Agostino Colli

Risk of severe liver disease in nonalcoholic fatty liver disease with normal aminotransferase levels: A role for insulin resistance and diabetes

It is uncertain whether patients with nonalcoholic fatty liver disease (NAFLD) and normal alanine aminotransferase (ALT) have a milder disease and should undergo liver biopsy. We reviewed the histological data of 458 Italian patients with NAFLD in whom liver biopsy was indicated by altered liver enzymes (395 cases, 86%), or persistently elevated ferritin or long‐lasting severe steatosis (63 cases). Factors associated with nonalcoholic steatohepatitis (NASH) and fibrosis ≥ 2 were identified by multivariate analysis. Patients with normal ALT were significantly older, had lower body mass index, fasting triglycerides, insulin resistance according to homeostasis model assessment (HOMA‐IR), ALT, and gamma‐glutamyltransferase, but a higher prevalence of hypertension. NASH was diagnosed in 59% and 74% of the patients with normal and increased ALT, respectively (P = 0.01). In the overall series of patients, NASH was independently predicted by ALT (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.04–1.19 per 10‐IU/mL increase) and diabetes (OR, 1.5; 95% CI, 1.1–2.0). The same variables were selected in patients with increased ALT, whereas in those with normal ALT, HOMA‐IR and ALT were independent predictors. Severe fibrosis was independently predicted by serum ferritin (OR, 1.04; 95% CI, 1.001–1.08 per 50‐ng/mL increase), ALT (OR, 1.07; 95% CI, 1.02–1.14), and diabetes (OR, 1.8; 95% CI, 1.4–2.3) in the overall series, serum ferritin and diabetes in those with increased ALT, and only HOMA‐IR (OR, 1.97; 95% CI, 1.2–3.7) in patients with normal ALT. Conclusion: Normal ALT is not a valuable criterion to exclude patients from liver biopsy. Alterations in glucose metabolism and insulin resistance in subjects with normal ALT should also be considered in the selection of NAFLD cases for histological assessment of disease severity and progression. (HEPATOLOGY 2008.)

Accuracy of Ultrasonography, Spiral CT, Magnetic Resonance, and Alpha-Fetoprotein in Diagnosing Hepatocellular Carcinoma: A Systematic Review

BACKGROUND AND AIM:In patients with chronic liver disease, the accuracy of ultrasound scan (US), spiral computed tomography (CT), magnetic resonance imaging (MRI), and alpha-fetoprotein (AFP) in diagnosing hepatocellular carcinoma (HCC) has never been systematically assessed, and present systematic review was aimed at this issue.METHODS:Pertinent cross-sectional studies having as a reference standard pathological examinations of the explanted liver or resected segment(s), biopsies of focal lesion(s), and/or a period of follow-up, were identified using MEDLINE, EMBASE, Cochrane Library, and CancerLit. Pooled sensitivity, specificity, and likelihood ratios (LR) were calculated using the random effect model. Summary receiver operating characteristic (SROC) curve and predefined subgroup analyses were made when indicated.RESULTS:The pooled estimates of the 14 US studies were 60% (95% CI 44–76) for sensitivity, 97% (95% CI 95–98) for specificity, 18 (95% CI 8–37) for LR+, and 0.5 (95% CI 0.4–0.6) for LR−; for the 10 CT studies sensitivity was 68% (95% CI 55–80), specificity 93% (95% CI 89–96), LR+ 6 (95% CI 3–12),and LR− 0.4 (95% CI 0.3–0.6); for the nine MRI studies sensitivity was 81% (95% CI 70–91), specificity 85% (95%CI 77–93), LR+ 3.9 (95%CI 2–7), and LR− 0.3 (95% CI 0.2–0.5). The sensitivity and specificity of AFP varied widely, and this could not be entirely attributed to the threshold effect of the different cutoff levels used.CONCLUSIONS:US is highly specific but insufficiently sensitive to detect HCC in many cirrhotics or to support an effective surveillance program. The operative characteristics of CT are comparable, whereas MRI is more sensitive. High-quality prospective studies are needed to define the actual diagnostic role of AFP.

Measurement of Spleen Stiffness to Evaluate Portal Hypertension and the Presence of Esophageal Varices in Patients With HCV-Related Cirrhosis

BACKGROUND & AIMS The hepatic vein pressure gradient (HVPG) is the standard used to determine the degree of portal hypertension (PH) and an important prognostic factor for patients with cirrhosis; HVPG values correlate with the presence of esophageal varices (EV). However, HVPG can only be accurately determined at specialized centers; noninvasive methods are needed to predict HVPG values and the presence of EV. We compared the diagnostic performance of spleen stiffness (SS) measurement by transient elastography with that of liver stiffness (LS) and of other recently proposed noninvasive tests. METHODS We measured SS and LS in 100 consecutive patients with hepatitis C virus-induced cirrhosis. Patients were also assessed by FibroScan, HVPG, esophagogastroduodenoscopy, and liver biopsy. We also analyzed LS-spleen diameter to platelet ratio score and platelet count to spleen diameter. RESULTS SS and LS were more accurate than other noninvasive parameters in identifying patients with EV and different degrees of PH. A linear model that included SS and LS accurately predicted HVPG values (R(2) = 0.85). The results were internally validated using bootstrap analysis. CONCLUSIONS Measurement of SS can be used for noninvasive assessment and monitoring of PH and to detect EV in patients with hepatitis C virus-induced cirrhosis.

Prevalence of genetic hemochromatosis in a cohort of Italian patients with diabetes mellitus.

The frequency of homozygous genetic hemochromatosis, whose putative gene has recently been identified [1], ranges from 0.2% to 0.4% in general populations from Australia [2], Europe [3], and North America [4]. Diabetes mellitus is reported in 20% to 50% of patients with hemochromatosis [5-8] and is known to negatively affect the disease course [5, 8]. Conversely, the prevalence of hemochromatosis was reported to range from 0.49% to 0.96% in three series of diabetic patients without a control population [9-11]. We studied the prevalence of genetic hemochromatosis in patients with diabetes from northern Italy and in an age- and sex-matched control group and evaluated the accuracy of serum ferritin levels and transferrin saturation in estimating the prevalence of hemochromatosis. Methods Study Design Outpatients attending diabetes clinics of four hospitals in northern Italy were recruited consecutively and screened for hemochromatosis. Standardization of the data collection procedures ensured data homogeneity. Criteria for the diagnosis of diabetes were as follows: fasting plasma glucose concentrations greater than 7.7 mmol/L (>140 mg/dL) on at least two occasions and plasma glucose concentrations greater than 11.1 mmol/L (>200 mg/dL) at 2 hours on an oral glucose tolerance test and on at least one other occasion during the 2-hour test after ingestion of 75 g of glucose. Patients with impaired glucose tolerance were excluded from the study. Outpatients with nonulcer dyspepsia or the irritable bowel syndrome served as the control group and were subdivided according to decades of age. Within each decade, the male-to-female ratio was similar to that in the diabetic group. All participants gave written consent to participate in the study, which was approved by the ethics committee of IRCCS, Ospedale Maggiore, Milano, Italy. Laboratory Methods Serum aspartate and alanine aminotransferase, alkaline phosphatase, -glutamyltranspeptidase, and bilirubin levels were measured by using an Olympus AU510 analyzer (Eppendorf-Netheler, Hamburg, Germany); hepatitis B surface antigen was determined by using radioimmunoassay (Abbott Laboratories, North Chicago, Illinois); and antibody to hepatitis C virus was determined by using recombinant immunoblot assay II (Ortho Diagnostic System, Milan, Italy). The colorimetric method (Ferro-Check II, Hyland, Milan, Italy) was used to determine serum iron levels (reference value, 11 to 29 mol/L [60 to 160 g/dL]) and serum transferrin levels (reference value, 2.00 to 3.00 g/L [200 to 300 mg/dL]). Transferrin saturation was derived from the following formula: serum iron/serum transferrin 0.80 (reference value 40). Serum ferritin levels (reference value, 30 to 300 g/L in men and 20 to 160 g/L in women) were measured by radioimmunoassay (Liso-Phase, Lepetit, Milan, Italy). Complete clinical and biochemical evaluation to exclude secondary iron overload was performed in patients and controls with a transferrin saturation greater than 55% and a serum ferritin level greater than 300 g/L (in women) or greater than 400 g/L (in men). These measurements were documented twice in samples obtained 1 month apart. Information about alcohol intake (g/d) was obtained, and random blood alcohol levels were determined to confidently exclude alcohol abuse. In the absence of contraindications, liver biopsy was done in patients with biochemical evidence of hemochromatosis, and siderosis was estimated semiquantitatively [12] and quantitatively (reference value, <150 g/100 mg of dry weight) [13]. A hepatic iron index (hepatic iron concentration/age) [14] greater than 1.9 was considered diagnostic for hemochromatosis [15]. All but one patient with hemochromatosis underwent venesections (220 mg of iron was removed each time). The total iron removed (in grams) was calculated by multiplying the number of venesections by 220. Statistical Analysis The Fisher exact test was used to compare diabetic patients with controls. Role of Funding Source Our funding source had no role in the collection, analysis, or interpretation of the data or in submission of the paper for publication. Results Of the 894 patients (418 men and 476 women), 117 had type 1 diabetes (13%; 56 men and 61 women) and 777 had type 2 diabetes (87%; 362 men and 415 women). The mean duration of diabetes was 11 9 years (range, 1 to 42 years). The mean age of patients with diabetes was 62 9 years (range, 18 to 70 years). The control group (467 patients) consisted of 234 men and 233 women (mean age, 60 11 years [range, 18 to 70 years]). Fifteen diabetic patients (1.7% of 894) and 2 controls (0.4% of 467) had persistently elevated transferrin saturation and serum ferritin levels. Four patients were subsequently excluded from the study because of long-term alcohol abuse (2 diabetic patients and 1 control) and recurrent pulmonary infections (1 diabetic patient). The remaining 12 diabetic patients (11 men and 1 woman) had type 2 diabetes. Transferrin saturation in these patients ranged from 70% to 100%, and serum ferritin levels ranged from 620 to 3200 g/L (Table 1). Table 1. Characteristics, Serum Iron-Related Indexes, Liver Histologic Findings, and Amount of Iron Removed in 12 Diabetic Patients and 1 Control with Genetic Hemochromatosis* Liver biopsy was performed in nine diabetic patients and one control. It was not performed in three of the diabetic patients because of refusal by one patient, a prolonged prothrombin time in one patient, and a low platelet count in one patient. Histologic evaluation of the liver revealed precirrhotic hemochromatosis in four patients and cirrhotic hemochromatosis in five patients. The single control with iron overload had liver fibrosis, with a hepatic iron index of 5.0. Iron depletion (that is, transferrin saturation <20% and serum ferritin level <50 g/L in the presence of mild anemia) was achieved in seven diabetic patients, and venesections are still being done in the remaining four patients. Patient 3 did not receive treatment because of liver failure and died 3 months after the diagnosis of hemochromatosis. The overall prevalence of hemochromatosis in this series of diabetic patients was 1.34% (95% CI, 0.7% to 2.3%) (12 of 894), compared with 0.2% (CI, 0.01% to 1.4%) in controls (1 of 467) (P = 0.032). The odds ratio of hemochromatosis in association with diabetes was 6.3 (CI, 1.1 to 37.7). When only patients with type 2 diabetes were considered, the prevalence of hemochromatosis was 1.54% (12 of 777 [95% confidence limits, 0.8 to 2.6]) (P = 0.019) and the odds ratio of hemochromatosis with type 2 diabetes was 7.3 (CI, 1.3 to 41.9). Table 2 gives a breakdown of the number of patients with elevated iron indexes and the final diagnoses in diabetic patients and controls who underwent complete clinical evaluation, including liver biopsy in patients with elevated transferrin saturation and serum ferritin levels. The initial transferrin saturation had a positive predictive value for hemochromatosis of 39% (CI, 22% to 58%); serum ferritin level had a positive predictive value of 18% (CI, 10% to 30%). The positive predictive values of a second test were 80% for transferrin saturation (CI, 52% to 95%) and 20% for serum ferritin level (CI, 11% to 32%). The positive predictive value for both indexes at first and second testing was 80% (CI, 52% to 95%). Table 2. Diabetic Patients and Controls with Elevated Serum Ferritin Levels and Transferrin Saturation at First and Second Testing Discussion In our series of diabetic patients, the prevalence of previously undiagnosed genetic hemochromatosis was statistically significantly higher than that in sex- and age-matched controls. Transferrin saturation was found to be the best screening tool for hemochromatosis. The overall prevalence (1.34%) of hemochromatosis in this series of diabetic patients is similar to the prevalence (0.96%) reported in an Australian series that used similarly strict diagnostic criteria [11]. The difference in the prevalence between our control group and our diabetic group, compared with the difference reported in the Australian study, could be attributable to the inclusion of a general population in the Australian study and the use of age- and sex-matched controls in our series. With regard to two European series of diabetic patients [9, 10], differences in the prevalence of genetic hemochromatosis between our study and the two European studies (1.34% compared with 0.49% and 0.52%, respectively) could be attributed to the use of less strict diagnostic criteria in the two European studies (for example, liver biopsy was not done for definitive diagnosis of hemochromatosis and no elevated cutpoint for iron-related indexes was used) and to the lack of a true control group. The type of diabetes was not specified in previous series [10, 11]. Of note, all of our diabetic patients with hemochromatosis had type 2 diabetes. This finding is not surprising because in hemochromatosis-related diabetes, as in type 2 diabetes, the insulin response to a meal is impaired and the glucagon response is intact or even exaggerated. That transferrin saturation accurately predicts hemochromatosis has been noted in the general population [16, 17] and in our study. However, serum ferritin levels can be influenced by alcohol abuse, chronic hepatitis C, tumors, and inflammatory conditions. This could be a particularly important limitation. In our series of diabetic patients, 16% had chronic infections and 54% had hepatic steatosis, with concomitant necrosis in some cases. This explains the high rate at which serum ferritin levels falsely indicated hemochromatosis. The observation that genetic hemochromatosis had not been previously diagnosed in the 12 diabetic patients, despite the long duration of follow-up after the diagnosis of diabetes, could be attributed both to unawareness of the frequency of hemochromatosis in Italy until recent years and to the relative paucity (40%) of characteristic clinic

Saccharomyces boulardii for the prevention of antibiotic-associated diarrhea in adult hospitalized patients: a single-center, randomized, double-blind, placebo-controlled trial.

OBJECTIVES:Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Probiotics were effective in preventing AAD and CDAD in several randomized controlled trials. This study was aimed at testing the effect of Saccharomyces boulardii on the occurrence of AAD and CDAD in hospitalized patients.METHODS:A single-center, randomized, double-blind, placebo-controlled, parallel-group trial was performed. Patients being prescribed antibiotics or on antibiotic therapy for <48 h were eligible. Exclusion criteria were ongoing diarrhea, recent assumption of probiotics, lack of informed consent, inability to ingest capsules, and severe pancreatitis. Patients received a capsule containing S. boulardii or an indistinguishable placebo twice daily within 48 h of beginning antibiotic therapy, continued treatment for 7 days after antibiotic withdrawal, and were followed for 12 weeks after ending antibiotic treatment.RESULTS:Of 562 consecutive eligible patients, 275 patients aged 79.2±9.8 years (134 on placebo) were randomized and 204 aged 78.4±10.0 years (98 on placebo) completed the follow-up. AAD developed in 13.3% (13/98) of the patients receiving placebo and in 15.1% (16/106) of those receiving S. boulardii (odds ratio for S. boulardii vs. placebo, 1.16; 95% confidence interval (CI), 0.53–2.56). Five cases of CDAD occurred, 2 in the placebo group (2.0%) and 3 in the probiotic group (2.8%; odds ratio for S. boulardii vs. placebo, 1.40; 95% CI, 0.23–8.55). There was no difference in mortality rates (12.7% vs. 15.6%, P=0.60).CONCLUSIONS:In elderly hospitalized patients, S. boulardii was not effective in preventing the development of AAD.

Are Colonoscopy and Bowel Ultrasound Useful for Assessing Response to Short-Term Therapy and Predicting Disease Outcome of Moderate-to-Severe Forms of Ulcerative Colitis?: A Prospective Study

OBJECTIVES:Mucosal healing has been proposed as an important sign of the efficacy of medical treatment of inflammatory bowel disease; however, direct evidence in ulcerative colitis (UC) is scarce. We evaluated the usefulness of colonoscopy and bowel ultrasound (US) as indexes of response to short-term therapy and as predictors of subsequent outcome in UC.METHODS:A total of 83 patients with moderate-to-severe UC were recruited; endoscopic and US severity was graded 0–3 at entry according to validated scores. Of the recruited patients, 74, who were clinically responsive to steroids, were followed up with repeated colonoscopy and bowel US at 3, 9, and 15 months from recruitment. Concordance between clinical, endoscopic, and US scores at various visits was determined by kappa statistics. Multiple unconditional logistic regression models were used to assess the predictivity of clinical, endoscopic, and US scores measured at 3 and 9 months on the development of endoscopic UC relapse within 15 months.RESULTS:A variable concordance was found over time between endoscopic and clinical score (weighted κ between 0.38 and 0.95), with high and consistent concordance between endoscopic and US scores (weighted κ between 0.76 and 0.90). On logistic regression analysis, moderate-to-severe endoscopic and US scores at 3 months were associated with a high risk of endoscopic activity at 15 months (odds ratio (OR): 5.2; 95% confidence interval (CI): 1.6–17.6 and OR: 9.1; 95% CI: 2.5–33.5, respectively).CONCLUSIONS:Bowel US may be used as a surrogate of colonoscopy in assessing the short-term response of severe forms of UC to therapy. Both US score and endoscopic score after 3 months of steroid therapy predict outcome of disease at 15 months.

Spleen stiffness measurement can predict clinical complications in compensated HCV-related cirrhosis: A prospective study

BACKGROUND & AIMS Hepatic venous pressure gradient (HVPG) measurement represents the best predictor of clinical decompensation (CD) in cirrhotic patients. Recently data show that measurement of spleen stiffness (SS) has an excellent correlation with HVPG levels. Aim of the present prospective study was to assess SS predictive value for CD compared to HVPG, liver stiffness (LS), and other non-invasive tests for portal hypertension in a cohort of patients with HCV-related compensated cirrhosis. METHODS From an initial cohort of 124 patients, 92 underwent baseline LS, SS, HVPG measurements and upper gastrointestinal endoscopy at enrolment and then followed-up for 2 years or until the occurrence of the first CD. Univariate and multivariate logistic regression models were used for determining judgement criteria associated parameters. Accuracy of predictive factors was evaluated using c statistic. The final model was internally validated using the bootstrap method. RESULTS During follow-up, 30 out 92 (32.6%) patients developed CD. At univariate analysis varices at enrolment, all non-invasive parameters, HVPG, and model for end-stage liver disease (MELD) resulted clinical predictors of CD. At multivariate analysis only SS (p=0.0001) and MELD (p=0.014) resulted as predictive factors. A decision algorithm based on the results of a predictive model was proposed to detect patients with low risk of decompensation. CONCLUSIONS This study shows that in compensated cirrhotic patients a SS and MELD predictive model represents an accurate predictor of CD with accuracy at least equivalent to that of HVPG. If confirmed by further studies, SS and MELD could represent valid alternatives to HVPG as prognostic indicator of CD in HCV-related cirrhosis.

Disposition of a flow‐limited drug (lidocaine) and a metabolic capacity–limited drug (theophylline) in liver cirrhosis

The plasma clearance after oral administration of a completely absorbed drug that is metabolized by the liver depends on its intrinsic clearance. In cirrhosis the bioavailability of a flow‐dependent drug increases because of both portosystemic shunting and hepatocyte dysfunction. A drug with a high extraction ratio, lidocaine, and a drug with a low extraction ratio, theophylline, were administered to 27 patients with cirrhosis and 16 control subjects. We found a significant impairment of both theophylline clearance (p < 0.001) and lidocaine clearance (p < 0.001) and an increase in the lidocaine peak concentration (p < 0.001). The three parameters were significantly correlated with each other. The impairment of theophylline metabolism did not correlate with other indexes of disease severity, whereas lidocaine clearance was lower and lidocaine peak level higher in patients with decompensated cirrhosis and evidence of portal hypertension. Thus impairment in lidocaine disposition, which reflects both hepatocyte dysfunction and portosystemic shunting, correlated closer with the severity of liver disease than did theophylline metabolism.

A non-invasive algorithm accurately predicts advanced fibrosis in hepatitis C: A comparison using histology with internal–external validation

BACKGROUND/AIMS Biochemical tests and ultrasonography (US) are useful in the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C (CH-C); however histology remains the reference standard. This multicenter, cross-sectional cohort study evaluated the accuracy of APRI (AST-to-platelet-ratio-index) and liver surface ultrasound nodularity (LSN), singularly and sequentially combined in an algorithm, in diagnosing advanced fibrosis (i.e. METAVIR F3,F4), to derive a prediction rule to confirm or exclude F3,F4. METHODS Four hundred and thirty consecutive CH-C patients with elevated ALT, grouped into a first cohort (training set), and an internal and an external validation cohort, were studied. APRI and LSN were compared to liver biopsy and sequentially combined in order to obtain a predictive rule for advanced fibrosis METAVIR F3,F4. RESULTS LSN was negative and APRI < or = 1 in 185/430 patients, whereas LSN was positive and APRI>2 in 46/430 cases, with a 94% diagnostic accuracy for presence/absence of F3, F4, respectively. In a further 60/430 patients, F3,F4 was detected with an accuracy of 83%. In the remaining cases no classification was possible. CONCLUSIONS An algorithm based on APRI and LSN confirms or excludes F3,F4 in 54% of CH-C patients with elevated ALT and suggests a highly probable diagnosis in a further one-sixth of patients, thus rendering liver biopsy unnecessary in these patients.

Ticlopidine-theophylline interaction

Ticlopidine, a new antithrombotic agent, and theophylline, a widely used bronchodilator drug, are both almost completely metabolized in the liver. To evaluate an interaction between these two drugs, we studied theophylline pharmacokinetics before, after 10 days of ticlopidine administration, and 1 month later in 10 healthy volunteers. We found a highly significant increase in the theophylline elimination half‐life (P < 0.001) and a comparable reduction in its total plasma clearance (P < 0.001) after ticlopidine treatment. Pharmacokinetic parameters returned to initial values within 30 days after ticlopidine withdrawal. Moreover, no changes in theophylline pharmacokinetic parameters were observed 3 months later, before and after 10 days of placebo administration. Our results seem to exclude direct liver toxicity and may suggest a reversible inhibition of the liver metabolic capacity of theophylline.