Navdeep Boparai

Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity

BACKGROUND & AIMS The spectrum of nonalcoholic fatty liver disease ranges from fatty liver alone to nonalcoholic steatohepatitis. Most previous studies have short follow-up and have not carefully delineated different histological types when determining clinical outcomes. The aim of this study was to compare clinical characteristics and outcomes of patients with different types of nonalcoholic fatty liver. METHODS All liver biopsy specimens from 1979 to 1987 with fat accumulation were assessed for inflammation, ballooning degeneration, Mallory hyaline, and fibrosis. Biopsy specimens were also assessed for histological iron and hepatitis C RNA. Outcomes were cirrhosis, mortality, and liver-related mortality. RESULTS Of 772 liver biopsy specimens, complete data were available in 132 patients. Fatty liver (type 1) did not differ from the other three types combined with respect to gender, race, age, or obesity. Cirrhosis was more common in the other types combined (22%) than fatty liver alone (4%; P </= 0.001). Overall mortality, histological iron, and hepatitis C did not differ between groups. Most of the liver-related deaths were in type 4. CONCLUSIONS The outcome of cirrhosis and liver-related death is not uniform across the spectrum of nonalcoholic fatty liver. These poor outcomes are more frequent in patients in whom biopsies show ballooning degeneration and Mallory hyaline or fibrosis.

Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes

BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is reported commonly in patients with type 2 diabetes mellitus (DM), which has been suggested as a risk factor for the progressive form of NAFLD, or nonalcoholic steatohepatitis. The aim of this study was to assess the outcome of patients with NAFLD and DM. METHODS A cohort of patients with NAFLD was identified, and patients with other causes of liver disease (alcohol, medication, etc.) were excluded. Clinical, pathological, and mortality data were available for this cohort. Patients were categorized and compared according to the presence or absence of DM. RESULTS Of 132 patients with NAFLD, 44 patients (33%) had an established diagnosis of DM. Patients with DM were older and had greater serum glucose and triglyceride levels and a greater aspartate aminotransferase-alanine aminotransferase ratio. Liver biopsy specimens from patients with DM showed more vacuolated nuclei and acidophilic bodies. Cirrhosis (histological or clinical) occurred in 25% of patients with DM (11 of 44 patients) and NAFLD compared with only 10.2% (9 of 88 patients) of patients without DM with NAFLD (P = 0.04). After adjusting for potential confounders (age, body mass index, and the presence of cirrhosis), both overall mortality (risk ratio [RR], 3.30; 95% confidence interval [CI], 1.76-6.18; P = 0.002) and mortality related to liver disease (RR, 22.83; 95% CI, 2.97-175.03; P = 0.003) were greater in diabetic patients with NAFLD. Markers of hepatic dysfunction (low albumin level, high total bilirubin level, and prolonged prothrombin time) were the only independent predictors of increased mortality. CONCLUSIONS Patients with NAFLD and DM are at risk for the development of an aggressive outcome, such as cirrhosis and mortality. This study supports the potential role of insulin resistance in the development of poor clinical outcomes in patients with NAFLD.

Health-related quality of life in chronic liver disease: the impact of type and severity of disease

OBJECTIVE:The type and severity of chronic liver disease may have different effects on health-related quality of life (HRQL). The aim of our study was to determine whether HRQL in patients with chronic liver disease differs by type and severity of disease and to identify which clinical and physiological factors affect this impairment.METHODS:In this study, HRQL was measured with a generic (Short Form 36) and a liver disease-specific (Chronic Liver Disease Questionnaire) questionnaire. Clinical, demographic, and laboratory data were collected at office visits. Patients HRQL scores were compared with the published norms and to the chronically ill populations. A total of 353 patients (mean age 50 yr, 51% men) with chronic liver disease, either viral disease (hepatitis B and C), cholestatic disease (primary biliary cirrhosis or primary sclerosing cholangitis), or hepatocellular disease were enrolled in the study.RESULTS:In general, HRQL in patients with chronic liver disease was lower than the normal population and was similar to that of patients with chronic obstructive pulmonary disease or congestive heart failure. In cirrhotic patients, some dimensions of HRQL were less impaired in patients with cholestatic disease than in those with hepatocellular diseases. More severe disease (higher Childs class) was associated with a lower Chronic Liver Disease Questionnaire score and the Short Form 36s physical component summary scores. Older age had a weak negative association with the physical aspects of HRQL.CONCLUSIONS:We conclude that chronic liver disease substantially reduces HRQL, and this impact does not differ markedly by type of disease. Older age and measures of disease severity were associated with poorer HRQL.

The Psychosocial Impact of Donating a Kidney: Long-Term Followup from a Urology Based Center

PURPOSE We conducted a psychosocial followup of living kidney donors from 1983 to 1995. MATERIALS AND METHODS A new questionnaire about donor satisfaction and the Medical Outcomes Study Short-Form Health Survey, a standardized measure of health related quality of life, were completed by 167 donors (67% response rate). RESULTS Of respondents 90% would make the same choice again and 83% would strongly encourage others to donate. However, 15% of respondents believed that donating had impacted negatively on their health and 23% reported negative financial consequences. Respondent health related quality of life was not impaired. The strongest correlates of donor dissatisfaction included a conflicted initial relationship with the recipient, believing that information given preoperatively had been inadequate and perceived damage to health or finances. CONCLUSIONS Only a minority of living kidney donors suffer psychosocial morbidity. Better psychological preparation for surgery and more consistent followup could decrease negative outcomes further.

Posaconazole for the Treatment of Azole-Refractory Oropharyngeal and Esophageal Candidiasis in Subjects with HIV Infection

BACKGROUND We evaluated the efficacy and safety of oral posaconazole for human immunodeficiency virus (HIV)-infected subjects with oropharyngeal candidiasis (OPC) and/or esophageal candidiasis (EC) who were clinically refractory to treatment with oral fluconazole or itraconazole. METHODS Subjects with confirmed OPC or EC who did not improve after receiving standard courses of fluconazole or itraconazole treatment were eligible for study enrollment. Subjects received either oral posaconazole (400 mg twice daily) for 3 days followed by oral posaconazole (400 mg once daily) for 25 days (regimen A; 103 patients) or oral posaconazole (400 mg twice daily) for 28 days (regimen B; 96 patients). The primary end point was cure or improvement after 28 days. Primary efficacy analyses were performed on the subset of treated subjects with refractory disease (e.g., baseline culture positive for fluconazole- or itraconazole-resistant Candida species or persistent or progressive clinical signs or symptoms consistent with treatment failure). RESULTS Of the modified intent-to-treat population, 132 (75%) of 176 subjects achieved a clinical response to posaconazole treatment. Clinical response rates were similar between regimen A recipients (75.3%) and regimen B recipients (74.7%). Clinical responses occurred in 67 (73%) of 92 subjects with baseline isolates resistant to fluconazole, 49 (74%) of 66 subjects with baseline isolates resistant to itraconazole, and 42 (74%) of 57 subjects with isolates resistant to both. Clinical response was achieved in 32 (74.4%) of 43 subjects with endoscopically documented EC. The most common treatment-related adverse events were diarrhea (11%), neutropenia (7%), flatulence (6%), and nausea (6%). Eight subjects (4%) discontinued therapy as a result of a treatment-related adverse event. CONCLUSIONS Posaconazole offers a safe and effective treatment option for HIV-infected subjects with azole-refractory OPC and/or EC.

Assessment of utilities and health-related quality of life in patients with chronic liver disease.

OBJECTIVES:Quantitative measures of the value patients place on the state of their health is crucial to understanding their experience, and to calculate quality-adjusted years of life for economic analyses. Patients’ values in chronic liver disease remain unexplored, although experts’ estimates of utilities have been examined. Our study tests the validity of a widely used utility measure in chronic liver disease and, if valid, establishes the decrement in health-related quality associated with chronic liver disease.METHODS:A total of 120 patients with chronic liver disease participated in the study (age 50 ± 10 yr; men 53%; cirrhosis 51%, chronic viral hepatitis 51%, and chronic cholestatic liver disease 30%). All patients completed three instruments: Health Utility Index Mark 2 (scores 0–1), Short Form-36 (scale scores 0–100), and a disease-specific health-related quality of life instrument (Chronic Liver Disease Questionnaire; scores 1–7).RESULTS:We found a moderate to strong correlation between scores on the three measures and that impairment worsened as the severity of disease worsened. Patients without cirrhosis and those with Childs A cirrhosis showed substantial decrement in utilities (0.82 and 0.83, respectively) in the range of patients surviving brain tumor. Those with Childs B and C showed a greater decrement (0.67 and 0.56) that was in the range experienced by patients who survive a stroke (0.67). Utilities assessed by Health Utility Index Mark 2 differed substantially from estimates by “expert.”CONCLUSIONS:We conclude that utilities should be based on patient reports and that the data from this study can inform economic analyses in studies of patients with chronic liver disease.

Cholestatic liver diseases and health-related quality of life.

OBJECTIVE:Symptoms associated with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) negatively affect health-related quality of life (HRQL). The aim of this study was to measure HRQL in patients with chronic cholestatic liver diseases and to determine factors associated with more severe impairment.METHODS:We conducted a cross-sectional study in which we documented patients’ demographic and clinical characteristics, and measured their HRQL using the Short Form-36 and Chronic Liver Disease Questionnaire. We assessed the association of HRQL impairment with disease severity (Childs-Pugh class and Mayo PBC Risk Score) and compared patients’ HRQL with those of a healthy population, and patients with congestive heart failure, chronic obstructive pulmonary disease, and diabetes.RESULTS:One hundred and four patients with PBC and PSC participated, of whom 73% were women, with an average age of 55 ± 12 yr. Of these patients, 61% had cirrhosis (37% Childs A, 23% Childs B, and 2% Childs C). Patients with cholestatic liver disease showed more HRQL impairment than the healthy population and were similar to patients with other chronic conditions. Additionally, patients who experienced severe itching showed profound HRQL impairment. In patients with PBC, Physical Component Summary (PCS) scores of the SF-36 and Chronic Liver Disease Questionnaire (CLDQ) scores fell from noncirrhotic to Childs A to Childs B/C and with worsening Mayo PBC Risk Scores. No other clinicodemographic data were associated with patients’ well-being.CONCLUSIONS:Patients with cholestatic liver disease (PBC and PSC) showed substantial impairment of HRQL, which is further affected by worsening disease severity. Disease-specific measures were better able to discriminate patients with varying severities.

Impact of lipid abnormalities in development and progression of transplant coronary disease: a serial intravascular ultrasound study

OBJECTIVES We sought to determine the role of conventional atherosclerosis risk factors in the development and progression of transplant coronary artery disease (CAD) using serial intravascular ultrasound imaging. BACKGROUND Transplant artery disease is a combination of allograft vasculopathy and donor atherosclerosis. The clinical determinants for each of these disease processes are not well characterized. Intravascular ultrasound imaging is the most sensitive tool to serially study these processes. METHODS Baseline intravascular ultrasound imaging was performed 0.9 +/- 0.5 months after transplantation to identify donor atherosclerosis. Follow-up imaging was performed at 1.0 +/- 0.07 year to evaluate progression of donor atherosclerosis and development of transplant vasculopathy. Conventional risk factors for CAD included recipient age, gender, smoking history, diabetes mellitus, hypertension and hypercholesterolemia. RESULTS Donor-transmitted atherosclerosis was present in 36 patients (39%). At follow-up, progression of donor lesions was seen in 15 patients (42%) and 42 patients (45%) developed transplant vasculopathy, leaving 35 patients (38%) without any disease. There was no difference in any conventional risk factors in patients with and without allograft vasculopathy. However, the severity of allograft vasculopathy was associated with a larger increase in low density lipoprotein (LDL) cholesterol from baseline (p = 0.02). High one-year posttransplant serum triglyceride level and pretransplant body mass index were the only significant predictors (p = 0.03) for progression of donor atherosclerosis. CONCLUSIONS Conventional atherosclerosis risk factors do not predict development of allograft vasculopathy, but greater change in serum LDL cholesterol level during the first year after transplant is associated with more severe vasculopathy. Therefore, maintenance of LDL cholesterol as close to pretransplant values as possible may help to limit the rate of progression of acquired allograft vasculopathy.

Risk factors for intracranial hemorrhage in adults on extracorporeal membrane oxygenation

OBJECTIVE Intracranial hemorrhage is a recognized complication in neonates and infants on extracorporeal membrane oxygenator support and various risk factors associated with this have been defined. The prevalence and risk factors associated with intracranial hemorrhage in adults on extracorporeal membrane oxygenator support are unknown and this study was performed to define these factors. METHODS A retrospective study of adults supported with extracorporeal membrane oxygenators at a single institution between January 1992 and December 1996 was performed. Age, gender, weight, body surface area, renal function, anticoagulation, coagulation variables, blood flow, arterial pressure, arterial cannulation sites, duration of support, extracranial bleeding, native cardiac function and presence of intracranial microemboli were analyzed to determine the risk factors for intracranial hemorrhage. RESULTS Fourteen out of 74 adults on extracorporeal membrane oxygenator support had intracranial hemorrhage (18.9%). An increased risk of intracranial hemorrhage showed a positive correlation with female gender (P = 0.02, odds ratio 6.5), use of heparin (P = 0.05, odds ratio 8.5), creatinine greater than 2.6 mg/ dl (P = 0.009, odds ratio 6.5), need for dialysis (P = 0.03, odds ratio 4.3) and thrombocytopenia (P = 0.007, odds ratio 18.3). Diminishing renal function and the need for dialysis were associated with increasing duration of support. Multivariable logistic regression showed female gender and thrombocytopenia, especially with platelet counts less than 50000 cells/mm3 to be the most important predictors of intracranial hemorrhage. Intracranial hemorrhage was associated with a mortality of 92.3% compared with a mortality of 61% in those without intracranial hemorrhage (P = 0.027). CONCLUSION Intracranial hemorrhage is a significant complication in adults on extracorporeal membrane oxygenator support. Judicious management of anticoagulation, prevention of renal failure and aggressive correction of thrombocytopenia may help to lower the risk of intracranial hemorrhage in adults on extracorporeal membrane oxygenator support.

Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection

IMPORTANCE The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVE To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor). DESIGN, SETTING, AND PARTICIPANTS This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included. INTERVENTIONS Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg. MAIN OUTCOMES AND MEASURES The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort. RESULTS Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea. CONCLUSIONS AND RELEVANCE In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01979939.