diseases in a pediatric patient, resulting in end stage liver disease. The progression to cirrhosis in a patient of this age suggests a more rapid progression of the combined diseases than with either disease alone.

Hepatic osteodystrophy in primary biliary cirrhosis: effects of medical treatment.

OBJECTIVES: Osteoporosis is a frequent extrahepatic complication of primary biliary cirrhosis. Although histologically similar to the osteoporosis commonly seen in postmenopausal females, the pathogenesis and management of bone disease in patients with primary biliary cirrhosis is poorly understood. The experience with a subgroup of patients with primary biliary cirrhosis treated with vitamin D, calcium, and estrogen supplementation was reviewed to determine the effects of medical treatment on hepatic osteodystrophy. METHODS: The records of 203 women with the diagnosis of primary biliary cirrhosis were reviewed retrospectively for lumbar spine bone mineral density, menopausal status, and supplementation with vitamin D, calcium, and estrogen. RESULTS: The 16 postmenopausal patients treated with estrogen replacement had a statistically significant increase in the lumbar spine bone mineral density at 1 yr (+0.014 +/- 0.049 vs. -0.03 +/- 0.046 g/cm2, p < 0.038), without a significant change in the serum bilirubin or alkaline phosphatase. In treated patients, vitamin D and calcium supplementation did not lead to significant improvement in lumbar spine bone mineral density. CONCLUSIONS: Calcium and vitamin D supplementation, even in the presence of vitamin D deficiency, do not improve lumbar spine bone mineral density in patients with primary biliary cirrhosis. Estrogen replacement in postmenopausal patients, however, does appear to improve lumbar spine bone mineral density without increasing clinical or biochemical cholestasis, a potential complication reported in animal studies. This study should serve as an impetus for a controlled trial of estrogen replacement in postmenopausal patients with primary biliary cirrhosis.

Effect of a transjugular intrahepatic portosystemic shunt on liver biochemical profiles.

PURPOSE: Transjugular intrahepatic portosystemic shunts (TIPS) have markedly simplified the care of patients with refractory variceal bleeding. Follow-up of liver biochemical profiles, however, has not been done in a prospective fashion. PATIENTS AND METHODS: Twenty-nine patients undergoing TIPS placement for refractory variceal bleeding underwent serial laboratory tests and assessment of encephalopathy to determine the effect of TIPS. Prothrombin time and aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, serum albumin, serum creatinine, and venous ammonia levels were checked prior to the procedure, at the time of discharge, and at 3 weeks, 3 months, and 6 months following the procedure. RESULTS: There was no statistically significant change in any of the obtained laboratory values at up to 6 months of follow-up. The change in aspartate aminotransferase level approached but did not reach statistical significance at the time of discharge and was thought to be secondary to hepatocellular trauma associated with the procedure. New onset of encephalopathy occurred in 18.2% of patients and was easily controlled with medical therapy. CONCLUSIONS: TIPS does not appear to have a significant effect on the liver biochemical profile with short-term follow-up. Hepatic encephalopathy does occur, however, in a significant number of patients but is easily controlled with medical therapy.

Bone disease in primary biliary cirrhosis: does ursodeoxycholic acid make a difference?

Ursodeoxycholic acid (UDCA) has been proposed as beneficial therapy for patients with primary biliary cirrhosis (PBC). The effects of UDCA on metabolic bone disease, a major source of morbidity in patients with PBC, are essentially unknown. Preliminary information suggests that UDCA may improve biochemical indices of bone disease, although information about the effects of UDCA on bone density is lacking. In this study, we describe the effects of UDCA on lumbar spine bone mineral densities over a 3-year period during which patients were enrolled in a randomized, double-blind, therapeutic trial of UDCA for the treatment of PBC. Lumbar spine dual-photon densitometry was measured at entry and annually. Eighty-eight patients, 50 in the UDCA group and 38 in the placebo group, had serial measurements available for up to 3 years. There was no statistical difference between the two treatment groups at entry with respect to histological stage, total bilirubin, age, use of calcium supplement, vitamin D levels, or estrogen. After 3 years of treatment, there was no significant difference in the lumbar spine bone densitometry measurements between the UDCA-treated and placebo groups. We conclude that, after 3 years of treatment, UDCA is not associated with statistically significant differences in the rate of bone loss from the lumbar spine in patients when compared with placebo despite beneficial effects of treatment on the underlying liver disease. Further efforts to define effective treatments for the bone disease need to be pursued.

Hypercholesterolemia and atherosclerosis in primary biliary cirrhosis: what is the risk?

Hypercholesterolemia is commonly associated with primary biliary cirrhosis. In the general population, elevated serum cholesterol is associated with an increased risk of atherosclerosis. The relative risk has been poorly defined in primary biliary cirrhosis patients with hyperlipidemia. In addition, the hyperlipidemic state seen with primary biliary cirrhosis has not been well studied. We prospectively observed 312 patients with primary biliary cirrhosis for a median of 7.4 yr. During this period, 128 patients died. The incidence of atherosclerotic death in patients with primary biliary cirrhosis was not statistically different when compared with an age-matched and sex-matched U.S. control population. A similar group of 50 consecutive PBC patients had detailed serum lipid profiles. Findings included progressive increases in total cholesterol and low-density lipoprotein cholesterol with an increasing histological stage or severity of disease. High-density lipoprotein cholesterol was elevated in all stages, with the highest levels in histological stage 2 and 3 disease. Triglycerides were normal or slightly elevated in all stages. Apoprotein A-I was elevated in all but histological stage 4 disease. Our study suggests the hyperlipidemia associated with primary biliary cirrhosis does not place these patients at risk for atherosclerotic death. In light of the limitations imposed by our relatively small sample size, however, additional patients should be studied. Furthermore, an examination of the pathophysiological mechanisms leading to hypercholesterolemia should be the topic of further study.

Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study.

Non-alcohol-induced steatohepatitis (NASH) is characterized by elevated serum aminotransferase activities with hepatic steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Our aim was to conduct a pilot study to evaluate the safety and estimate the efficacy of ursodeoxycholic acid (UDCA) and clofibrate in the treatment of NASH. Forty patients were diagnosed with NASH based on a compatible liver biopsy with other causes of liver disease, including alcohol abuse, excluded by history, serum tests, and use of ultrasound. Twenty-four patients received 13 to 15 mg/kg/d of UDCA for 12 months. Sixteen patients with hypertriglyceridemia were placed on clofibrate, 2 g/day for 12 months. Twenty-five women and 15 men entered the study. Six of 40 patients (15%) withdrew because of side effects. Four additional patients were withdrawn because of noncompliance; one of them later required liver transplantation. In the UDCA group, the decreases in mean serum levels of alkaline phosphatase, alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) as well as histological grade of steatosis were significant. Among the patients treated with clofibrate, no change from baseline was found in mean ALT, aspartate transaminase (AST), GGT, bilirubin, triglycerides, and cholesterol, or in histological grade of steatosis, inflammation, or fibrosis after 12 months of treatment as compared with entry. Alkaline phosphatase activities decreased significantly from baseline. Despite the known lipid-lowering effects of clofibrate, it did not appear to be of clinical benefit in the treatment of NASH in this 1-year pilot study. However, treatment of NASH with UDCA for 12 months resulted in significant improvement in alkaline phosphatase, ALT, GGT, and hepatic steatosis. The possible benefit of UDCA therapy should be further investigated in the context of a randomized, controlled trial.

A prognostic model for the outcome of liver transplantation in patients with cholestatic liver disease.

We studied the outcome of 436 patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) who underwent orthotopic liver transplant (OLT) at three major liver transplant centers. Univariate predictors of outcome included age, Karnofsky score, Child's class, Mayo risk score, United Network for Organ Sharing (UNOS) status, nutritional status, serum albumin, serum bilirubin, international normalized ratio, and the presence of ascites, encephalopathy, renal failure (serum creatinine > 2 mg/dL), and edema refractory to diuretics. Using these predictors, we developed a four variable mathematical prognostic model to help the liver transplant physician predict the following: 1) the amount of intraoperative blood loss; 2) the number of days in the intensive care unit (ICU); and 3) severe complications after surgery. The model uses age, renal failure, Child's class, and United Network for Organ Sharing status. This study is the first to model the outcome of liver transplant in patients with a specific etiology of chronic liver disease (PBC or PSC). The model may be used to help select patients for OLT and to plan the timing of their transplantation.

Liver transplantation for hepatitis C: recurrence and disease progression in 300 patients.

The time progression of allograft damage in patients with recurrent hepatitis C after orthotopic liver transplantation (OLT) is not precisely determined. The aim of this analysis is to study the progression of disease recurrence and its impact on patient and graft survival. Data for 300 patients who underwent OLT for hepatitis C were analyzed regarding the incidence of histological recurrence, risk factors, immunosuppressive regimen, rejection episodes, and survival. For patients with histological recurrence, the timing and risks for disease progression were analyzed. Data for 30 patients who underwent retransplantation were studied. Histological recurrence occurred in 40.3% of patients, 27.2% of whom progressed to bridging fibrosis or cirrhosis. Eighty-seven percent of the patients experienced recurrence of disease within 24 months of OLT. Patients with histological recurrence within 6 months of OLT had an increased risk for progression to cirrhosis compared with patients with recurrence later than 6 months (risk ratio, 2.3). Recurrence within 1 year was associated with decreased patient and graft survival rates at 1 and 5 years (65.1% and 56.4% versus 80.6% and 78.4%; P =.004 and P =.0008, respectively). Patients with histological recurrence had a greater incidence of acute cellular rejection, as well as multiple episodes of rejection, steroid-resistant rejections, and greater cumulative doses of corticosteroids. Histological recurrence after OLT for hepatitis C is common and usually occurs within 2 years of OLT. Early recurrence negatively affects patient and graft survival. Host factors impacting on recurrence need further study. A relation between the hepatitis C virus, allograft rejection, and immunosuppression exists and needs investigation.