Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration.

BACKGROUND: With its increasing incidence, nonalcoholic fatty liver disease (NAFLD) is of particular concern in the Veterans Health Administration (VHA). AIMS: To evaluate risk factors for advanced fibrosis in biopsy-proven NAFLD in the VHA, to identify patients at risk for adverse outcomes. METHODS: In randomly selected cases from VHA databases (2005-2015), we performed a retrospective case-control study in adults with biopsy-defined NAFLD or normal liver. RESULTS: Of 2091 patients reviewed, 399 met inclusion criteria. Normal controls (n = 65) had normal liver function. The four NAFLD cohorts included: NAFL steatosis (n = 76), nonalcoholic steatohepatitis (NASH) without fibrosis (n = 68), NAFLD/NASH stage 1-3 fibrosis (n = 82), and NAFLD/NASH cirrhosis (n = 70). NAFLD with hepatocellular carcinoma (HCC) was separately identified (n = 38). Most patients were older White men. NAFLD patients with any fibrosis were on average severely obese (BMI>35 kg/m2 ). Diabetes (54.4%-79.6%) and hypertension (85.8%-100%) were more common in NAFLD with fibrosis or HCC. Across NAFLD, 12.3%-19.5% were enrolled in diet/exercise programs and 0%-2.6% had bariatric surgery. Hispanics exhibited higher rates of NASH (20.6%), while Blacks had low NAFLD rates (1.4%-11.8%), particularly NAFLD cirrhosis and HCC (1.4%-2.6%). Diabetes (OR 11.8, P < .001) and BMI (OR 1.4, P < .001) were the most significant predictors of advanced fibrosis. CONCLUSIONS: In the VHA, diabetes and severe obesity increased risk for advanced fibrosis in NAFLD. Of these patients, only a small proportion (~20%) had enrolled in diet/exercise programs or had bariatric surgery (~2%). These results suggest that providers should focus/tailor interventions to improve outcomes, particularly in those with diabetes and severe obesity.

Lapatinib-induced liver injury characterized by class II HLA and Gilbert's syndrome genotypes.

Lapatinib is a clinically important component of the treatment for HER2-positive metastatic breast cancer and has an acceptable safety profile. Lapatinib-associated Hy's Law cases have been characterized using human leukocyte antigen (HLA) DQA1*02:01/DRB1*07:01 and Gilbert's syndrome UGT1A1*28/*28 genotypes. The HLA-positive cases had higher alanine aminotransferase (ALT) elevation, whereas the HLA-negative cases had a higher incidence of Gilbert's syndrome. The findings of our study, which extend this HLA association to lapatinib-associated serious liver injury, emphasize the importance of Gilbert's syndrome in the interpretation of Hy's Law and may lead to methods for enhancing patient safety.

Virtual reality, ultrasound-guided liver biopsy simulator: development and performance discrimination.

OBJECTIVES: The aim of this article was to identify and prospectively investigate simulated ultrasound-guided targeted liver biopsy performance metrics as differentiators between levels of expertise in interventional radiology. METHODS: Task analysis produced detailed procedural step documentation allowing identification of critical procedure steps and performance metrics for use in a virtual reality ultrasound-guided targeted liver biopsy procedure. Consultant (n=14; male=11, female=3) and trainee (n=26; male=19, female=7) scores on the performance metrics were compared. Ethical approval was granted by the Liverpool Research Ethics Committee (UK). Independent t-tests and analysis of variance (ANOVA) investigated differences between groups. RESULTS: Independent t-tests revealed significant differences between trainees and consultants on three performance metrics: targeting, p=0.018, t=-2.487 (-2.040 to -0.207); probe usage time, p = 0.040, t=2.132 (11.064 to 427.983); mean needle length in beam, p=0.029, t=-2.272 (-0.028 to -0.002). ANOVA reported significant differences across years of experience (0-1, 1-2, 3+ years) on seven performance metrics: no-go area touched, p=0.012; targeting, p=0.025; length of session, p=0.024; probe usage time, p=0.025; total needle distance moved, p=0.038; number of skin contacts, p<0.001; total time in no-go area, p=0.008. More experienced participants consistently received better performance scores on all 19 performance metrics. CONCLUSION: It is possible to measure and monitor performance using simulation, with performance metrics providing feedback on skill level and differentiating levels of expertise. However, a transfer of training study is required.

Case definition and phenotype standardization in drug-induced liver injury.

Drug-induced liver injury (DILI) is the most frequent reason cited for the withdrawal of approved drugs from the market and accounts for up to 15% of the cases of acute liver failure. Investigators around the globe have begun to identify and study patients with DILI; several large registries and tissue banks are being established. In order to gain the maximum scientific benefit from these efforts, the definitions and terminology related to the clinical phenotypes of DILI must be harmonized. For this purpose, an international DILI Expert Working Group of clinicians and scientists reviewed current DILI terminology and diagnostic criteria so as to develop more uniform criteria that would define and characterize the spectrum of clinical syndromes that constitute DILI. Consensus was established with respect to the threshold criteria for definition of a case as being DILI, the pattern of liver injury, causality assessment, severity, and chronicity. Consensus was also reached on approaches to characterizing DILI in the setting of chronic liver diseases, including autoimmune hepatitis (AIH).

Exploring factors that influence general dental practitioners when providing advice to help prevent caries in children.

OBJECTIVE: To increase understanding about how and to whom general dental practitioners provide preventive advice to reduce caries in young children. DESIGN: Qualitative study using semi-structured interviews. SETTING: The North West of England. Interviews took place between March and September 2003. SUBJECTS AND METHODS: Ninety-three general dental practitioners practising within the general dental service were interviewed about the care they provide to young children. The interviews were recorded, transcribed and analysed using a constant comparative method. RESULTS: Children with caries were more likely to be questioned about diet and oral hygiene and if dentists believed parents to be motivated they were more inclined to spend time providing advice. Most dentists seemed to believe that education was the key to preventing caries and gave preventive advice in the form of a short educative talk. There was little use of visual aids or material for parents to take home. CONCLUSION: Preventive advice is given in an ad hoc way with no formal targeting. Most dentists deliver preventive advice as a short educative talk with no props or additional materials. Use of visual aids, providing materials for parents to take home and greater emphasis on partnership might help improve the impact of advice.

Exploring the content of the advice provided by general dental practitioners to help prevent caries in young children.

OBJECTIVES: To increase understanding about the content of preventive advice and care offered by general dental practitioners to young children. DESIGN: Qualitative study using semi-structured interviews. Setting The North West of England. Interviews took place between March and September 2003. SUBJECTS AND METHODS: Ninety-three general dental practitioners practising within the general dental service were interviewed about the care they provide to young children. The interviews were recorded, transcribed and analysed using a constant comparative method. RESULTS: Preventive advice given to parents of young children is usually about sugar consumption and tooth brushing behaviour but the emphasis and specific messages provided varies among general dental practitioners. Use of fluorides varied considerably, suggesting that some dentists either have reservations or are unclear about the appropriate use of fluorides. The study indicates important variation in the content of preventive care. CONCLUSION: There is important variation in the approach of general dental practitioners to the core activity of preventing caries in young children and some views expressed are not supported by the evidence base.

Bone cement or bone substitute augmentation of pedicle screws improves pullout strength in posterior spinal fixation.

Pedicle screws are widely used to fix posterior spinal implants. However, in some situations, such as at the ends of long constructs in scoliosis correction, the screws may pull out of the pedicles. This limits the use of pedicle screw fixation where bone quality is poor. The aim of this study was to investigate the effect of using either a low-viscosity bone cement (Palacos LV) or a bone augmentation material (Cortoss) on the pullout strength of typical pedicle screws (5 mm USS Schanz screws). Ten lumbar calf vertebrae were implanted with pedicle screws. One screw was inserted as normal, and the contralateral screw was augmented with Palacos LV or Cortoss. A plate was then cemented to the posterior surface of each pedicle and the screws were pulled out using a tensile testing machine. The pullout strength of the non-augmented screws was 1203+/-260 N, while the pullout strength of the augmented screws was 1970+/-220 N (Palacos LV) and 2021+/-342 N (Cortoss). Both Palacos LV and Cortoss significantly increased the pullout strength (p=0.0213 and p=0.0029, respectively). There was no significant difference between the Palacos LV and Cortoss groups (p=0.79).

Tolerability and safety of alosetron during long-term administration in female and male irritable bowel syndrome patients.

OBJECTIVES: Alosetron (Lotronex) is a new therapeutic agent for irritable bowel syndrome (IBS) in women with diarrhea-predominant IBS. This multicenter randomized, double-blind, placebo-controlled study assessed the safety and tolerability of alosetron during long-term (< or = 12 months) treatment. METHODS: A total of 859 subjects (637 female and 222 male) with IBS were enrolled from 130 sites in the United States and were randomized 3:1 to receive 1 mg alosetron or placebo b.i.d. for 48 wk; of the subjects, 649 (76%) were randomized to the alosetron group and 212 (24%) to the placebo group. Of the original group, 850 subjects received at least one dose of alosetron (n = 640) or placebo (n = 210). RESULTS: In all, 59% of the subjects completed the study. Safety data were similar in treatment groups and within age, sex, racial origin, and hormone use. Adverse events were reported by 83% (530/640) and 76% (159/210) of subjects in the alosetron and placebo groups, respectively, (p < 0.05) and were similar with the exception of constipation; 32% of subjects receiving alosetron reported constipation, compared to 5% in the placebo group (p < 0.001). Most reports (72%) of constipation were of mild or moderate severity, and 66% of subjects with constipation had single episode of 8 days median duration. Constipation occurred a median of 13 days after initiating treatment and resolved spontaneously, with laxative, or after a brief interruption of therapy. Of the subjects, 4% (11/210) in the alosetron and 5% (28/ 640) in the placebo group experienced serious adverse events. Two deaths occurred in subjects with pre-existing cardiovascular risk factors; neither death was attributed to the study drug. CONCLUSIONS: Alosetron 1 mg b.i.d. for 12 months was well tolerated. Constipation is the most frequent adverse event, with a higher incidence of transient constipation in alosetron-treated patients, typically occurring in the first month of treatment.

Evaluation of a workplace hemochromatosis screening program.

Hemochromatosis is a common inherited disorder of iron metabolism with significant health consequences for the employed population. Although screening for hemochromatosis has been recommended, workplace screening programs remain uncommon. In the first year of a newly initiated corporate screening program, 1968 employees were tested. The screening algorithm included measurement of serum iron and transferrin and subsequent ferritin levels in those employees with elevated iron/transferrin ratios. Thirteen percent of men and 21% of women had elevated iron/transferrin ratios. Of these, 14 men and 2 women had elevated ferritin levels. Of these 16, three had liver biopsies and all three have hemochromatosis. The cost of the screening program was $27,850. The cost per diagnosis was $9283 and the cost per year of life saved was $928. These costs compare very favorably with other common workplace screening programs. Several barriers to obtaining definitive diagnoses on all patients with a positive screening result were identified; strategies to overcome these barriers would further enhance the cost effectiveness of the program. We conclude that workplace hemochromatosis screening is highly cost effective and should be incorporated into health promotion/disease prevention programs.

Additional investigations fail to alter the diagnosis of irritable bowel syndrome in subjects fulfilling the Rome criteria.

OBJECTIVE: Irritable bowel syndrome (IBS) is diagnosed by the presence of a constellation of symptoms fulfilling the Manning or Rome Criteria, after exclusion of organic disease. To exclude other diagnoses that might contribute to the abdominal pain or bowel symptoms experienced by subjects with IBS, numerous screening algorithms have been advocated, incorporating lactose hydrogen breath tests, thyroid function tests, fecal ova and parasite determination, and colonic endoscopy/radiography. The utility of these tests in uncovering alternative diagnoses, other than IBS, was examined in 1452 patients. METHODS: Data were combined from two large multinational studies of IBS patients. All patients exhibited symptoms meeting the Rome criteria for IBS for at least 6 months before study entry. If prior evaluation had been > 2 yr previously, patients underwent colonic endoscopy/radiography at study entry. In addition, thyroid function tests, fecal ova and parasite determination, and a lactose hydrogen breath test were performed. RESULTS: Lactose malabsorption was diagnosed in 23% (256/1122) of patients. Colonic abnormalities were detected in 2% (7/306) of patients; in four patients, colonic inflammation (n = 3) or obstruction (n = 1) may have contributed to symptoms of abdominal pain or altered bowel habits. Abnormal thyroid-stimulating hormone levels were detected in 6% (67/1209) of patients, of whom half were hypothyroid and half were hyperthyroid. Positive fecal ova and parasite tests were noted in 2% (19/1154) of patients. CONCLUSIONS: Examination of screening tests in 1452 patients with an established history of IBS revealed an incidence of lactose malabsorption comparable to that in the general U.S. population and a low incidence of thyroid dysfunction, ova and parasite infestation, or colonic pathology. The limited detection rates, added costs, and inconvenience of these tests suggest that their routine use in the diagnostic evaluation of established IBS patients should be scrutinized.

Liver disease in pregnancy.

Acute viral hepatitis is the most common cause of jaundice in pregnancy. The course of acute hepatitis is unaffected by pregnancy, except in patients with hepatitis E and disseminated herpes simplex infections, in which maternal and fetal mortality rates are significantly increased. Chronic hepatitis B or C infections may be transmitted to neonates; however, hepatitis B virus transmission is effectively prevented with perinatal hepatitis B vaccination and prophylaxis with hepatitis B immune globulin. Cholelithiasis occurs in 6 percent of pregnancies; complications can safely be treated with surgery. Women with chronic liver disease or cirrhosis exhibit a higher risk of fetal loss during pregnancy. Preeclampsia is associated with HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome, acute fatty liver of pregnancy, and hepatic infarction and rupture. These rare diseases result in increased maternal and fetal mortality. Treatment involves prompt delivery, whereupon the liver disease quickly reverses. Therapy with penicillamine, trientine, prednisone or azathioprine can be safely continued during pregnancy.

Alterations in colonic mucosal vessels in patients with cirrhosis and noncirrhotic portal hypertension.

Changes in intestinal mucosal microvasculature as a cause of lower gastrointestinal hemorrhage in patients with portal hypertension have been well documented clinically, but the analogous histomorphological changes have not been well characterized. The goal of this study was to evaluate qualitative and quantitative changes in colonic mucosal vessels in patients with cirrhosis or clinically evident portal hypertension and to correlate these changes with endoscopic and clinical findings. Colon biopsy or resection specimen slides from 46 patients with biopsy-proven cirrhosis (44 patients) or noncirrhotic portal hypertension (two patients) were reviewed. Immunoperoxidase stain for CD34 antigen was used to facilitate visualization of mucosal vessels, and vessel diameter was measured with a micrometer. Patients with inflammatory bowel disease were excluded. Twenty-four normal colon biopsy specimens served as controls. Mucosal vessels were divided into superficial, intermediate, and deep layers. As a group, the cirrhotic patients had a significantly higher mean diameter of vessels in all three layers. Qualitatively, increased numbers of small vessels and prominent branching were noted, especially in the superficial and intermediate layers. Tortuous, thick-walled vessels, suggesting arterialization of venules, were present in some cases. Eleven patients had endoscopic findings suggestive of vascular abnormalities, including erythematous mucosal patches, red macules, and telangiectasias. Eighteen had esophageal varices, and five had portal gastropathy. Nineteen patients had gastrointestinal (GI) bleeding, localized to the lower GI tract in 11. These qualitative and quantitative findings suggest that colonic mucosal vascular lesions are common in portal hypertension and may represent a potential source of clinically significant lower GI hemorrhage in these patients.

Effect of postoperative complications on health and employment following liver transplantation.

The influence of postoperative complications on employment and health status following orthotopic liver transplantation (OLT) remains elusive. Postoperative complications were scored prospectively using a standardized medical outcome classification in each patient transplanted at Duke University from October 1992 to January 1995. Functional status was evaluated by using the Karnofsky score. Between 12 and 18 months following transplantation, patients were asked to complete mailed questionnaires to assess employment and health status (SF-36). The response rate was 86% (42 of 49 eligible patients). The mean patient age was 48 yr. Sixteen of 42 patients (38%) exhibited minimal or no postoperative complications, and 62% exhibited moderate to severe postoperative complications. Age, gender, education, UNOS status for severity of disease, insurance status, and Karnofsky score did not correlate with postoperative complications. Postoperative complications did not predict employment post-transplantation. Paradoxically, patients with minimal or no postoperative complications perceived that their health status was significantly impaired post-transplantation, as evidenced by a median score of 0 in the role-physical subscale of the SF-36, in contrast to those patients with moderate or severe postoperative complications who exhibited a median score of 25 (p < 0.01). Similarly, patients with minimal or no postoperative complications had significantly lower scores on the mental health subscale than those with moderate or severe complications, with median score of 60 vs. 78 (p < 0.03). The physical functioning subscale was not affected by postoperative complications. Thirteen of 42 (31%) respondents returned to full employment post-transplantation. Health perceptions differed with respect to employment status post-transplantation. Patients unemployed post-transplantation exhibited a median score of 55 in the physical functioning subscale, a value much lower than the median score of 80 in the patients who were employed post-transplantation (p < 0.02). No differences in the role physical or mental health subscales were noted with respect to employment status post-transplantation. Employment status was unaffected by Karnofsky status, indicating that functional status does not predict employment. In conclusion, patients exhibited very poor health perceptions post-transplantation, irrespective of postoperative complications. Prospective evaluation of patients undergoing liver transplantation revealed that medical complications did not affect employment post-transplantation.

Medical problems occurring after orthotopic liver transplantation.

Liver transplantation is complicated by specific medical problems. Diabetes mellitus occurs in 4-20% of patients undergoing liver transplantation. Patients with primary sclerosing cholangitis and ulcerative colitis experience up to a 13% incidence of colon cancer after transplantation. Lymphomas occur in 1-3% of patients after transplantation and account for 57% of malignancies occurring in adult patients. Atraumatic bone fractures occur in 22-38% of patients and neurological complications, including seizures, headache, and neuropathy occur in 19-47% of patients following liver transplantation. Patients undergoing liver transplantation may experience recurrence of their primary liver disease: hepatitis B, hepatitis C, primary biliary cirrhosis, autoimmune hepatitis, or primary sclerosing cholangitis. In patients not receiving immunoprophylaxis after transplantation for chronic hepatitis B, recurrent hepatitis B is seen in up to 90% of patients. This can be markedly reduced with hyperimmune globulin immunoprophylaxis. Recurrent hepatitis C is seen in the majority of patients; current treatment modalities are inadequate. Recurrence of primary biliary cirrhosis or primary sclerosing cholangitis in the allograft is infrequent. Autoimmune hepatitis may recur in up to 26% of patients following liver transplantation. Primary disease recurrence in the allograft and preventive strategies are discussed.

Hepatitis C in pregnancy.

OBJECTIVE: To review the epidemiology and clinical course of hepatitis C virus (HCV) infection, to examine current data on the vertical transmission of HCV to neonates, and to develop recommendations for intrapartum and postpartum follow-up of neonates born to HCV-infected mothers. DATA SOURCES: The English-language medical literature from 1988 to 1996 was reviewed through MEDLINE. METHODS OF STUDY SELECTION: Case series evaluating vertical transmission of HCV infection in neonates, determined by HCV RNA testing, after delivery and breast-feeding were reviewed and summarized. TABULATION, INTEGRATION, AND RESULTS: Vertical transmission of HCV infection was examined with respect to maternal human immunodeficiency virus (HIV) status (as heterosexual transmission of HCV is enhanced in HIV-positive patients) and chronicity of HCV infection. Vertical transmission of HCV from HIV-negative mothers with chronic hepatitis C ranged from 0 to 18%. The risk of HCV vertical transmission from HIV-negative mothers with acute hepatitis C may be higher than that from mothers with chronic HCV infection. Vertical transmission of HCV was proportional to maternal HCV RNA levels; no transmission was noted in women without HCV RNA, whereas the greatest transmission was noted in women with HCV RNA greater than 1 million copies/mL. Vertical transmission of HCV from HIV-positive mothers with chronic hepatitis C ranged from 6 to 36%. In colostrum, HCV RNA was found to be present in low titers. No studies have documented transmission of HCV infection to infants via breast-feeding. CONCLUSION: Vertical transmission of HCV complicates up to 18% of pregnancies in HCV-positive, HIV-negative women and 6-36% in HCV-positive, HIV-positive women. The highest rates of vertical transmission of HCV were noted in women with high HCV RNA or concurrent HIV infection. Breast-feeding has not been associated with vertical transmission of HCV infection.

Recurrence of nonalcoholic steatohepatitis in a liver transplant recipient.

A 42-year-old white man with morbid obesity and hypertriglyceridemia was noted to have nonalcoholic steatohepatitis (NASH) at the time of a laparoscopic cholecystectomy for presumed gallstone pancreatitis. His postoperative course was complicated by a 50-kg weight loss and continued right upper quadrant pain. Repeat liver biopsy revealed NASH with accompanying micronodular cirrhosis. Due to progressive fatigue, he underwent an orthotopic liver transplantation complicated by a 36-kg weight gain. Sixteen months posttransplantation, a liver biopsy revealed the recurrence of NASH. Screening for defects in fatty acid oxidation proved negative.