Chronic intestinal pseudo-obstruction: a diagnosis to be considered.

Chronic intestinal pseudoobstruction (CIPO) is a rare entity characterized by recurrent clinical episodes of intestinal obstruction in which no mechanical cause is identified. There are multiple causes for this syndrome but two main groups can be distinguished: a) secondary to a systemic non-gastrointestinal disease; and b) primary or idiopathic originated from alterations in the components of the intestinal wall. The latter forms are the most uncommon and their diagnosis is generally difficult. In the present article, we describe nine patients with CIPO that were diagnosed in our center over the last six years. Four of them were diagnosed with primary or idiopathic form of CIPO and another four were clearly secondary to a systemic disease. The ninth case, which was initially diagnosed as secondary, is probably also a primary form of the disease. The number of patients diagnosed in our center, even thought small, makes us to hypothesize that the prevalence of CIPO is probably greater than is generally believed and that the reasons of its rarity are the incomplete understanding of its physiopathology and the difficulties to achieve a correct diagnosis.

Chronic intestinal pseudo-obstruction: a diagnosis to be considered

Chronic intestinal pseudoobstruction (CIPO) is a rare entitycharacterized by recurrent clinical episodes of intestinal obstructionin which no mechanical cause is identified. There are multiplecauses for this syndrome but two main groups can be distinguished:a) secondary to a systemic non-gastrointestinal disease;and b) primary or idiopathic originated from alterations in thecomponents of the intestinal wall. The latter forms are the mostuncommon and their diagnosis is generally difficult. In the presentarticle, we describe nine patients with CIPO that were diagnosedin our center over the last six years. Four of them were diagnosedwith primary or idiopathic form of CIPO and another four wereclearly secondary to a systemic disease. The ninth case, whichwas initially diagnosed as secondary, is probably also a primaryform of the disease. The number of patients diagnosed in our center,even thought small, makes us to hypothesize that the prevalenceof CIPO is probably greater than is generally believed andthat the reasons of its rarity are the incomplete understanding ofits physiopathology and the difficulties to achieve a correct diagnosis(AU)

Enfermedad grasa del hígado no alcohólica. Desde la resistencia a la insulina a la disfunción mitocondrial / Non-alcoholic fatty liver disease. From insulin resistance to mitochondrial dysfunction

La enfermedad grasa del hígado no alcohólica representa unconjunto de lesiones hepáticas similares a las que produce el alcoholque se aparecen en personas que no consumen alcohol de formaabusiva. Cuando las lesiones consisten en degeneración grasae hidrópica, inflamación y, eventualmente, fibrosis se habla de esteatohepatitisno alcohólica (EHNA). No se conoce con exactitudla patogenia de estas lesiones, pero en la mayoría de los casos seasocian a la resistencia a la insulina. Consecuencia de esta, se producela lipólisis del tejido adiposo abdominal y la llegada excesivade ácidos grasos al hígado. Esto, junto con un trastorno para laexportación de los triglicéridos en forma de VLDL, determina laformación de un hígado graso. El componente inflamatorio y degenerativohepatocelular de la EHNA se atribuye al estrés oxidativo.En la génesis de este interviene la pérdida de actividad de lacadena respiratoria mitocondrial. Esto puede ser originado por elTNF-alfa, la inducción de la iNOS, la formación de peroxinitrito y lanitración en tirosina de las enzimas de esa cadena. Consecuenciasdel estrés oxidativo son: peroxidación de los lípidos de las membranascelulares, activación de las células estrelladas del hígado, fibrosishepática, inflamación crónica y apoptosis

Non-alcoholic fatty liver disease represents a set of liver lesionssimilar to those induced by alcohol that develop in individuals withno alcohol abuse. When lesions consist of fatty and hydropic degeneration,inflammation, and eventually fibrosis, the condition isdesignated non-alcoholic steatohepatitis (NASH). The pathogenesisof these lesions is not clearly understood, but they are associatedwith insulin resistance in most cases. As a result, abdominal fattissue lipolysis and excessive fatty acid uptake by the liver occur.This, together with a disturbance of triglyceride export as VLDL,results in fatty liver development. Both the inflammatory and hepatocellulardegenerative components of NASH are attributed tooxidative stress. Mitochondrial respiratory chain loss of activityplays a critical role in the genesis of latter stress. This may be initiatedby an increase in the hepatic TNF-alpha, iNOS induction, peroxynitriteformation, tyrosine nitration and inactivation of enzymesmaking up this chain. Consequences of oxidative stress include:lipid peroxidation in cell membranes, stellate cell activation in theliver, liver fibrosis, chronic inflammation, and apoptosis

Biologic therapies for chronic inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC) make up the so-called chronic inflammatory bowel disease (IBD). Advances in the understanding of IBD pathophysiologic mechanisms in the last few years have allowed the development of novel therapies such as biologic therapies, which at least theoretically represent a more specific management of this disease with fewer side effects. Currently, the only effective and widely accepted biologic therapy for the treatment of intraluminal, fistulizing CD, both for remission induction and maintenance, is infliximab. The role of other monoclonal antibodies such as adalimumab is not clearly established. It could be deemed an alternative for patients with allergic reactions to infliximab, and for those with lost response because of anti-infliximab antibody development. However, relevant issues such as dosage and administration regimen remain to be established. Anti-integrin a4 therapies, despite encouraging results in phase-3 studies, are still unavailable, as their marketing authorization was held back in view of a number of reports regarding progressive multifocal leukoencephalopathy cases. Immunostimulating therapy may be highly relevant in the near future, as it represents a novel strategy against disease with the inclusion of granulocyte-monocyte colony-stimulating factors.Regarding ulcerative colitis, results from the ACT-1 and ACT-2 studies showed that infliximab is also useful for the management of serious UC flare-ups not responding to standard treatment, which will lead to a revision of therapeutic algorithms, where this drug should be given preference before intravenous cyclosporine. In the next few years, the role of anti-CD3 drugs (vilisilizumab), T-cell inhibiting therapies, and epithelial repair and healing stimulating factors will be established.

Chronic primary intestinal pseudo-obstruction from visceral myopathy.

Chronic intestinal pseudo-obstruction is an uncommon syndrome characterized by relapsing episodes suggesting intestinal obstruction during which no mechanical causes are identified to account for symptoms. Etiologic factors may be manifold. Among them a number of neurologic conditions, gastrointestinal smooth muscle myopathies, endocrino-metabolic and autoimmune diseases, and the use of selected drugs stand out. We report a case of chronic intestinal pseudo-obstruction originating in a sporadic, primary intestinal myopathy that corresponds to no type thus far described. A histological study of the intestinal wall showed disrupted muscle bundles and the presence of interstitial edema. Myocytes had severe degenerative changes, and no alterations were seen in submucosal and myenteric plexus neurons. The activity of enzyme complexes in the mitochondrial respiratory chain, and of thymidine phosphorylase was normal. No mitochondrial DNA changes were seen.

Tratamientos biológicos en la enfermedad inflamatoria crónica intestinal / Biologic therapies for chronic inflammatory bowel disease

La enfermedad de Crohn (EC) y la colitis ulcerosa (CU) constituyenla denominada enfermedad inflamatoria crónica intestinal(EII). Los avances producidos en los últimos años en el conocimientode los mecanismo fisiopatológicos de la EII han permitidoel desarrollo de nuevos tratamientos, como son las terapias biológicas,que suponen, al menos teóricamente un manejo más especificode esta enfermedad y con menos efectos secundarios. En elmomento actual, la única terapia biológica eficaz y aceptada parael tratamiento de la EC intraluminal y fistulizante es el infliximab,tanto para inducir la remisión como para el mantenimiento de lamisma. El papel de otros anticuerpos monoclonales como el adalimumabno esta claramente establecido. Se podría perfilar comouna alternativa en los pacientes con reacciones alérgicas al infliximaby en aquellos que han perdido la respuesta al fármaco por eldesarrollo de anticuerpos al mismo. Sin embargo quedan por determinaraspectos importantes como son las dosis y al pauta deadministración. Las terapias anti-integrina α4, a pesar de los resultadosprometedores de los estudios en fase 3, no se encuentranaún disponibles por estar detenida la comercialización del fármacodebido a la comunicación de varios casos de leucoencefalopatíamultifocal progresiva. En un futuro próximo, quizá tenga gran relevanciala terapia inmunoestimulante que utiliza una nueva estrategiafrente a la enfermedad y que incluye factores estimulantes delas colonias de los granulocitos y monocitos.En la colitis ulcerosa, los resultados de los estudios ACT-1 yACT-2, han demostrado que el infliximab es un fármaco útil en eltratamiento de los brotes graves de CU sin respuesta al tratamientoestándar lo que obligará a revisar los algoritmos de tratamientoy anteponer este fármaco a la ciclosporina intravenosa. En lospróximos años, probablemente quedará definido el papel de losfármacos anti-CD3 (vilisilizumab) y de las terapias inhibidoras delos linfocitos T o del empleo de factores estimulantes de la reparacióny cicatrización epitelial

Crohn's disease (CD) and ulcerative colitis (UC) make up theso-called chronic inflammatory bowel disease (IBD). Advances inthe understanding of IBD pathophysiologic mechanisms in the lastfew years have allowed the development of novel therapies suchas biologic therapies, which at least theoretically represent a morespecific management of this disease with fewer side effects. Currently,the only effective and widely accepted biologic therapy forthe treatment of intraluminal, fistulizing CD, both for remission inductionand maintenance, is infliximab. The role of other monoclonalantibodies such as adalimumab is not clearly established. Itcould be deemed an alternative for patients with allergic reactionsto infliximab, and for those with lost response because of anti-infliximabantibody development. However, relevant issues such asdosage and administration regimen remain to be established. Antiintegrinα4 therapies, despite encouraging results in phase-3 studies,are still unavailable, as their marketing authorization was heldback in view of a number of reports regarding progressive multifocalleukoencephalopathy cases. Immunostimulating therapy maybe highly relevant in the near future, as it represents a novel strategyagainst disease with the inclusion of granulocyte-monocytecolony-stimulating factors.Regarding ulcerative colitis, results from the ACT-1 and ACT-2studies showed that infliximab is also useful for the managementof serious UC flare-ups not responding to standard treatment,which will lead to a revision of therapeutic algorithms, where thisdrug should be given preference before intravenous cyclosporine.In the next few years, the role of anti-CD3 drugs (vilisilizumab),T-cell inhibiting therapies, and epithelial repair and healing stimulatingfactors will be established

Pseudo-obstrucción intestinal crónica primaria debida a miopatía visceral / Chronic primary intestinal pseudo-obstruction from visceral myopathy

La pseudo-obstrucción intestinal crónica es un síndrome infrecuentecaracterizado por episodios recidivantes, sugestivos de obstrucciónintestinal, durante los cuales no se detectan causas mecánicasque justifiquen la sintomatología. Los factores etiológicospueden ser múltiples. Entre ellos destacan diversas enfermedadesneurológicas, miopatías de la musculatura lisa gastrointestinal, enfermedadesendocrino-metabólicas y autoinmunes y el uso de determinadosfármacos. Presentamos un caso de pseudo-obstrucciónintestinal crónica originada por una miopatía intestinalprimaria y esporádica que no corresponde a ningún tipo descritohasta el momento. El estudio histológico de la pared intestinalmostró que los haces musculares estaban desestructurados y queexistía edema intersticial. Los miocitos presentaban marcadoscambios degenerativos y no existían alteraciones en las neuronasde los plexos submucoso y mientérico. La actividad de los complejosenzimáticos de la cadena respiratoria mitocondrial y de la timidinafosforilasa fue normal. No se detectaron alteraciones en elADN mitocondrial

Chronic intestinal pseudo-obstruction is an uncommon syndromecharacterized by relapsing episodes suggesting intestinalobstruction during which no mechanical causes are identified toaccount for symptoms. Etiologic factors may be manifold. Amongthem a number of neurologic conditions, gastrointestinal smoothmuscle myopathies, endocrino-metabolic and autoimmune diseases,and the use of selected drugs stand out. We report a case ofchronic intestinal pseudo-obstruction originating in a sporadic,primary intestinal myopathy that corresponds to no type thus fardescribed. A histological study of the intestinal wall showed disruptedmuscle bundles and the presence of interstitial edema. Myocyteshad severe degenerative changes, and no alterations wereseen in submucosal and myenteric plexus neurons. The activity ofenzyme complexes in the mitochondrial respiratory chain, and ofthymidine phosphorylase was normal. No mitochondrial DNAchanges were seen

Non-alcoholic fatty liver disease. From insulin resistance to mitochondrial dysfunction.

Non-alcoholic fatty liver disease represents a set of liver lesions similar to those induced by alcohol that develop in individuals with no alcohol abuse. When lesions consist of fatty and hydropic degeneration, inflammation, and eventually fibrosis, the condition is designated non-alcoholic steatohepatitis (NASH). The pathogenesis of these lesions is not clearly understood, but they are associated with insulin resistance in most cases. As a result, abdominal fat tissue lipolysis and excessive fatty acid uptake by the liver occur. This, together with a disturbance of triglyceride export as VLDL, results in fatty liver development. Both the inflammatory and hepatocellular degenerative components of NASH are attributed to oxidative stress. Mitochondrial respiratory chain loss of activity plays a critical role in the genesis of latter stress. This may be initiated by an increase in the hepatic TNFalpha, iNOS induction, peroxynitrite formation, tyrosine nitration and inactivation of enzymes making up this chain. Consequences of oxidative stress include: lipid peroxidation in cell membranes, stellate cell activation in the liver, liver fibrosis, chronic inflammation, and apoptosis.

Incontinencia fecal, un problema ignorado y encubierto / Fecal incontinence, an ignored and concealed problem

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Tumor necrosis factor-alpha increases ATP content in metabolically inhibited L929 cells preceding cell death.

The effects of tumor necrosis factor-alpha (TNF) on ATP levels were studied in metabolically inhibited L929 cells. Treatment of these cells with TNF in the presence of actinomycin D or cycloheximide induces cyclic changes in the intracellular ATP content preceding cell death. After 3 h of incubation, the intracellular ATP content increased by 48 +/- 6% (p < 0.001), but at 4 h, it decreased to the control level. Two hours later, it increased again by 23 +/- 5% over the control level (p < 0.001). Coinciding with cell death, ATP content decreased progressively until almost complete depletion. These changes in ATP content were associated with parallel alterations in the respiratory coupling and with increased generation of reactive oxygen species. The mechanism by which TNF/actinomycin D or TNF/cycloheximide increased cellular ATP seemed to be dependent on the mitochondrial ATP synthesis and related to the cytotoxic effect of TNF, since blockade of mitochondrial electron transport prevented the increase in cellular ATP, the formation of reactive oxygen species, and the apoptotic cell death caused by TNF. We suggest that the TNF/actinomycin D- or TNF/cycloheximide-induced changes in intracellular ATP levels may be involved in the cytotoxic effect of TNF in metabolically inhibited L929 cells.

Tumor necrosis factor alpha inhibits collagen alpha 1(I) gene expression in rat hepatic stellate cells through a G protein.

BACKGROUND & AIMS: Tumor necrosis factor alpha (TNF-alpha) inhibits collagen gene expression in cultured fibroblasts. By binding to cell surface receptors, TNF-alpha promotes signals within the cells. The purpose of this study was to investigate the role played by G proteins in TNF-alpha-induced inhibition of collagen gene expression. METHODS: Effect of TNF-alpha on collagen alpha 1(I) messenger RNA (mRNA) level was measured in cultured hepatic stellate cells in basal condition and after inhibiting or activating G proteins or the major intracellular signal transduction pathways. RESULTS: TNF-alpha significantly decreased the level of alpha 1(I) collagen mRNA. Treatment of cells with pertussis toxin inhibited this effect, whereas blocking adenylate cyclase or protein kinase A had no effect. Likewise, blocking phospholipase A2, phospholipase C1 calcium channels, calmodulin, or protein kinase C did not eliminate the inhibitory effect of TNF-alpha on collagen mRNA. On the other hand, C2-ceramide and sphingomyelinase reproduced the effect of TNF-alpha on collagen gene expression, and TNF-alpha did not increase the effect of sphingomyelinase. CONCLUSIONS: TNF-alpha-induced inhibition of alpha 1(I) collagen gene expression in a hepatic stellate cell line may be mediated by a pertussis toxin-sensitive G protein. TNF-alpha may inhibit this gene by using sphingomyelin/ceramide as an intracellular signal transduction pathway.

Down-regulation of tumor necrosis factor receptors by blockade of mitochondrial respiration.

We have studied the effect of blockade of mitochondrial respiration on the binding of human 125I-TNF alpha to L929 cell receptors. Specific TNF alpha binding was decreased to about 20-40% of controls by blocking mitochondrial respiration. This effect was dose- and time-related and was observed independently of the level at which the respiration was blocked (respiratory chain, proton backflow, ATPase, anaerobiosis). This blockade had no effect on the half-life of the specific TNF alpha binding, the internalization or degradation of TNF alpha-receptor complexes, or the number of TNF alpha-binding sites. Scatchard analysis of TNF alpha binding data indicated a 2-4-fold decrease in the affinity of these binding sites. These effects did not appear to be related to the protein kinase C activity or to reactive oxygen radicals, since they were not antagonized by pretreatment of cells with oxygen radical scavengers, deferoxamine, or inhibitors of protein kinase C. Decrease in TNF alpha binding capacity correlated significantly with cellular ATP content (r = 0.94; p < 0.01) and with the cytocidal activity of TNF alpha against L929 cells. These findings suggest that blockade of mitochondrial respiration down-regulates the binding of TNF alpha to cells, most likely by changing the affinity of receptors for this cytokine. This down-regulation may increase the resistance of cells to TNF alpha cytotoxicity.

Toxic oil stimulates collagen synthesis acting at a pretranslational level in cultured fat-storing cells.

BACKGROUND/AIMS: The toxic oil syndrome appeared in Spain in 1981 as a result of ingestion of rapeseed oil denatured with aniline. Some patients developed scleroderma-like skin lesions and liver cirrhosis. Mechanisms of these fibrotic lesions are not known. The present study was designed to investigate the effect of toxic oils on collagen metabolism. METHODS: We measured the relative rate of collagen production, absolute rate of collagen synthesis, production, secretion, and degradation, proline transport, steady-state levels of procollagen alpha 1(l)-messenger RNA (mRNA) in cultured fat-storing cells, and chloramphenicol acetyltransferase activity in transfected cells. RESULTS: Toxic oils increased collagen synthesis, procollagen alpha 1(l)-mRNA levels, and chloramphenicol acetyltransferase activity in cultured fat-storing cells. Effect on collagen production correlated with lipid peroxide content in oils. Cycloheximide, alpha-tocopherol, and methylene blue prevented the increase in procollagen alpha 1(l)-mRNA. Oleylanilide and linoleylanilide, markers for toxic oils, reproduced the stimulatory effects of toxic oils on collagen production and procollagen alpha 1(l)-mRNA. CONCLUSIONS: Toxic oils increased collagen synthesis by acting on the promoter of procollagen alpha 1(l) gene, probably through lipid peroxides derived from acylanilides. We suggest that toxic oil may have stimulated procollagen gene expression through the formation of adducts of aldehydes with some transcription factor.

Reversal of carbon tetrachloride induced changes in microviscosity and lipid composition of liver plasma membrane by colchicine in rats.

Colchicine is beneficial in the treatment of cirrhotic patients, it prevents changes in plasma membrane bound enzymes induced by CCl4 intoxication. In this study, lipid composition and microviscosity were measured in liver plasma membranes isolated from rats given CCl4. Microviscosity values increased in rats given CCl4 for six weeks but fell considerably in those given CCl4 for 10 weeks. Both these changes were absent when colchicine was given with CCl4. The cholesterol/phospholipid molar ratios and lipid peroxide values increased but plasma membrane phospholipids, the length of fatty acyl chains, and the unsaturation index fell significantly after CCl4 intoxication. Colchicine treatment also prevented these changes. Changes in the lipid composition of liver plasma membranes were significantly correlated with lipid peroxidation. Colchicine prevents changes in the physicochemical properties of liver plasma membranes induced by longterm CCl4 treatment, probably by blocking peroxidation of unsaturated fatty acids.

Diminished cytochrome b content and toxic oxygen metabolite production in circulating neutrophils from patients with Crohn's disease.

Phagocytic, chemotactic, and oxidative metabolic capacity of circulating neutrophils was studied in 20 patients with Crohn's disease. In vitro tests of chemotaxis and phagocytosis of isolated neutrophils from patients did not differ from that of healthy controls. However, superoxide anion production by phorbol-myristate-acetate and formylmethionyl-leucyl-phenylalanine-stimulated neutrophils from patients with Crohn's disease was significantly diminished compared with controls. Measurement of cytochrome b559 in total membranes of neutrophils from patients showed that it was significantly lower than in controls. Disease activity did not correlate either with the production of superoxide anion or with the cytochrome b559 content. It is concluded that oxidative metabolism is impaired in neutrophils from patients with Crohn's disease and that this defect could be caused by a reduced content in membrane b-type cytochrome. Although this defective neutrophil function may contribute to granuloma formation, other factors have to be implicated in disease inflammatory activity.

Metabolic clearance rate of arginine vasopressin in patients with cirrhosis.

Metabolic clearance rate and half-time of arginine vasopressin were measured in 43 cirrhotic patients and 10 control subjects. Synthetic arginine vasopressin was infused intravenously at a rate of 500 pg/min/kg of body weight for 75 min. The metabolic clearance rate was significantly reduced, and the half-time of arginine vasopressin after stopping the infusion was significantly increased in patients with cirrhosis, particularly in those with ascites and in those with moderate or severe liver dysfunction. Changes in metabolic clearance rate and half-time of arginine vasopressin correlated with the score of the liver dysfunction, prothrombin activity and levels of serum albumin and bilirubin but not with parameters of kidney function (serum creatinine levels and clearance of creatinine). We conclude that reduced metabolic clearance rate and prolonged half-time of vasopressin in plasma are frequent findings in cirrhotic patients with poor liver function. This impaired catabolism of antidiuretic hormone may contribute to maintaining elevated plasma levels of this hormone in these patients and may be an additional factor leading to fluid retention and to dilutional hyponatremia.