Risk factors for failure to meet listing requirements in liver transplant candidates with alcoholic cirrhosis.

BACKGROUND: The majority of liver transplant centers require a 6-month abstinence period before listing candidates for liver transplantation with alcoholic cirrhosis and a persistent sobriety thereafter. We attempted to identify risk factors for failure to comply with these requirements. METHODS: Ninety-nine consecutive patients with alcoholic cirrhosis were referred for liver transplant evaluation between September 1996 and May 1998. The mean age was 49 years, 74% were male, and 54% were hepatitis C virus positive. To be listed, patients had to meet the following requirements. All patients received extensive psychosocial evaluations and were frequently monitored with random urine and blood alcohol tests; patients found positive were excluded or removed from the liver transplant waiting list. Detailed patient information was entered into a computerized database, and 36 discreet variables were analyzed in relation to success (patient listed and remained on the list) or failure (not listed or removed from the list based on noncompliance). RESULTS: Forty-nine patients were successfully listed. Nineteen received a transplant, with a 95% 1-year patient and graft survival rate and 21% alcohol relapse rate after transplantation. Twenty-two patients had either medical contraindication and/or died before transplant listing. Twenty-four patients were never listed and four were removed from the list due to recurrent alcoholism, for a total of 28 failures. Our statistical analysis identified five significant risk factors for failure: (I) living arrangement (alone/family versus community/friend), P=0.006; (II) history of suicide ideation, P=0.03; (III) history of previous alcohol-related hospitalization, P=0.01; (IV) lack of previous alcoholic rehabilitation before transplant evaluation, P=0.001; and (V) failure to accept further alcoholic rehabilitation before orthotopic liver transplantation, P=0.01. CONCLUSIONS: Our experience confirms that transplantation can be extremely successful in properly selected patients with alcoholic cirrhosis. We identified several predictive psychosocial factors of early alcoholic recidivism in transplant candidates.

Hepatitis C kinetics: mathematical modeling of viral response to therapy.

Mathematical models have been used to study the dynamics of HIV. Using these same principles, the dynamics of hepatitis C virus (HCV) are reviewed during interferon (IFN) therapy. After initiating IFN treatment, there is an IFN dose-dependent exponential decline in viral RNA levels within the first 48 hours. This rapid 1.0 to 2.0 log decline was best explained by an effect of IFN in inhibiting viral production with a varying degree of effectiveness. By applying mathematical principles, viral serum half-life was estimated to be 3.0 hours and viral production rat was calculated to be 1.0 x 10(12) virions per day. After this rapid first-phase decline there was a slower second phase decline in viral levels that was highly variable between subjects. This phase was dependent on the rate of elimination of HCV-infected liver cells. The rapidity of the second phase proved to be the best predictor of early viral clearance. The use of these models to understand the life cycle of viruses and their response to therapy is reviewed.

Differences in viral dynamics between genotypes 1 and 2 of hepatitis C virus.

Many studies have shown that patients infected with hepatitis C virus (HCV) of genotype 2 have better response to interferon (IFN)-alpha treatment than genotype 1 patients; however, the mechanisms responsible for this difference are not understood. In this study, viral dynamics during high-dose IFN induction treatment were compared between the genotypes. Patients in each group received 10 MU of IFN-alpha2b for 14 days, and HCV RNA levels were frequently determined. Nonlinear fitting, both individually for each patient and using a mixed-effects approach, of the viral kinetic data to a mathematical model of the IFN effect on HCV infection was performed. The antiviral effectiveness of IFN in blocking virus production, the free virion clearance rate, and the HCV-infected cell death rate were all significantly higher for genotype 2 patients than for genotype 1 patients. Thus, the better response rate of patients infected with HCV genotype 2 is multifactorial. This is the first finding of a difference in viral dynamics between subtypes of the same virus and demonstrates the importance of subtype-specific virus-host-drug interactions.

The ureteric ring.

A ureteric ring is a smooth, concentric ring-like narrowing occurring in the upper third of the ureter. It is nonobstructive and may be transient and bilateral. There is a slight female preponderance. They are seen in all age groups and are common in the neonate together with transient changes. A ureteric ring has a characteristic appearance and is believed to result from contraction of circular muscle.

Hepatitis C viral dynamics.

It is apparent that the sooner the virus is cleared from the serum following IFN monotherapy, the better the sustained virologic response rates. It is also clear that in patients infected with HCV genotype 1a and 1b, standard dosages of IFN-alpha 2b (3 MU) administered three times a week are inadequate for a substantial and sustained lowering of HCV RNA serum levels. Understanding the kinetics and dynamics of HIV and HBV has greatly improved the understanding of the life cycle of these viruses and their response to therapy. Studies of the kinetics of HCV following initiation of IFN monotherapy have revealed that IFN-alpha 2b causes a rapid dose-dependent (3 < 5 < 10 = 15 MU) reduction in HCV RNA levels within 24 to 48 hours. This rapid exponential decline in RNA levels is best explained by an effect of IFN on viral production or release. The dose of other IFN products that maximally suppresses viral levels needs to be determined. Mathematical calculations reveal that HCV has a serum half-life of 3 hours and a viral production rate of 1.0 x 10(12) virions/d. After this rapid decline, there is a slower phase of viral decline that varies widely among patients and is attributed to the death rate of infected liver cells. The rate of decline of the second phase, which is probably mediated by immune clearance of infected liver cells, is the best viral kinetic predictor of early viral clearance. This kinetic information indicates that in patients infected with HCV genotype 1a or 1b, initial therapy with IFN should be daily and initial doses should be sufficient to reduce viral levels by more than 95% within 48 hours. Whether higher doses of IFN will alter or enhance the second phase of viral decline needs to be investigated. Also, the effect of ribavirin on IFN-mediated changes in HCV RNA levels needs to be investigated in carefully performed kinetics studies to better determine its mechanism of action. Defining the viral kinetics in patients infected with HCV genotype 2 or 3 and in patients who do not respond to IFN therapy will also improve the approach to therapy.

Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.

To better understand the dynamics of hepatitis C virus and the antiviral effect of interferon-alpha-2b (IFN), viral decline in 23 patients during therapy was analyzed with a mathematical model. The analysis indicates that the major initial effect of IFN is to block virion production or release, with blocking efficacies of 81, 95, and 96% for daily doses of 5, 10, and 15 million international units, respectively. The estimated virion half-life (t1/2) was, on average, 2.7 hours, with pretreatment production and clearance of 10(12) virions per day. The estimated infected cell death rate exhibited large interpatient variation (corresponding t1/2 = 1.7 to 70 days), was inversely correlated with baseline viral load, and was positively correlated with alanine aminotransferase levels. Fast death rates were predictive of virus being undetectable by polymerase chain reaction at 3 months. These findings show that infection with hepatitis C virus is highly dynamic and that early monitoring of viral load can help guide therapy.

Early HCV RNA values after interferon predict response.

The aim of this study is to determine in patients infected with hepatitis C virus (HCV) whether early HCV RNA measurements at 48 hr following standard doses of interferon-alpha (IFN-alpha) (3 million IU) would predict response during six months of therapy. Twenty-three patients with HCV were treated with IFN-alpha 3 million IU three times a week and HCV RNA levels were quantified by branched-chain (b-)DNA analysis at baseline and 24 and 48 hr following IFN-alpha and at one, three, and six months. Mean baseline HCV RNA levels significantly declined from 6.0 +/- 1.6 Meq/ml at baseline to 2.4 +/- 0.7 Meq/ml 24 hr after IFN-alpha. However, HCV RNA values increased to 4.3 +/- 1.1 Meq/ml by 48 hr. Mean HCV RNA values at one and six months were not significantly lower than 48-hr values. In six patients in whom HCV RNA was negative by bDNA at 48 hr, three were negative by polymerase chain reaction at six months. Of the 17 patients who were positive by bDNA at 48 hr, all were positive at one and three months; and in the nine of nine who continued therapy for six months, there was no further decrease in HCV RNA levels. In patients receiving standard doses of IFN-alpha (3 million IU), serum RNA values 48 hr after the first injection predict long-term response.

Impact of alcohol on the histological and clinical progression of hepatitis C infection.

In patients infected with the hepatitis C virus (HCV), 20% to 30% will progress to cirrhosis in over two to three decades. Viral and host factors that are important in the clinical and histologic progression of HCV infection are not entirely certain. It has been suggested that liver disease is worse in alcoholics infected with HCV. In the present retrospective study, we examined the effect of moderate alcohol intake on the histologic and clinical progression of HCV infection and assessed whether other variables such as gender, length of exposure, mode of exposure, HCV RNA levels, and ferritin levels also independently impacted disease progression. Liver biopsies were analyzed for the degree of fibrosis, presence of cirrhosis, and histologic activity by using the Histologic Activity Index of Knodell. Patients were divided into two groups based on whether their alcohol intake was significant or not significant. Significant alcohol intake was defined as > 40 g alcohol/day in women and > 60 g of alcohol/day in men for > 5 years. Groups were further divided based on the decades of exposure to HCV. There was no difference in the age or length of exposure to HCV in the alcohol and the alcohol-free group. HCV RNA serum levels, ferritin levels, and viral genotypes were similar in both groups. There was a two- to threefold greater risk of liver cirrhosis and decompensated liver disease in the alcohol group. Also, the rate to which subjects developed cirrhosis was faster in the alcohol group with 58% being cirrhotic by the second decade as opposed to 10% being cirrhotic in the nonalcohol group by the second decade. The histologic and clinical acceleration of liver disease was independent of the mode of exposure or sex. In summary, alcohol intake is an independent risk factor in the clinical and histologic progression of HCV infection.

The inaccuracy of duplex ultrasonography in predicting patency of transjugular intrahepatic portosystemic shunts.

BACKGROUND & AIMS: A prospective double-blinded study with preset sonographic criteria has not been performed to assess the accuracy of duplex ultrasonography in determining the patency of transjugular intrahepatic portosystemic shunts (TIPS). The purpose of this study was to determine the sensitivity and specificity of duplex ultrasonography in predicting shunt malfunction using accepted preset sonographic criteria. METHODS: Sixty ultrasonographic and venographic follow-up comparisons were made on 38 cirrhotic patients who had undergone TIPS placement for variceal bleeding (n = 28) or intractable ascites (n = 10). Ultrasonographic results were analyzed by one of two board-certified ultrasonographers without knowledge of venographic findings. RESULTS: Of the 31 occluded (n = 8) and stenotic (n = 23) shunts, ultrasonography accurately predicted a shunt malfunction (occlusion or stenosis) in only 11 studies and incorrectly predicted patency in 20. Compared with venography, ultrasonography had a sensitivity of 35% and a specificity of 83% in predicting TIPS stenosis or occlusion. CONCLUSIONS: These results suggest that duplex sonography is not a sensitive test in predicting the presence of a hemodynamically significant stenosis and that shunt status should be assessed by venography and direct portal pressure measurements until a more reliable and proven noninvasive ultrasonographic criterion is devised.

Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa.

To determine if the clearance of hepatitis C genotype 1 virus (HCV) is dependent on the dose of interferon alfa-2b (IFN-alpha2b), the acute clearance of HCV after a single dose of either 3, 5, or 10 mIU of IFN-alpha was compared in patients with chronic hepatitis C. HCV-RNA levels following IFN-alpha administration were measured. At 24 hours, mean percentage serum viral reduction was 41.4%, 63.7%, and 85.5% for 3, 5, and 10 mIU, respectively (P < .001). At 48 hours, the mean viral reduction was consistently less than the reduction at 24 hours, averaging 22.9%, 61.9%, and 74.3%, respectively (P < .001), indicating that the drug effect diminishes before 48 hours. Regression analysis showed a positive correlation between dose and percent reduction of HCV-RNA levels (r = .6; P < .001). A mathematical model showed that such dose dependence is expected if IFN-alpha partially blocks viral production. Minimum clearance and production rates of HCV were estimated from measurements of HCV-RNA levels after the 10-mIU dose. HCV decay followed an exponential decline with a minimum estimate of the viral clearance rate constant of 2.8 per day, corresponding to a virion half-life of 0.3 days or less. A minimal estimate of the daily HCV production and clearance is 3.7 x 10(11) virions per day, indicating a high rate of replication and turnover. These results indicate that there is a dose-dependent effect of IFN-alpha in clearance of HCV genotype 1. Because the virion production rate is very rapid and because the current recommended dose of IFN-alpha (3 mIU) is often ineffective, larger doses should be considered to treat genotype 1-infected patients.

Effect of obesity on pharmacokinetics and biologic effect of interferon-alpha in hepatitis C.

To examine potential adverse effects of obesity in reducing the response to interferon-alpha (IFN-alpha) in chronic hepatitis C (HCV), IFN-alpha and HCV RNA levels in serum and the 2',5'-oligoadenylate synthetase (2-5 OAS) levels in peripheral blood mononuclear cells (PBMC) were compared between six obese and five nonobese patients before and after a single, 10 mIU dose of IFN-alpha2b. There were no differences in the mean histologic activity index between the two groups. The maximal IFN concentration and the area under the serum IFN concentration-time curve were higher in nonobese patients. These two parameters were inversely correlated with body weight and body surface area. No differences were found in the mean reduction in HCV RNA levels between the two groups following IFN-alpha. The maximal 2-5 OAS level after treatment divided by the pretreatment 2-5 OAS level (2-5 OAS response ratio) was greater in the nonobese patients, suggesting stronger biologic response upon exposure to exogenous IFN-alpha in nonobese patients.

Assessment of technical competence during ERCP training.

BACKGROUND: Successful performance of diagnostic and therapeutic ERCP requires skillful manipulation of the duodenoscope and accessories. The evaluation process for assessing competency is still in evolution. Recommendations for the number of examinations has ranged from 35 to 200, made without the benefit of prospective data. METHODS: Pancreatic and common bile duct cannulation rates were prospectively recorded for 21 trainees and 9 proctors over 6 years in a large university-based training program. Trainee success rates were compared to those of the proctor and learning curves were constructed. RESULTS: Trainees performed 641 examinations over 6 years. Each did an average of 31 examinations (range, 10 to 96). For both pancreatic duct and common bile duct cannulation, there was a rapid linear rise of the success curve extending up to the fortieth procedure. Pancreatic duct cannulation rates exceeded those of the common bile duct. CONCLUSIONS: This is the first prospective evaluation of acquisition of skills in ERCP. Although the rapid rise of the learning curve ends at the fortieth examination, the 85% level of selective cannulation is not reached for the pancreas duct until the seventieth procedure and is not reached for the common bile duct even at 100 procedures. These data suggest a threshold of at least 100 procedures.

Comparison of rigid and flexible esophagoscopy in the diagnosis of esophageal disease: diagnostic accuracy, complications, and cost.

Rigid esophagoscopy has been used by otolaryngologists for evaluation of the esophagus for over 100 years. Few studies have examined the diagnostic accuracy of rigid esophagoscopy in patients with carcinoma of the head and neck. The goal of our study was to compare the diagnostic accuracy, complication rate, and costs of rigid esophagoscopy and flexible fiber-optic endoscopy in the evaluation of the esophagus in patients with head and neck carcinoma. We retrospectively reviewed the records of 195 patients with head and neck carcinoma who underwent both rigid esophagoscopy and flexible fiber-optic endoscopy within a 6-month period. We discovered 10 cases with discordant findings, of which 5 (50%) were esophageal carcinoma. The estimated cost was less for flexible endoscopy. No complications were reported in either procedure. Our study suggests that flexible fiber-optic endoscopy should replace rigid esophagoscopy in the evaluation of the esophagus in patients with head and neck carcinoma.

Diagnosis and management of fulminant hepatic failure.

Fulminant hepatic failure is defined as the development of hepatic encephalopathy within 8 weeks of the onset of illness. While there are many causes of FHF, viral hepatitis, particularly hepatitis B, remains the most common etiology. Several drugs and toxins can also lead to FHF, most notably acetaminophen. Even with improvements in ICU care, mortality remains very high for these patients. Conservative management focuses on invasive monitoring and the prevention and treatment of complications like cerebral edema, infection, renal failure, and coagulopathy. Only orthotopic liver transplantation has reduced mortality from 80% to 30% to 50%. Therefore, the goals of management and treatment now include determining which patients are appropriate for liver transplant and finding a donor in a timely fashion.