Renin and electrolytes indicate the mineralocorticoid activity of fludrocortisone: a 6 year study in primary adrenal insufficiency.

CONTEXT: Fludrocortisone (FC) is the mineralocorticoid (MC) replacement treatment for patients with primary adrenal insufficiency (PAI). OBJECTIVE: To explore the dose of FC treatment and its relationship with glucocorticoid therapy, sodium, potassium, renin and clinical parameters. SETTING: Monocentric cohort. PATIENTS: Data of 193 patients with PAI (130 autoimmune) were collected during baseline (T0), intermediate (T1) and last follow-up visit (T2, respectively, after a mean of 38 and 72 months). MAIN OUTCOME MEASURE: Utility of endocrine and clinical parameters to titrate FC dose. RESULTS: FC dose (50-75 µg/daily) was stable in the follow-up in half patients. The MC activity of FC was dose-dependent: we observed a reduced but significant positive linear correlation between FC dose and sodium (r = 0.132) and negative linear correlation between FC and potassium (r = - 0.162) or renin (r = - 0.131, all p < 0.01). An overall reduction in the FC dose was observed at T2 in the group with longer follow-up (> 60 months, p < 0.05). Higher doses of FC were observed in patients with low-normal renin, especially in autoimmune PAI (86 vs 65 µg/daily, p < 0.05). On the contrary, reduced sodium and increased potassium levels were observed in patients with high renin at T2. The number of cardiovascular events (15 in the whole cohort) was similar in patients sorted by renin levels or FC dose. CONCLUSIONS: Renin and electrolytes can indicate the MC activity of FC treatment: they should be routinely evaluated and used to titrate its dose that can be reduced in the long-term follow-up.

Second primary neoplasms in patients with lung and gastroenteropancreatic neuroendocrine neoplasms: Data from a retrospective multi-centric study.

BACKGROUND: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population. AIM: This study aimed to analyze the occurrence of second primary malignancies. METHODS: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included. RESULTS: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms. CONCLUSION: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy.

Genotypes and haplotypes in the 3' untranslated region of the HLA-G gene and their association with clinical outcome of hematopoietic stem cell transplantation for beta-thalassemia.

Polymorphisms in the 3' untranslated region (3'UTR) of HLA-G, an important player in immunological tolerance, could be involved in post-transcriptional expression control, and their association with different clinical immune-related conditions including autoimmunity and transplantation is of mounting interest. Most studies have focused on a 14 base pair (bp) insertion/deletion (ins/del), while additional single-nucleotide polymorphisms (SNPs) in the HLA-G 3'UTR have been described but not extensively investigated for their clinical relevance. Here we have comparatively studied the association between 3'UTR haplotypes of HLA-G, or the 14 bp ins/del, with clinical outcome of HLA-identical sibling hematopoietic stem cell transplantation (HSCT) in 147 Middle Eastern beta-thalassemia patients. Sequence based typing of 3'UTR HLA-G polymorphisms in the patients and in 102 healthy Italian blood donors showed strong linkage disequilibrium between the 14 bp ins/del and five 3'UTR SNPs, which together could be arranged into eight distinct haplotypes based on expectation-maximization studies, with four predominant haplotypes (UTRs1-4). After HSCT, we found a moderate though not significant association between the presence of UTR-2 in double dose and protection from acute graft versus host disease (hazard ratio (HR) 0.45, 95% confidence intervals (CI): 0.14-1.45; P = 0.18), an effect that was also seen when the corresponding 14 bp ins/ins genotype was considered alone (HR 0.42, 95% CI: 0.16-1.06; P = 0.07). No association was found with rejection or survival. Taken together, our data show that there is no apparent added value of considering entire 3'UTR HLA-G haplotypes for risk prediction after allogeneic HSCT for beta-thalassemia.

[Identification and evaluation of liver damage in subjects exposed to occupational risk from general anesthetics]. / Identificazione e valutazione del danno epatico in soggetti esposti a rischio occupazionale da anestetici generali.

BACKGROUND: The program Hepascore was produced by an interdisciplinary group working in the Laboratory of Clinical Informatics of the San Giovanni Battista Hospital in Turin with the aim of supporting physicians in the early diagnosis of hepatic damage and in its qualitative and quantitative characterization. The methodology used by this program can be useful especially for investigations concerning Industrial Medicine, which intend to control the occupational risk due to environmental exposure, not only to perform an early diagnosis (secondary prevention), but also to control the temporal evolution of the disease, by comparing significant data in a reproducible way. OBJECTIVE: This study was conducted with the aim of monitoring, by using the screening protocol of Hepascore, a group of workers exposed to an occupational risk by general anaesthetics, assessing the reliability of the proposed model and comparing it to the conventional approach in a cost/effectiveness analysis. METHODS: We evaluated 280 subjects (nurses and physicians) professionally exposed to anaesthetic gas; the environmental presence of anaesthetic agents was tested in all operating room of the hospital by the measurement of halogenated anaesthetics and nitrogen protoxide in the air. All the 280 subjects were submitted to a complete clinical evaluation and laboratory analyses, as recommended by monitoring protocols; in parallel, but independently from the clinical evaluation, also the sequential way used in the program Hepascore (a first screening phase evaluating only a few laboratory parameters, followed by a confirmation phase based on a larger number of blood tests with more restricted limits) was performed. The protocol applied in this study foresaw that subjects in which clinical evaluation and/or Hepascore brought to suspect a 'likely' liver alteration, had to be investigated thoroughly and to be reevaluated after 6 months by clinical examination and by Hepascore. RESULTS: The environmental determinations did never demonstrate the presence of anaesthetics over the threshold value (50 ppm for the N2O and 2 ppm for halogenated anaesthetics). The conventional clinical evaluation recognized as pathological 22 subjects with one or more liver parameters altered, which were explained as mild cytolytic or cholestatic alterations. The screening protocol carried out by Hepascore in the preliminary phase evidenced as pathological 38 subjects on 280 and 22 of them (corresponding to the 22 subjects identified by the clinical evaluation) were confirmed in the following phase (disease likely). CONCLUSIONS: This fact confirms that the sequential approach used by Hepascore provides the same outcomes obtained by performing all tests in the entire population under study, allowing a saving of 57% of the total cost spent for the traditional evaluation. The sequential approach proposed by Hepascore could be employed in all the clinical settings in which an evaluation of liver functional state is required, both in presence of environmental risk factors and in the case of a programme for the optimization of the population's food habits.

An electronic medical diary for computer assisted patient management.

The Electronic Medical Diary (EMD) is a tool for supporting the daily registration and storage of clinical events related to a specific patient. The collection of all patient-specific clinical data forms the patient database (PDB) which can be defined as a computer-based record able to replace the traditional paper record. The PDB is organized according to the clinical database (CDB), which is a structured terminology of most important clinical data, and may be connected with the many online tools (OLT) which can improve the flow of information within the hospital information system (HIS). In this paper we present the preliminary results of a project aimed at creating an EMD designed in accordance with the methodological model based on the problem-oriented approach. This EMD is patient-centered and each action it enables is related to at least one of the identified problems and one of the current diagnostic hypotheses. The permanent link of the EMD with the CDB is one of the most important features of the prototype here described. It allows the standardization of patients' data, their sharing among all operators involved, and a better organization of the patient management process.

Clinical database. Structure, development strategies and expected clinical applications.

The paper provides the description of a data-base developed to include in a quite structured format most clinical data used for patient management in a hospital setting. The system was aimed at achieving a reasonable compromise between the significant but complex solutions the research offers and the real needs of medical practice. First of all, the paper defines the requirements for designing a computerized clinical database according to a patient-centered clinical approach. Then, it describes the structure of a prototype aimed at classifying clinical data as a hierachy and describing them according to a structural approach. Next, problems related to the management and upgrading of the system are identified and possible solutions described, with a particular emphasis or knowledge acquisition, refinement and specialization, and on problems related to the functional aspects required for clinical applications. Finally, some meaningful clinical applications are outlined, which use the computerized clinical database as the standard for knowledge organization and data sharing.

A modular approach for representing and executing clinical guidelines.

In this paper, we propose an approach for managing clinical guidelines. We outline a modular architecture, allowing us to separate two conceptually distinct aspects: the representation (and acquisition) of clinical guidelines and their execution. We propose an expressive formalism, which allows one to deal with the context-dependent character of clinical guidelines and also takes into account different temporal aspects. We also describe our tool for acquiring clinical guidelines, which provides a user-friendly interface to physicians, and automatically detects many forms of syntactic and semantic inconsistencies in the guidelines being acquired. In the second part of the paper, we describe a flexible engine for executing clinical guidelines (e.g. for clinical decision support applications, for medical education, or for integrating guidelines into the clinical practice), focusing our attention on temporal issues.

Evidence of an increased nitric oxide production in primary biliary cirrhosis.

OBJECTIVE: Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have been extensively studied, until now few articles have addressed the assessment of nitric oxide production in primary biliary cirrhosis. This study was directed to evaluate circulating nitrosyl-hemoglobin levels as well as neutrophil elastase and soluble adhesion molecule concentrations in this condition, by assuming these parameters as possible markers of either inflammatory response or neutrophil activation. METHODS: Laboratory investigations were performed in 30 patients with primary biliary cirrhosis, in 13 patients with postviral and/or alcoholic cirrhosis, and in a group of eight subjects with chronic hepatitis. RESULTS: Although no difference was detected with respect to chronic hepatitis subjects, higher levels of nitrosyl-hemoglobin adducts were found in primary biliary cirrhosis patients than in postviral or alcoholic cirrhotics and in normal subjects (3.55+/-1.75 arbitrary units vs 1.95+/-0.57 and 0.84+/-0.34, p = 0.0004 and p < 0.0001, respectively). Similarly, more elevated concentrations of neutrophil elastase (213.7+/-192.0 microg/L vs 51.1+/-34.3 and 38.0+/-11.5, p < 0.0001 and p < 0.0001, respectively) as well as of soluble forms of intercellular adhesion molecule 1 and endothelial-leukocyte adhesion molecule 1 were shown in primary biliary cirrhosis patients than in subjects with cirrhosis of other etiologies and in controls. CONCLUSIONS: Highly enhanced nitric oxide production in primary biliary cirrhosis could be related to the development of strong inflammation and at least partially to neutrophil activation, thus suggesting a putative role of these cellular mediators in the development of liver damage owing to their ability to synthesize and release a wide variety of important factors, including elastase and nitric oxide.

Executing clinical guidelines: temporal issues.

In our previous work, we proposed a domain-independent language to describe clinical guidelines and a graphical tool to acquire them. In this paper, we describe an approach to execute clinical guidelines. We propose a flexible execution engine that can be used in clinical decision support applications, and also for medical education, or for integrating guidelines into the clinical workflow. We also focus our attention on temporal issues in the execution of guidelines, including the treatment of composite, concurrent and/or cyclic actions.

Validation of ICTERUS, a knowledge-based expert system for Jaundice diagnosis.

The study aimed to describe an example of the assessment and validation of knowledge-based clinical expert systems. The paper focuses on ICTERUS, an expert system for jaundice diagnosis. It describes system design, the methodology applied for upgrading and validating the program, and the most important outcomes of the validation procedure. The clinical validation of the system on a very large European database (Euricterus Project) shows that diagnostic conclusions are reliable in about 70% of eligible cases. This figure appears acceptable for a system which provides decision support only on the basis of clinical data, assuming that the final decision is achieved under user responsibility. Expected biases, limitations and inconsistencies in the practical application of the system are discussed.

[HEPASCORE: a decision-support system for the identification, clinical staging and functional assessment of hepatopathies]. / HEPASCORE: un sistema di supporto alla decisione per l'identificazione, la stadiazione clinica e la valutazione funzionale delle epatopatie.

A decision support system (HEPASCORE) has been developed to optimize the application of objective criteria for qualitative and quantitative assessment of liver function; clinical and laboratory data are automatically processed, and conclusions are explained. Early recognition of abnormal liver states is performed according to a sequential approach, based at first on clinical rules utilizing data from history and physical examination, then confirming or denying the hypothesis by means of selected laboratory tests. Once an abnormal condition is defined, clinical severity can be evaluated by use of suitable scores, either prognostic or focused on major clinical complications. In addition, selected sets of biochemical tests can be used to score one or more functional aspects. Lastly, whenever quantitative estimates of residual liver function are requested, dynamic tests can be applied to measure meaningful parameters such as functioning liver mass and functional hepatic plasma flow. HEPASCORE has been successfully applied to exclude liver abnormalities in subjects at risk, to follow up liver patients, to predict the natural outcomes of severe liver diseases, to foresee the adverse effects of drugs undergoing first-pass liver extraction and the side effects of invasive procedures. While the proposals contained in the system could be further modified for specific needs, they reflect a satisfactory methodological approach, and the program serves as a useful support to decisions regarding the identification and functional evaluation of hepatopathies. The system was developed with Microsoft Access 7.0 and runs on a personal computer under Windows 95.

A systems approach in hepatology.

Systems analysis has been applied to hepatology with the aim of providing a reasonable organisation of domain knowledge and supporting the improvement of clinical performance. To this extent liver structures and functions have been classified and defined, clinical parameters have been carefully selected and suitably associated to describe individual liver functions, and methodological criteria for clinical evaluation have been assessed. Three major outcomes of such an approach, respectively concerning the development of a shareable clinical database, the application of a suitable methodology for clinical reasoning, and the computer-based support to medical decision-making, have been discussed.

Scoring procedures in clinical hepatology.

A major problem in the assessment of liver function is represented by the quantification of the different aspects on which it relies (biosynthesis, drug metabolism, bile secretion, etc.) and of the clinical severity, with important prognostic implications. Another field that can be supported by quantification procedures is the histological evaluation of chronic hepatitis (necro-inflammatory activity and fibrosis). Finally, scoring systems can be usefully applied in clinical practice as a tool which supports medical decisions in very difficult diagnostic processes. In all the above considered fields, the scoring procedures have the important advantage to allow the standardisation of clinical procedures as well as to facilitate the statistical manipulation of data in controlled clinical trials. This paper reviews numerical scoring systems utilised in hepatology and their clinical applications.

Short-term effects of transjugular intrahepatic portosystemic shunt (TIPS) on functional liver plasma flow in patients with advanced cirrhosis.

AIMS/BACKGROUND: TIPS, an effective procedure applied for the treatment of complications of portal hypertension, is potentially followed by worsening of the hyperdynamic circulation of cirrhosis and the impairment of liver function. The aim of the present study was to evaluate short-term changes of functional liver plasma flow after application of TIPS, using the hepatic (extrarenal) clearance of D-sorbitol (S-HCl). METHODS: Twenty-five cirrhotic patients submitted to TIPS for prevention of variceal rebleeding entered the study. At steady-state, during constant infusion of a solution of D-sorbitol (25 mg/min), appropriate blood and urine samples were collected in order to calculate S-HCI before and 120 min after TIPS opening. In addition, the hepatic extraction ratio of D-sorbitol was directly measured at the level of the right (Er), where TIPS was applied, and of the left (El) hepatic veins; meanwhile the portocaval gradient (PCG) was registered, before and after stent dilation. A comparison of values obtained before and after TIPS application was performed by Student's t-test for paired data. RESULTS: After application of TIPS, a substantial reduction was observed in PCG (12.1+/-4.2 vs 24.8+/-4.3 mmHg; p<0.001) and Er values (20.6+/-14.8 vs 57.5+/-22.3 %; p<0.001) but not El values (47.4+/-22.0 vs 53.4+/-21.4 %; p=0.178). S-HCl measured 120 min after TIPS opening was not statistically different from pre-TIPS values (389.2+/-212.1 vs 394.6+/-152.7 ml/min; p=0.892), although S-HCl variations in Child-Pugh class B patients were positively correlated with portal pressure variations (r=0.63, p=0.016). CONCLUSION: Our results demonstrate that in patients with advanced cirrhosis, TIPS procedure, while effective in reducing portal hypertension, does not lead to alterations in the functional liver plasma flow within the first 2 h.

Prediction by mathematical simulation of different pathophysiological effects on D-sorbitol bioavailability.

In this study a mathematical model was applied to predict how changes in hepatic extraction ratio (E), fractional portal inflow (P) and renal elimination ratio (R) may affect fractional D-sorbitol bioavailability in cirrhotic patients. D-sorbitol bioavailability was computed as the ratio between cumulative urinary outputs measured after infusion into the superior mesenteric (Uma) or the hepatic artery (Uha) and a systemic vein (Usv). The present work was aimed at explaining by mathematical simulation the very large difference observed in the regression lines when plotting Uma or Uha against Usv values. The study was performed by considering a pathophysiological model of the hepatic circulation and simulating independent variations of the above considered parameters or assuming particular pathophysiological conditions like hepatic arterialization and hepatofugal flow. Computational results account for the wide dispersion of experimental data obtained in previous studies and provide reasonable explanations of unexpected findings.

Arterial-venous shunting in liver cirrhosis.

Controversial data exist in the literature about the presence and clinical relevance of hepatic arterial-venous shunting. An interesting opportunity for reconsidering the problem has been provided by the use, in the study of liver function, of D-sorbitol, a substance whose first-pass hepatic extraction is very high in normal subjects, while being directly related to circulatory alterations in liver cirrhosis. Because of this property, the systemic bioavailability of D-sorbitol during hepatic arterial infusion can be assumed to reflect arterial-venous shunting. Thirteen biopsy-proven cirrhotic patients (ages 35-66 years), who required diagnostic arterial catheterization, entered the study. Patients were studied on two subsequent days, in which a sterile pyrogen-free solution (1.5%) of D-sorbitol was administered by direct low-rate infusion (15 mg/min for 20 min) into the hepatic artery and the systemic circulation, respectively. Urine samples were spontaneously collected for 8-hr periods before and during/after each infusion. The hepatic arterial bioavailability of D-sorbitol was calculated as the ratio between the net cumulative urinary outputs of D-sorbitol after infusions into the hepatic artery and the systemic vein. Observed values confirm the existence and the large variability (0-88.7%) of hepatic arterial-venous shunting in cirrhotic patients.

Contextual and temporal clinical guidelines.

In this paper, we propose an approach for managing clinical guidelines. We sketch a modular architecture, allowing us to separate conceptually distinct aspects in the management and use of clinical guidelines. In particular, we describe the clinical guidelines knowledge representation module and we sketch the acquisition module. The main focus of the paper is the definition of an expressive formalism for representing clinical guidelines, which allows one to deal with the context dependent character of clinical guidelines and takes into account different temporal aspects.

Removal systems of immunoglobulin A and immunoglobulin A containing complexes in IgA nephropathy and cirrhosis patients. The role of asialoglycoprotein receptors.

BACKGROUND: Whereas the complex removal routes hypothesized for IgA containing immune complexes (IC) and macromolecules can be adequately analyzed by a recently proposed IgA1-IgG aggregate probe (Lab Invest, 66: 86-95), the relative significance of the asialoglycoprotein receptors in IgAIC clearance is still uncertain. EXPERIMENTAL DESIGN: The removal kinetics of 99mTc diethylenetriamine-pentaacetic acid-conjugated asialo alpha 1 acid glycoprotein (AAGP) and 123I-labeled IgA1-IgG aggregate were analyzed in 11 cirrhosis patients and 13 IgAN patients of comparable age. RESULTS: IgA1-IgG aggregate mean plasma clearance rate was delayed in IgA neuropathy (IgAN) patients (slope 0.038 minutes-1, range 0.027 to 0.053) compared with normals (0.047 minutes-1, range 0.038 to 0.053, p = 0.05). The liver was the main organ involved in the IgA1-IgG removal. When compared with normals, (34.3 minutes, range 29.8 to 42.2), the liver mean transit time (MTT) was significantly (p < 0.02) prolonged in IgAN patients (41.3 minutes, 33.6 to 52.3). Participation of spleen in clearance was observed in some patients and was almost invariably concurrent with normal clearance parameters. Conversely, 9 out of 11 cirrhosis patients had a remarkable splenic uptake, but the blood clearance rate was invariably delayed (0.022 minutes-1, 0.014 to 0.028, p < 0.003) and liver MTT extremely prolonged (122.4 minutes, 52.4 to 400, p < 0.003). In IgAN patients with delayed clearance of the IgA1-IgG aggregate, a distinct trend of progression towards renal failure was noted. AAGP clearance was also delayed in cirrhosis patients: slope = 0.166 minutes-1, 0.108 to 0.247, p = 0.05 as compared with both normals (0.230, 0.173 to 0.289) and IgAN patients (0.250, 0.184 to 0.254). Liver MTT in cirrhosis patients was extremely prolonged: 240.6 minutes, 132.5 to 400 minutes, p < 0.007 compared with both normals (90.0 minutes, 82.7 to 96.6) and IgA patients (92.2 minutes, 70.3 to 107.1). AAGP clearance parameters in normals and IgAN patients were not statistically different. MTT values of AAGP and IgA1-IgG aggregate were strictly related (p = 0.008), suggesting that asialoglycoprotein receptors are partially involved in the clearance of the IgA1-IgG aggregate probe. CONCLUSIONS: Some patients with IgAN have a prolonged circulation of an IgAIC miming probe, probably due to an impaired macrophage function. Other possibilities of prolonged circulation of IgAIC in these patients should imply an abnormal IgA glycosylation pattern that allows IC to escape from an effective asialoglycoprotein receptor system. In cirrhosis patients, all of the removal routes of IgA and IgA containing IC are greatly altered suggesting a causative role in the development of an associated, often clinically inapparent, glomerular disease.

Combined evaluation of total and functional liver plasma flows and intrahepatic shunting.

A diagnostic protocol was studied, designed to evaluate the main parameters of liver circulation in man. A water solution of D-sorbitol (S) and indocyanine green (ICG) was infused intravenously in six controls and nine cirrhotics. Steady-state renal and hepatic S clearances as well as hepatic ICG clearance were calculated. In controls the values (mean +/- SD) of the independent measurements of S and ICG hepatic clearance were 978 +/- 107 and 519 +/- 142 ml/min, respectively, while in cirrhotic patients they were 554 +/- 238 and 231 +/- 90 ml/min. Owing to the kinetic properties of S, its hepatic clearance may be regarded as a measure of functional liver plasma flow (FLPF). The total liver plasma flow (TLPF) values (mean +/- SD), calculated according to Fick's principle, were 1091 +/- 157 ml/min (S method) and 1033 +/- 153 ml/min (ICG method) in controls, and 1251 +/- 554 and 1284 +/- 677 ml/min in cirrhotics. In controls, FLPF was found to be very close to TLPF. In cirrhotic patients the difference between TLPF and FLPF (ranging from 169 to 2093 ml/min when measured by S method) was considered as an approximate estimate of intrahepatic shunting. The procedure is safe and simple and may add a new dimension to the investigation of hepatic circulation.

Educational applications of a knowledge-based expert system for medical decision making in hepatology.

An expert system for medical decision making in hepatology has been developed with the aim of assisting medical education. The knowledge representation is based on different slots respectively concerned with structural and protypical description, and system control. Reasoning is performed at two levels considering in sequence syndromes and diseases. Explanations are available at any time during the reasoning process. Educational facilities are provided by using the help sections of the system, which include definitions and descriptions of finding in both health and disease, as well as summaries defining essential clinical and pathophysiological features of all diagnostic hypotheses. The system provides the following educational functions: support to medical decision making, differential diagnosis, knowledge-base consultation, system description and clinical simulation. A good correspondence was found between the conclusions and suggestions provided by the system and those of the attending physicians. The program, which was written in PROLOG and developed under MS-DOS Operating System, runs on IBM-compatible personal computers equipped with hard-disk and mouse.