Zvi Ackerman

Femoral neck osteopenia in patients with inflammatory bowel disease.

Objective:The mechanism of bone loss in patients with inflammatory bowel disease (IBD) is not completely understood. The aim of this study was to assess indices of bone turnover and bone mineral density (BMD) in the lumbar spine and femoral neck in IBD patients.Methods:Sixty-three patients with Crohns disease and 41 with ulcerative colitis were studied. Serum bone-specific alkaline phosphatase (B-ALP), osteocalcin, parathyroid hormone (PTH), 25 hydroxyvitamin D, interleukin-6 (IL-6), and urinary N-telopeptide cross linked type 1 collagen (NTX) were determined. BMD of the lumbar spine and femoral neck was determined by dual x-ray absorptiometry in 59 patients.Results:In the femoral neck 42% of the patients had osteopenia (−2.5 SD < BMD T score < −1 SD) and another 41% had osteoporosis (BMD T score < −2.5). In the spine 34% of the patients had osteopenia and additional 42% had osteoporosis. BMD T scores were lower in the femoral neck compared to the spine. Reduced BMD was unrelated to gender, disease type, lifetime corticosteroid dose, but inversely correlated with disease duration (r =−0.36, p < 0.05). Serum IL-6 was higher in IBD patients compared to controls. A reduced level of osteocalcin, a marker of bone formation, was present in 7% of patients and an increase in NTX, a marker of bone resorption, in 25% of them. Osteoporotic IBD patients (spine or hip BMD T score < −2.5) had increased serum IL-6, osteocalcin and PTH level compared to nonosteoporotic patients.Conclusions:There is a high prevalence of reduced BMD at the spine and femoral neck in IBD patients, which is more severe in the hip. Bone turnover in osteoporotic IBD patients is associated with an increase in osteocalcin, PTH and IL-6. IL-6 may play a role in the pathogenesis of bone loss in IBD.

Fructose-Induced Fatty Liver Disease: Hepatic Effects of Blood Pressure and Plasma Triglyceride Reduction

The most known risk factor for nonalcoholic fatty liver disease (NAFLD) is the metabolic syndrome. In this study, we characterized changes in liver pathology, hepatic lipid composition, and hepatic iron concentration (HIC) occurring in rats given fructose-enriched diet (FED), with and without therapeutic maneuvers to reduce blood pressure and plasma triglycerides. Rats were given FED or standard rat chow for 5 weeks. Rats on FED were divided into 4 groups: receiving amlodipine (15 mg/kg per day), captopril (90 mg/kg per day), bezafibrate (10 mg/kg per day) in the last 2 weeks, or a control group that received FED only. FED rats had hepatic macrovesicular and microvesicular fat deposits develop, with increase in hepatic triglycerides (+198%) and hepatic cholesterol (+89%), but a decrease in hepatic phospholipids (−36%), hypertriglyceridemia (+223%), and hypertension (+15%), without increase in HIC. Amlodipine reduced blood pressure (−18%), plasma triglycerides (−12%), but there was no change in hepatic triglycerides and phospholipids concentrations. Captopril reduced blood pressure (−24%), plasma triglycerides (−36%), hepatic triglycerides (−51%), and hepatic macrovesicular fat (−51%), but increased HIC (+23%), with a borderline increase in hepatic fibrosis. Bezafibrate reduced plasma triglycerides (−49%), hepatic triglycerides (−78%), hepatic macrovesicular fat (−90%), and blood pressure (−11%). We conclude that FED rats can be a suitable model for human NAFLD. Drugs administered to treat various aspects of the metabolic syndrome could have hepatic effects. An increase in HIC in rats with NAFLD could be associated with increased hepatic fibrosis.

Treatment of chronic hepatitis C virus infection via antioxidants : Results of a phase I clinical trial

Background: The pathogenesis of chronic hepatitis C virus (HCV) infection is associated with a defective host antiviral immune response and intrahepatic oxidative stress. Oxidative stress and lipid peroxidation play major roles in the fatty liver accumulation (steatosis) that leads to necro-inflammation and necrosis of hepatic cells. Previous trials suggested that antioxidative therapy may have a beneficial effect on patients with chronic HCV infection. Aims: To determine the safety and efficacy of treatment of chronic HCV patients via a combination of antioxidants. Methods: Fifty chronic HCV patients were treated orally on a daily basis for 20 weeks with seven antioxidative oral preparations (glycyrrhizin, schisandra, silymarin, ascorbic acid, lipoic acid, L-glutathione, and alpha-tocopherol), along with four different intravenous preparations (glycyrrhizin, ascorbic acid, L-glutathione, B-complex) twice weekly for the first 10 weeks, and followed up for an additional 20 weeks. Patients were monitored for HCV-RNA levels, liver enzymes, and liver histology. Assessment of quality of life was performed using the SF-36 questionnaire. Results: In one of the tested parameters (eg, liver enzymes, HCV RNA levels, or liver biopsy score), a combination of antioxidants induced a favorable response in 48% of the patients (24). Normalization of liver enzymes occurred in 44% of patients who had elevated pretreatment ALT levels (15 of 34). ALT levels remained normal throughout follow-up period in 72.7% (8 of 11). A decrease in viral load (one log or more) was observed in 25% of the patients (12). Histologic improvement (2-point reduction in the HAI score) was noted in 36.1% of the patients. The SF-36 score improved in 26 of 45 patients throughout the course of the trial (58% of the patients). Treatment was well tolerated by all patients. No major adverse reactions were noted. Conclusions: These data suggest that multi antioxidative treatment in chronic HCV patients is well tolerated and may have a beneficial effect on necro-inflammatory variables. A combination of antiviral and antioxidative therapies may enhance the overall response rate of these patients.

Ischemic hepatitis: Clinical and laboratory observations of 34 patients

Ischemic hepatitis, a relatively infrequent disorder occurring in 0.16% to 0.50% of patients admitted to medical intensive care units, often follows episodes of hypotension or acute heart failure. Investigating the clinical characteristics of patients with ischemic hepatitis may add to our understanding of the pathogenesis and significance of this syndrome. We therefore conducted a retrospective analysis of 34 patients to examine the possible contribution of the various baseline characteristics to the severity of the hepatic damage. In all patients liver disease was unexpected and in some, liver dysfunction dominated the clinical picture. All patients had high serum glutamic pyruvic transaminase (SGPT) and lactic dehydrogenase (LDH) levels (mean +/- SE, 2073 +/- 255 international units and 6085 +/- 748 international units, respectively). The mean SGPT/LDH ratio was 0.34. Most patients had coagulopathy with a prolonged prothrombin time (mean +/- SE, 5.86 +/- 1.37 international normalized ratio [INR]). The most common diagnosis on admission was respiratory distress secondary to various causes. Before the development of the hepatic dysfunction, respiratory failure and hypoxemia were observed in 68% of the patients, whereas hypotension was observed in only 38%. More than 90% of the patients had three or more associated comorbid conditions. The most frequent of these were left heart failure (88.2%), right heart failure (67.6%), chronic obstructive lung disease (58.8%), and chronic renal failure (55.9%). During the acute episode, more than 90% of the patients had transient deterioration of their renal functions. Hypoglycemia was noted in 11 patients (32.4%), and the glucose level was inversely correlated with the SGPT level (r = -0.43, p = 0.01). Stepwise multiple regression analysis showed that left heart failure, systolic blood pressure lower than 90 mm Hg, and female gender, together, accounted for 34% of the variance of the peak SGPT levels (p = 0.002). Fourteen (41.2%) patients died during the 3-month follow-up period, but none from the hepatic injury. None of the clinical or laboratory parameters measured predicted mortality. Clearly, ischemic hepatitis is associated with a high risk of death. The characteristic patients are those with multiple underlying systemic diseases and conditions, especially those with left heart failure. Liver function test results and levels of liver enzymes should be monitored in these patients, particularly when they are admitted for respiratory deterioration and episodes of hypotension.

Increased Urinary N-Telopeptide Cross-linked Type 1 Collagen Predicts Bone Loss in Patients With Inflammatory Bowel Disease

OBJECTIVE:Reduced bone mineral density (BMD) is common in patients with inflammatory bowel disease (IBD), but the factors associated with its longitudinal rate of change have not been established. We prospectively assessed the rate of change in BMD, and its association with biochemical markers of bone turnover.METHODS:Twenty-two patients with Crohns disease and 14 ulcerative colitis patients age 37.1 ± 11.6 yr were followed for 2 yr. Lumbar spine (L2–L4) and femoral neck BMD were measured by dual x-ray absorptiometry at baseline and 24 months. Bone-specific alkaline phosphatase, osteocalcin, urinary N-telopeptide crosslinked type 1 collagen (NTx), parathyroid hormone, and 25-hydroxyvitamin-D were determined at baseline.RESULTS:At baseline, 59% of Crohns patients and 43% of ulcerative colitis patients were osteoporotic, with spine or femoral neck BMD T-score <−2.5. Spine BMD, and spine and femoral neck T-scores were lower and disease duration was longer in nine patients with ileal resection compared with nonoperated patients (0.84 ± 0.15 g/cm2vs 0.96 ± 0.11 g/cm2, −3.0. ± 1.5 vs−1.7 ± 1.3, −3.2 ± 1.5 vs−2.2 ± 1.0, respectively; all p < 0.05). At 24 months, 13/36 (36%) and 14/36 (39%) patients experienced spinal and femoral neck bone loss, respectively, with mean annual percent BMD changes of −2.0% and −1.5%, respectively. NTx, a bone resorption marker, inversely correlated with spinal BMD rate of change (r =−0.4, p < 0.05). Using quartiles analysis, patients with the highest NTx (Q4) experienced the greatest decrease in spine BMD compared with patients with the lowest NTx (Q1).CONCLUSIONS:Spine and femoral neck bone loss continues over time in more than one-third of IBD patients. Increased NTx level predicts spinal bone loss in IBD patients.

Expression of serum amyloid A, in normal, dysplastic, and neoplastic human colonic mucosa: implication for a role in colonic tumorigenesis.

Serum amyloid A (SAA) is an acute phase reactant, whose level in the blood is elevated in response to trauma, infection, inflammation, and neoplasia. Elevated levels of SAA in the serum of cancer patients were suggested to be of liver origin rather than a tumor cell product. The role of SAA in human malignancies has not been elucidated. We investigated the expression of SAA at various stages of human colon carcinoma progression. Nonradioactive in situ hybridization applied on paraffin tissue sections from 26 colon cancer patients revealed barely detected SAA mRNA expression in normal looking colonic epithelium. Expression was increased gradually as epithelial cells progressed through dysplasia to neoplasia. Deeply invading colon carcinoma cells showed the highest levels of SAA. Expression was also found in colon carcinoma metastases. Cells of lymphoid follicles of the intestinal wall, inflammatory cells, ganglion cells, and endothelial cells, also expressed SAA mRNA. Immunohistochemical staining revealed SAA protein expression that colocalized with SAA mRNA expression. RT-PCR analysis confirmed the expression of the SAA1 and SAA4 genes in colon carcinomas, expression that was barely detectable in normal colon tissues. These findings indicate local and differential expression of SAA in human colon cancer tissues and suggest its role in colonic tumorigenesis.

Correlation Between Serum Alanine Aminotransferase Activity and Age: An Inverted U Curve Pattern

BACKGROUND:Alanine aminotransferase (ALT) activity is the most widely used laboratory test for the recognition of liver disease. Normality limits for values of serum ALT activity have been questioned lately. One reason for this recent uncertainty may be an unrecognized decline in aminotransferase levels in the aging population.AIMS:Cross-sectional evaluation of the association between age and ALT activity.METHODS:Laboratory data of residents in single home for the aged and of adult subjects in three general practice clinics in Jerusalem, Israel were reviewed, excluding subjects with known liver disease. A single laboratory performed all the tests. We examined the associations of serum aminotransferase levels with age, sex, body-mass-index (BMI), and estimated glomerular filtration rate (GFR). Polynomial regression and analysis of variance (ANOVA) with corrections for multiple comparisons were utilized for the statistical analyses.RESULTS:One hundred and twenty-eight individuals from the home for the aged and 207 individuals from three family practices were included. ALT activity linearly regressed with age (r = 0.22, p < 0.0001). However, polynomial regression revealed a better fit (r = 0.33, p < 0.0001), creating an inverted U curve with a peak at 40–55 yr. According to age groups, serum ALT level was 19 ± 13 U/L in those under 40 yr, 25 ± 19 U/L in 40–55 yr olds, 22 ± 10 U/L in 56–72 yr olds, 17 ± 9 U/L in 73–83 yr olds, and 13 ± 5 U/L in 83–100 yr olds (p < 0.0001). GFR (r = 0.1, p < 0.05) and BMI (r = 0.14, p < 0.01) weakly correlated with ALT. Gender also associated with ALT; 22 ± 15 U/L in men, and 17 ± 11 U/L in women (p < 0.005). Multiple regression analysis including age, gender, GFR, and BMI revealed that age (p = 0.01) and gender (p = 0.04) retained association with ALT activity. No such associations were noted for aspartate aminotransferase (AST) activity.CONCLUSIONS:Our data suggest a significant association between age and serum ALT activity. This association is not a simple linear correlation, but rather an inverted-U-like relation. Thus, when interpreting the laboratory results of a subject suspected of liver disease, age should probably be taken into account. Larger-scale studies are needed to better characterize this issue.

The Familial Mediterranean Fever ( MEVF ) Gene as a Modifier of Crohn's Disease

OBJECTIVES:Crohns disease (CD) has been reported to be more frequent among non-Ashkenazi Jewish patients suffering from familial Mediterranean fever (FMF). Interestingly, functional similarities between the CD susceptibility gene (NOD2/CARD15) and the FMF gene (MEFV) have been described: both belong to the death domain containing protein family, important in the regulation of apoptosis, cytokine processing and inflammation.AIMS:To investigate the prevalence of MEFV mutations in Jewish non-Ashkenazi CD patients and its putative effect on CD presentation.METHODS:Germline DNA of 105 Israeli CD patients of non-Ashkenazi and mixed Ashkenazi–non-Ashkenazi ethnic background was analyzed for three most common MEFV mutations: M694V, V726A, and E148Q. Five patients (4.7%) with a clinical diagnosis of FMF were included. Data obtained from each patient included: age of onset, disease location, and behavior, the presence of extraintestinal manifestations of CD and therapeutic regimens.RESULTS:The overall prevalence of mutation carriers among non-FMF-CD patients was 13% (13/100). A stricturing disease pattern was observed in 56% (10/18) of all carriers, FMF-CD, and non-FMF-CD patients, and in 25% (22/87) of noncarriers (OR: 3.7, 95% CI: 1.3–10.5, p = 0.015). The prevalence of fistulas was comparable in both groups. Extraintestinal manifestations were significantly more frequent among carriers than noncarriers (65%vs 32%, OR 3.9, 95% CI = 1.3–11.5, p = 0.015). No differences were observed in disease location and disease severity.CONCLUSIONS:MEFV mutations are not associated with CD susceptibility, yet the presence of these mutations appears to be associated with a stricturing disease pattern and extraintestinal disease manifestations of CD.

Neurological abnormalities associated with celiac disease

BackgroundCeliac disease (CD) is a gluten-sensitive enteropathy in genetically susceptible individuals. Anecdotal reports suggest that the nervous system might be affected in the disorder, but the severity and prevalence of such an involvement have not been systematically evaluated.Materials and methodsAnalysis of files of CD patients diagnosed between 1980 and 1999 for neurological abnormalities. Diagnosis of CD was based on the modified criteria of the European Society for Pediatric Gastroenterology and Nutrition.ResultsOf 148 CD patients, 18 (12%) had 21 neurological disorders that could not be attributed to any other condition including muscle abnormality (3), epilepsy (3), psychiatric disease (4), peripheral neuropathy (3), cerebrovascular disease (1), myelopathy (1) and Down syndrome (2). Other disorders probably unrelated to CD were present in 8 patients.ConclusionIf this association is not coincidental, both the central and the peripheral nervous systems may be affected in CD by a spectrum of neurological disorders that are either the outcome of CD or share the same pathogenesis with the enteropathy.

Low Alanine Aminotransferase Activity in Older People Is Associated with Greater Long‐Term Mortality

OBJECTIVES: To find possible association between liver enzymes and mortality in older people.