A phase II dose finding study of darbepoetin alpha and filgrastim for the management of anaemia and neutropenia in chronic hepatitis C treatment.

Dose reductions of pegylated interferon alpha and ribavirin may be avoided by using growth factors. This phase II clinical trial assesses the dose, efficacy and safety of darbepoetin alpha and filgrastim for treatment of anaemia and neutropenia associated with combination therapy for hepatitis C virus (HCV). Chronic hepatitis C patients (n = 101) received pegylated interferon alpha-2b (1.5 mug/kg once weekly) and ribavirin (800-1400 mg once daily). Patients with anaemia [haemoglobin (Hb) /= 0.75 x 10(9)/L and <10 x 10(9)/L. During antiviral therapy, 52% of patients required darbepoetin alpha, filgrastim or both. Hb at the time of darbepoetin alpha initiation was 10.2 +/- 0.4 g/dL. After 81 days of darbepoetin alpha, Hb increased by 1.9 +/- 1.0 g/dL to 12.1 +/- 1.1 g/dL (P < 0.0001). Filgrastim resulted in a significant increase in ANC [0.75 +/- 0.16 x 109/L to 8.28 +/- 5.67 x 10(9)/L (P < 0.0001)]. In treatment-naïve patients, 48% achieved sustained virological response (SVR), whereas 27% of patients previously treated with a course of pegylated interferon alpha achieved SVR. Low viral load, nongenotype 1 and treatment with growth factors were independently associated with SVR. Mild and severe anaemia were associated with quality of life impairments. Darbepoetin alpha resulted in an improvement in the Vitality domain of Short Form-36. No significant adverse events were related to growth factors. During anti-HCV therapy, filgrastim improved neutropenia and darbepoetin alpha improved both anaemia and quality of life. Future randomized clinical trials are needed to establish the impact of growth factors in improving sustained virological response.

Mode of delivery and risk of fecal incontinence in women with or without inflammatory bowel disease: questionnaire survey.

BACKGROUND: Elective cesarean section (CS) may be recommended for patients with Crohn's disease and perineal involvement. Little is known about CS rates in parous women with inflammatory bowel disease (IBD), nor the possible long-term impact of vaginal delivery and episiotomy on continence in women with IBD. METHODS: Questionnaires were sent to all 777 regional members of a Colitis and Crohn's Disease patient association. Male members were asked to request their unaffected female spouse/partner to complete the forms in order to give a "control" group for comparison. RESULTS: Forms were returned by 491 members (response rate 63%). CS had been undertaken for 37 of the 229 parous women with IBD (16%) versus 15 of the 116 without IBD (13%) (chi(2) = 0.62, P = NS). Only 2 women had undergone CS due to IBD. Of the parous women with IBD, 75 (33%) had persisting problems with fecal incontinence, of whom 21 (28%) dated this back to the time of vaginal delivery. By contrast, only 2 (2%) of the parous control group had suffered persisting fecal incontinence following vaginal delivery (chi(2) = 8.27, P < 0.01). CONCLUSIONS: Persisting fecal incontinence is reported by a significant minority of parous women with IBD, of whom over one-quarter date this back to vaginal delivery. CS is rarely recommended due to IBD alone. If our findings are confirmed in prospective studies, the threshold for recommending CS may need to be lowered for patients with IBD.

Alcohol Related Non-traumatic Rhabdomyolysis and Compartment Syndrome.

Rhabdomyolysis is a serious and life-threatening condition in which skeletal muscle is damaged, commonly resulting in acute renal failure. The causes of this clinical entity can be traumatic and non-traumatic. In the latter group, alcohol is the commonest cause. This report describes the case of a 25 year old man who presented with rhabdomyolysis leading to acute renal failure after an alcohol binge. He presented with painful legs and lower extremity compartment syndrome. The patient recovered with surgical fasciotomy and renal support. This case illustrates the importance of early recognition and treatment of alcohol related non-traumatic rhabdomyolysis and compartment syndrome.

The metabolic syndrome and nonalcoholic fatty liver disease.

Accumulating evidence supports an association between nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome, diabetes, and obesity. The epidemiology, pathogenesis, and approach to treatment of NAFLD follow the same trends as these other metabolic disorders, and insulin resistance is the key event linking NAFLD to these diseases. The impairment in fat and glucose metabolism that ensues once insulin resistance occurs leads to similar biochemical and clinical abnormalities in patients with NAFLD. Many recent studies investigating the cellular and genetic basis of these diseases have led to a better understanding of their pathogenesis and insight into treatment and management. The most effective treatment thus far is weight loss and the use of insulin-modulating pharmacologic agents. A few additional treatment strategies include the use of lipid-lowering, antioxidants or cytoprotective agents, but there is no single therapeutic approach that is effective for managing NAFLD. Future therapies may combine drugs that target specific pathways involved in NAFLD pathogenesis.

Survival and resource utilization in liver transplant recipients: the impact of admission to the intensive care unit.

The organ allocation system for liver transplantation was recently changed to address criticisms that it was too subjective and relied too heavily on total waiting time. The new system, Model for End-Stage Liver Disease and Pediatric Model for End-Stage Liver Disease (MELD/PELD), stratifies patients based on the risk of 3-month pretransplant mortality, allocating livers thereby. There is concern that such a scheme gives priority to the sickest patients, who may not enjoy good posttransplant outcomes. The aim of the present study was to compare the outcomes of liver transplant recipients who had been admitted to the intensive care unit (ICU) to those who had not. Admission to the ICU is considered here to be another indicator of the severity of illness. Patients who underwent liver transplantation at the Cleveland Clinic between January 1, 1993 and October 31, 1998 and were at least 18 years of age were coded for liver transplantation as status 2, 2A, and 2B (n = 112). These patients fell into three groups: those who had been admitted to an ICU before transplantation (group A, n = 16), those who had been admitted to the hospital but not to an ICU (group B, n = 63), and those who were living at home and had undergone an elective transplant (group C, n = 33). Clinical and demographic information (age, sex, race, disease severity, disease etiology, and cold ischemia time) were associated with patient survival, patient/graft survival, and posttransplant resource utilization (hospital length of stay and hospital charges). Age, sex, race, etiology of disease, and cold ischemia time were similar among the three groups. Patient survival, patient/graft survival, and hospital charges were not statistically different between the three groups. The median length of stay was statistically different only between groups B and C (P =.006). Our data support the idea that if severely ill patients with end-stage liver disease are selected appropriately, liver transplant outcomes are similar to those observed among subjects who are less ill and are transplanted electively from home.

Chronic hepatitis C and superimposed nonalcoholic fatty liver disease.

BACKGROUND/AIMS: Hepatitis C and nonalcoholic fatty liver disease (NAFL) are the two most common forms of liver disease in the United States. Recently, obesity and its associated risk factors have been suggested to enhance HCV-related fibrosis. The aim of this study was to assess the impact of hepatic steatosis, steatohepatitis, and its associated risk factors on HCV-related fibrosis. METHODS: Patients with untreated, biopsy-proven, chronic hepatitis C (6/97-3/99) were included. Clinical and demographic data at the time of liver biopsy were obtained from chart review and verified by telephone survey. One hepatopathologist reviewed all pathologic specimens, using the modified histological activity index score and the Ishak staging for fibrosis and a NAFL pathologic protocol. RESULTS: One hundred and seventy patients with hepatitis C were included [age: 48.7+/-9.33 (years), body mass index (BMI): 28.1+/-5.7 (kg/m2) and type 2 diabetes mellitus (DM): 14%]. Of these, 77 (45.3%) had no or mild fibrosis and 93 (54.7%) had advanced fibrosis. Hepatic steatosis was seen in 90 (52.9%) patients. The grade of steatosis was associated with markers of obesity only. Age (p=0.002), type 2 DM (p=0.04), and superimposed steatohepatitis (p=0.047) were independently associated with advanced fibrosis. Superimposed nonalcoholic steatohepatitis (NASH) was seen in 17 (10%) patients. Patients with superimposed NASH were mostly obese (76.5%), males (62%) with 16% having type 2 diabetes and a BMI 33.8+/-7.12. CONCLUSION: In patients with chronic hepatitis C, type 2 DM and superimposed steatohepatitis are independently associated with advanced fibrosis.

Interferon alpha 2B and ribavirin in severe recurrent cholestatic hepatitis C.

Severe recurrent cholestatic hepatitis C after liver transplantation has a poor prognosis and no standard therapy is currently available. Four cases of severe recurrent cholestatic hepatitis C treated with a combination of interferon alpha 2b and ribavirin are described. All four patients were transplanted for hepatitis C-related cirrhosis. The mean age at transplantation was 45 years (range 41-51 years). Three of the patients were male and one was female. All four patients had hepatitis C virus viremia before and after liver transplantation. At 2 to 23 months after liver transplantation, all four patients developed jaundice, cholestatic elevation of liver enzymes, and histopathology consistent with severe recurrent cholestatic hepatitis C. Combination of interferon and ribavirin was given with prompt virological suppression. Despite this rapid viral suppression, all four patients developed progressive graft failure with three deaths.

Hepatic encephalopathy.

In the last decade, a significant amount of research has been devoted to the pathogenesis and treatment of hepatic encephalopathy (HE). Non-invasive neuroimaging techniques such as magnetic resonance imaging and spectroscopy have become important research tools. The search for a suitable animal model of HE associated with cirrhosis is still ongoing. Moreover, consensus terminology and diagnostic criteria for HE in humans are badly needed.

Predictors of mortality and resource utilization in cirrhotic patients admitted to the medical ICU.

BACKGROUND AND OBJECTIVE: Cirrhotic patients admitted to the medical ICU (MICU) are associated with high mortality rates and high resource utilization. This study identifies specific predictors of increased mortality and resource utilization and uses them to develop and validate prognostic models in cirrhotic patients admitted to the MICU. METHODS: Cirrhotic patients admitted to the MICU were identified from the Critical Care Section database (January 1993 to October 1998). Clinical data were extracted from chart review including hospital course variables, mortality, and length of stay (LOS). Total cost per case (TCPC) was obtained from the Transition System INC: Multivariate logistic and linear regression analyses identified the independent predictors of increased mortality and resource utilization used for model building (MB) and model validation (MV). RESULTS: A total of 582 cases were randomized to the MB and MV groups. Each group contained 240 cases after exclusion criteria were applied. The MICU mortality rate was 36.6%, and the in-hospital mortality rate was 49.0%. Acute physiology, age, and chronic health evaluation (APACHE) III score (odds ratio [OR], 4.7; 95% confidence interval [CI], 2.70 to 8.16; p < 0.001), mechanical ventilation (OR, 4.57; 95% CI, 2.35 to 8.34); p < 0.001), and the use of pressors (OR, 7.57; 95% CI, 4.35 to 13.18; p < 0.001) were independent predictors of MICU mortality. APACHE III score (OR, 4.96; 95% CI, 2.97 to 8.29; p < 0.001), the use of pressors (OR, 6.55; 95% CI, 3.66 to 11.72; p < 0.001), and acute renal failure (ARF) (OR, 4.31; 95% CI, 2.41 to 7.71; p < 0.001) were independent predictors of in-hospital mortality. Increased LOS in the MICU was associated with mechanical ventilation, ARF, bronchoscopy, bacteremia, use of pressors, transjugular intrahepatic portosystemic shunt (TIPS), and never received cardiopulmonary resuscitation (CPR) (p < 0.005). Source of admission, platelet transfusion, bacteremia, pneumonia, and never received CPR were independently associated with increased total LOS (p < 0.001). Mechanical ventilation, platelet transfusion, bronchoscopy, TIPS, sepsis, and never received CPR were independent predictors of increased TCPC (p < 0.001). CONCLUSION: Simple prognostic models for mortality and resource utilization have been developed for cirrhotic patients admitted to the MICU.

Transjugular intrahepatic portosystemic shunts (TIPS): a decade later.

Since the introduction of transjugular intrahepatic portosystemic shunt (TIPS) 10 years ago, it has been used increasingly in the management of portal hypertension and its complications. TIPS is now considered the procedure of choice for management of refractory variceal bleeding. Its role in the management of refractory ascites, hepatic hydrothorax, hepatorenal syndrome, and hepatopulmonary syndrome still awaits further prospective studies. The two main complications of TIPS are hepatic encephalopathy and shunt malfunction. Generally, TIPS stenosis or occlusion is a major drawback requiring routine surveillance of TIPS with doppler ultrasound. Venography with balloon dilation of the stent or placement of serial or parallel stents may be required in some cases. Promising modalities of preventing TIPS malfunction (e.g., brachy-therapy, covered stents, or anti-platelet derived growth factor) are currently being investigated.

Outcome of de novo hepatitis C virus infection in heart transplant recipients.

The outcome of de novo hepatitis C virus (HCV) infection in heart transplant recipients of HCV-antibody positive organs is not known. The aim of the study was to determine the short-term outcome of de novo HCV infection in recipients of HCV-positive donor organs. HCV-antibody negative recipients of HCV-antibody positive hearts were identified from January 1, 1991 to February 28, 1998. Control patients matched for year of transplantation were also identified. Twenty-eight patients (22 males, mean age of 56 +/- 11 SD) received hearts from HCV-antibody-positive donors. The control group was similar to the patients in all clinical and demographic aspects. Twenty-three patients had detectable viremia by reverse-transcription polymerase chain reaction (RT-PCR). Of these 23 patients with de novo HCV infection, 7 (30%) developed HCV-related liver disease. Three patients (13%) had chronic hepatitis and 4 patients (17%) developed severe acute cholestatic hepatitis (ACH). Mycophenolate mofetil (MMF) use (P =.04) and high viral load at onset of acute liver disease (P =.02) were associated with ACH. Overall survival was similar between patients with de novo HCV infection and controls (P =.20). Development of ACH (P =.02) and MMF use (P =.0009) were associated with decreased survival in patients with de novo HCV infection. The present study showed that survival of patients with de novo HCV infection was similar to a matched control group. HCV-related severe ACH is associated with a poor short-term outcome in patients with de novo HCV infection. MMF use may be associated with a higher incidence of HCV-related severe ACH and a poor short-term outcome.