Pathology and pathogenesis of human leptospirosis: a commented review.

Leptospirosis is an acute bacterial septicemic febrile disease caused by pathogenic leptospires, which affect humans and animals in all parts of the world. Transmission can occur by direct contact with infected animals or, more commonly, through indirect contact with water or soil contaminated with urine from infected animals. Leptospires enter the body by penetrating mucous membranes or skin abrasions and disseminate through the hematogenic route. In humans, leptospirosis may cause a wide spectrum of symptoms. Most cases have a biphasic clinical presentation, which begins with the septicemic phase followed by immune manifestations. The severe forms of the disease may be life threatening with multisystem damage including renal failure, hepatic dysfunction, vascular damage, pulmonary hemorrhage and muscle lesions. In this review, we present and discuss the pathogenesis of the human disease and the mechanisms of cell membrane injuries, which occur mainly due to the presence of leptospires and/or their antigen/s in the host tissues.

Correction: Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and Allopurinol in oxidative stress and muscle fiber damage.

[This corrects the article DOI: 10.1371/journal.pone.0179199.].

Pathology and pathogenesis of human leptospirosis: a commented review

Leptospirosis is an acute bacterial septicemic febrile disease caused by pathogenic leptospires, which affect humans and animals in all parts of the world. Transmission can occur by direct contact with infected animals or, more commonly, through indirect contact with water or soil contaminated with urine from infected animals. Leptospires enter the body by penetrating mucous membranes or skin abrasions and disseminate through the hematogenic route. In humans, leptospirosis may cause a wide spectrum of symptoms. Most cases have a biphasic clinical presentation, which begins with the septicemic phase followed by immune manifestations. The severe forms of the disease may be life threatening with multisystem damage including renal failure, hepatic dysfunction, vascular damage, pulmonary hemorrhage and muscle lesions. In this review, we present and discuss the pathogenesis of the human disease and the mechanisms of cell membrane injuries, which occur mainly due to the presence of leptospires and/or their antigen/s in the host tissues.

Pathology and pathogenesis of human leptospirosis: a commented review

Leptospirosis is an acute bacterial septicemic febrile disease caused by pathogenic leptospires, which affect humans and animals in all parts of the world. Transmission can occur by direct contact with infected animals or, more commonly, through indirect contact with water or soil contaminated with urine from infected animals. Leptospires enter the body by penetrating mucous membranes or skin abrasions and disseminate through the hematogenic route. In humans, leptospirosis may cause a wide spectrum of symptoms. Most cases have a biphasic clinical presentation, which begins with the septicemic phase followed by immune manifestations. The severe forms of the disease may be life threatening with multisystem damage including renal failure, hepatic dysfunction, vascular damage, pulmonary hemorrhage and muscle lesions. In this review, we present and discuss the pathogenesis of the human disease and the mechanisms of cell membrane injuries, which occur mainly due to the presence of leptospires and/or their antigen/s in the host tissues.

Ecstasy induces reactive oxygen species, kidney water absorption and rhabdomyolysis in normal rats. Effect of N-acetylcysteine and Allopurinol in oxidative stress and muscle fiber damage.

BACKGROUND: Ecstasy (Ec) use produces hyperthermia, excessive sweating, intense thirst, an inappropriate antidiuretic hormone secretion (SIADH) and a multisystemic toxicity due to oxidative stress (OS). Intense thirst induces high intake of pure water, which associated with SIADH, usually develops into acute hyponatremia (Hn). As Hn is induced rapidly, experiments to check if Ec acted directly on the Inner Medullary Collecting Ducts (IMCD) of rats were conducted. Rhabdomyolysis and OS were also studied because Ec is known to induce Reactive Oxygen Species (ROS) and tissue damage. To decrease OS, the antioxidant inhibitors N-acetylcysteine (NAC) and Allopurinol (Allo) were used. METHODS: Rats were maintained on a lithium (Li) diet to block the Vasopressin action before Ec innoculation. AQP2 (Aquaporin 2), ENaC (Epitheliun Sodium Channel) and NKCC2 (Sodium, Potassium, 2 Chloride) expression were determined by Western Blot in isolated IMCDs. The TBARS (thiobarbituric acid reactive substances) and GSH (reduced form of Glutathione) were determined in the Ec group (6 rats injected with Ec-10mg/kg), in Ec+NAC groups (NAC 100mg/Kg/bw i.p.) and in Allo+Ec groups (Allo 50mg/Kg/i.p.). RESULTS: Enhanced AQP2 expression revealed that Ec increased water transporter expression, decreased by Li diet, but the expression of the tubular transporters did not change. The Ec, Ec+NAC and Allo+Ec results showed that Ec increased TBARS and decreased GSH, showing evidence of ROS occurrence, which was protected by NAC and Allo. Rhabdomyolysis was only protected by Allo. CONCLUSION: Results showed that Ec induced an increase in AQP2 expression, evidencing another mechanism that might contribute to cause rapid hyponatremia. In addition, they showed that NAC and Allo protected against OS, but only Allo decreased rhabdomyolysis and hyperthermia.

Lp25 membrane protein from pathogenic Leptospira spp. is associated with rhabdomyolysis and oliguric acute kidney injury in a guinea pig model of leptospirosis.

Acute kidney injury (AKI) from leptospirosis is frequently nonoliguric with hypo- or normokalemia. Higher serum potassium levels are observed in non-survivor patients and may have been caused by more severe AKI, metabolic disarrangement, or rhabdomyolysis. An association between the creatine phosphokinase (CPK) level and maximum serum creatinine level has been observed in these patients, which suggests that rhabdomyolysis contributes to severe AKI and hyperkalemia. LipL32 and Lp25 are conserved proteins in pathogenic strains of Leptospira spp., but these proteins have no known function. This study evaluated the effect of these proteins on renal function in guinea pigs. Lp25 is an outer membrane protein that appears responsible for the development of oliguric AKI associated with hyperkalemia induced by rhabdomyolysis (e.g., elevated CPK, uric acid and serum phosphate). This study is the first characterization of a leptospiral outer membrane protein that is associated with severe manifestations of leptospirosis. Therapeutic methods to attenuate this protein and inhibit rhabdomyolysis-induced AKI could protect animals and patients from severe forms of this disease and decrease mortality.

MicroRNA Transcriptome Profiling in Heart of Trypanosoma cruzi-Infected Mice: Parasitological and Cardiological Outcomes.

Chagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism. Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms. Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase. In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders. We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection. Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection. Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval. Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation. The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.

The hamster (Mesocricetus auratus) as an experimental model of toxocariasis: histopathological, immunohistochemical, and immunoelectron microscopic findings.

Toxocariasis is a globally distributed parasitic infection caused by the larval stage of Toxocara spp. The typical natural hosts of the parasite are dogs and cats, but humans can be infected by the larval stage of the parasite after ingesting embryonated eggs in soil or from contaminated hands or fomites. The migrating larvae are not adapted to complete their life cycle within accidental or paratenic hosts like humans and laboratory animals, respectively, but they are capable of invading viscera or other tissues where they may survive and induce disease. In order to characterize hamsters (Mesocricetus auratus) as a model for Toxocara canis infection, histopathological and immunohistochemistry procedures were used to detect pathological lesions and the distribution of toxocaral antigens in the liver, lungs, and kidneys of experimentally infected animals. We also attempted to characterize the immunological parameters of the inflammatory response and correlate them with the histopathological findings. In the kidney, a correlation between glomerular changes and antigen deposits was evaluated using immunoelectron microscopy. The hamster is an adequate model of experimental toxocariasis for short-term investigations and has a good immunological and pathological response to the infection. Lung and liver manifestations of toxocariasis in hamsters approximated those in humans and other experimental animal models. A mixed Th2 immunological response to T. canis infection was predominant. The hamster model displayed a progressive rise of anti-toxocaral antibodies with the formation of immune complexes. Circulating antigens, immunoglobulin, and complement deposits were detected in the kidney without the development of a definite immune complex nephropathy.

Detection of Schistosoma mansoni infection by TaqMan® Real-Time PCR in a hamster model.

An experimental study in hamsters was performed to evaluate the capability for detecting Schistosoma mansoni DNA in serum and fecal samples during the pre and post-egg-laying periods of infection using TaqMan® Real-Time PCR system (qPCR), was compared with the circumoval precipitin test (COPT) and the Kato-Katz technique, especially among individuals with low parasitic burden. Twenty-four hamsters were infected with cercariae. Three hamsters were sacrificed per week under anesthesia, from 7 days post infection (DPI) up to 56 DPI. A serum sample and a pool of feces were collected from each hamster. The presence of S. mansoni eggs in fecal samples was evaluated by Kato-Katz method and in the hamsters gutby histopathology. Detection of S. mansoni DNA was performed using qPCR and S. mansoni antibody using COPT. The first detection of eggs in feces by Kato-Katz method and S. mansoni DNA in feces by qPCR occurred 49 DPI. Nevertheless, S. mansoni DNA was detected in serum samples from 14 up to 56 DPI. COPT was positive at 35 DPI. The results not only confirm the reliability of S. mansoni DNA detection by qPCR, but also demonstrate that serum is a trustworthy source of DNA in the pre patent infection period.

Human hemorrhagic pulmonary leptospirosis: pathological findings and pathophysiological correlations.

BACKGROUND: Leptospirosis is a re-emerging zoonosis with protean clinical manifestations. Recently, the importance of pulmonary hemorrhage as a lethal complication of this disease has been recognized. In the present study, five human necropsies of leptospirosis (Weil's syndrome) with extensive pulmonary manifestations were analysed, and the antibodies expressed in blood vessels and cells involved in ion and water transport were used, seeking to better understand the pathophysiology of the lung injury associated with this disease. PRINCIPAL FINDINGS: Prominent vascular damage was present in the lung microcirculation, with decreased CD34 and preserved aquaporin 1 expression. At the periphery and even inside the extensive areas of edema and intraalveolar hemorrhage, enlarged, apparently hypertrophic type I pneumocytes (PI) were detected and interpreted as a non-specific attempt of clearence of the intraalveolar fluid, in which ionic transport, particularly of sodium, plays a predominant role, as suggested by the apparently increased ENaC and aquaporin 5 expression. Connexin 43 was present in most pneumocytes, and in the cytoplasm of the more preserved endothelial cells. The number of type II pneumocytes (PII) was slightly decreased when compared to normal lungs and those of patients with septicemia from other causes, a fact that may contribute to the progressively low PI count, resulting in deficient restoration after damage to the alveolar epithelial integrity and, consequently, a poor outcome of the pulmonary edema and hemorrhage. CONCLUSIONS: Pathogenesis of lung injury in human leptospirosis was discussed, and the possibility of primary non-inflammatory vascular damage was considered, so far of undefinite etiopathogenesis, as the initial pathological manifestation of the disease.

Regression of albuminuria and hypertension and arrest of severe renal injury by a losartan-hydrochlorothiazide association in a model of very advanced nephropathy.

Treatments that effectively prevent chronic kidney disease (CKD) when initiated early often yield disappointing results when started at more advanced phases. We examined the long-term evolution of renal injury in the 5/6 nephrectomy model (Nx) and the effect of an association between an AT-1 receptor blocker, losartan (L), and hydrochlorothiazide (H), shown previously to be effective when started one month after Nx. Adult male Munich-Wistar rats underwent Nx, being divided into four groups: Nx+V, no treatment; Nx+L, receiving L monotherapy; Nx+LH, receiving the L+H association (LH), and Nx+AHHz, treated with the calcium channel blocker, amlodipine, the vascular relaxant, hydralazine, and H. This latter group served to assess the effect of lowering blood pressure (BP). Rats undergoing sham nephrectomy (S) were also studied. In a first protocol, treatments were initiated 60 days after Nx, when CKD is at a relatively early stage. In a second protocol, treatments were started 120 days after Nx, when glomerulosclerosis and interstitial fibrosis are already advanced. In both protocols, L treatment promoted only partial renoprotection, whereas LH brought BP, albuminuria, tubulointerstitial cell proliferation and plasma aldosterone below pretreatment levels, and completely detained progression of renal injury. Despite normalizing BP, the AHHz association failed to prevent renal damage, indicating that the renoprotective effect of LH was not due to a systemic hemodynamic action. These findings are inconsistent with the contention that thiazides are innocuous in advanced CKD. In Nx, LH promotes effective renoprotection even at advanced stages by mechanisms that may involve anti-inflammatory and intrarenal hemodynamic effects, but seem not to require BP normalization.

Characterization of leptospiral proteins that afford partial protection in hamsters against lethal challenge with Leptospira interrogans.

Leptospirosis is a worldwide zoonosis caused by pathogenic Leptospira. The whole-genome sequence of Leptospira interrogans serovar Copenhageni together with bioinformatic tools allow us to search for novel antigen candidates suitable for improved vaccines against leptospirosis. This study focused on three genes encoding conserved hypothetical proteins predicted to be exported to the outer membrane. The genes were amplified by PCR from six predominant pathogenic serovars in Brazil. The genes were cloned and expressed in Escherichia coli strain BL21-SI using the expression vector pDEST17. The recombinant proteins tagged with N-terminal 6xHis were purified by metal-charged chromatography. The proteins were recognized by antibodies present in sera from hamsters that were experimentally infected. Immunization of hamsters followed by challenge with a lethal dose of a virulent strain of Leptospira showed that the recombinant protein rLIC12730 afforded statistically significant protection to animals (44 %), followed by rLIC10494 (40 %) and rLIC12922 (30 %). Immunization with these proteins produced an increase in antibody titres during subsequent boosters, suggesting the involvement of a T-helper 2 response. Although more studies are needed, these data suggest that rLIC12730 and rLIC10494 are promising candidates for a multivalent vaccine for the prevention of leptospirosis.

Acute kidney injury in human leptospirosis: an immunohistochemical study with pathophysiological correlation.

Tubulointerstitial nephritis is a common clinicopathological finding in leptospirosis. Clinically, nonoliguric acute kidney injury (AKI), hypokalemia, sodium, and magnesium wasting frequently occur in leptospirosis. The exact mechanisms of renal involvement remain largely unclear. Immunohistochemistry to detect expression of the endogenous sodium/hydrogen exchanger isoform 3 (NHE 3), aquaporin 1 and 2, alpha-Na(+)K(+)ATPase, and sodium-potassium-chloride cotransporter in its NKCC2 isoform was performed on kidneys removed during autopsy of human leptospirosis cases and kidneys removed during autopsy of human non-leptospirosis cases with and without evidence of acute tubular necrosis (ATN). A decrease in NHE 3, aquaporin 1, and alpha-Na(+)K(+)ATPase expression occurred in proximal convoluted tubule cells. Expression of aquaporin 1 was preserved along the descending thin limb of the loop of Henle in the outer medulla. alpha-Na(+)K(+)ATpase expression was essentially preserved in the distal tubules, i.e., the thick ascending limb of the loop of Henle, macula densa, and distal convoluted tubule. Aquaporin 2 expression in the collecting tubules was enhanced compared to those of non-leptospirotic kidneys. NKCC2 cotransport isoform was expressed in the thick ascending limb of the loop of Henle and was essentially preserved in leptospirotic kidneys. Primary injury of the proximal convoluted tubules is regarded as the hallmark of the kidney in leptospirosis. Sodium and water transport are particularly affected with increased distal potassium excretion, hypokalemia, and polyuria. Enhanced expression of aquaporin 2 in medullary collecting tubules is probably an attempt to retain water during the nonoliguric phase of renal failure.

Endomyocardial fibrosis: pathological and molecular findings of surgically resected ventricular endomyocardium.

Endomyocardial fibrosis (EMF) is a restrictive cardiomyopathy of unknown etiology prevalent in tropical regions affecting the inflow tract and apex of one or both ventricles, which show fibrous thickening of the endocardium and adjacent myocardium. Surgical treatment is recommended for patients in functional classes III or IV (New York Heart Association). The gross and histological features of the heart have been comprehensively studied in autopsies, but studies in surgical samples are still lacking. Histological and immunohistochemical features of EMF in surgical samples collected from 32 patients were described and correlated with clinical data. Polymerase chain reaction (PCR) and reverse transcription-PCR, performed on formalin fixed endomyocardial samples, were used retrospectively to detect genomes of certain cardiotropic viruses and Toxoplasma gondii. Ventricular endocardium was thickened by superficial acellular hyaline collagen fibers type I and III, with predominance of the former type. Besides fibrosis, a chronic inflammatory process and an anomalous lymphatic rich vascular pattern were observed in the deep endocardium, connected to the terminal coronary circulation of the myocardium, which might be an important pathological finding concerning EMF pathogenesis. Molecular analysis of the endomyocardium revealed high incidence of cardiotropic infective agents (6/12, 50%); however, their role in the disease pathogenesis is still controversial.

Lsa21, a novel leptospiral protein binding adhesive matrix molecules and present during human infection.

BACKGROUND: It has been well documented over past decades that interaction of pathogens with the extracellular matrix (ECM) plays a primary role in host cell attachment and invasion. Adherence to host tissues is mediated by surface-exposed proteins expressed by the microorganisms during infection. The mechanisms by which pathogenic leptospires invade and colonize the host remain poorly understood since few virulence factors contributing to the pathogenesis of the disease have been identified. Whole-genome sequencing analysis of L. interrogans allowed identification of a repertoire of putative leptospiral surface proteins. RESULTS: Here, we report the identification and characterization of a new leptospiral protein that exhibits extracellular matrix-binding properties, called as Lsa21 (leptospiral surface adhesin, 21 kDa). Compatible with its role in adhesion, the protein was shown to be surface-exposed by indirect immunofluorescence. Attachment of Lsa21 to laminin, collagen IV, and plasma fibronectin was specific and dose dependent. Laminin oxidation by sodium metaperiodate reduced the protein-laminin interaction in a concentration-dependent manner, indicating that laminin sugar moieties are crucial for this interaction. The gene coding for Lsa21 is present in pathogenic strains belonging to the L. interrogans species but was not found in the saprophytic L. biflexa serovar Patoc strain Patoc 1. Loss of gene expression occurs upon culture attenuation of pathogenic strains. Environmental factors such as osmolarity and temperature affect Lsa21 expression at the transcriptional level. Moreover, anti-Lsa21 serum labeled liver and kidney tissues of human fatal cases of leptospirosis. CONCLUSION: Our data suggest a role of Lsa21 in the pathogenesis of leptospirosis.

TNF blockade aggravates experimental chronic Chagas disease cardiomyopathy.

Chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi, is an inflammatory dilated cardiomyopathy associated with increased circulating levels of TNF-alpha. We investigate whether TNF blockade with Etanercept during the chronic phase of T. cruzi infection could attenuate experimental CCC development. The effect of Etanercept was evaluated after 11 months of T. cruzi infection on survival, parasitism, left ventricular function, intensity of myocarditis, fibrosis, and left ventricular mRNA expression of cytokines and TNF-alpha-induced genes. Left ventricular function was significantly reduced in treated animals as compared to infected untreated animals. Blood and cardiac parasitism as well as survival rate were not altered with Etanercept treatment. Inflammatory infiltrates were located predominantly in the subendocardic region in treated animals, whereas in untreated animals inflammation was scattered throughout the myocardium. Left ventricular mRNA IL-10 expression was significantly higher, and iNOS, significantly lower in treated than in untreated animals. mRNA expression of TNF-alpha, IFN-gamma, TGF-beta, A20 and ANP was similar in both groups. Our results suggest that TNF-alpha/LT-alpha blockade with Etanercept enhances left ventricular dysfunction in T. cruzi-induced chronic cardiomyopathy and the absence of TNF signaling may be deleterious to the failing heart in Chagas disease cardiomyopathy.

Expression of beta-1 integrin in human developing salivary glands and its parallel relation with maturation markers: in situ hybridisation and immunofluorescence study.

BACKGROUND AND OBJECTIVE: Salivary gland development entails co-ordinated processes involving complex molecular interactions in which integrins have a fundamental role. The integrins are a family of heterodimeric transmembrane receptors comprising alpha and beta subunits that mediate intercellular and extracellular signals involved in the organisation of cells in tissues and organs during development. The beta-1 integrin in particular have been implicated in proliferation and differentiation of cells involved in the development of epithelial tissues. To understand the role of beta-1 integrin in salivary gland development we have studied its expression in human foetal tissues. DESIGN: In situ hybridisation was used to compare the expression and localisation of integrin beta-1 with differentiation markers in developing human salivary glands obtained from foetuses of 8-24 weeks gestation. RESULTS: Integrin beta-1 first appeared during bud stage in a few cells and its distribution increased as salivary gland morphogenesis progressed. This increased pattern of beta-1 integrin expression was coincident with the appearance of the differentiation markers CK14, CK low MW and smooth-muscle actin. CONCLUSIONS: The developmentally regulated expression of integrin beta-1 in association with the establishment of a mature phenotype indicated by salivary gland tissue differentiation markers is suggestive of its role in salivary gland morphogenesis.

Reversal of renal tubule transporter downregulation during severe leptospirosis with antimicrobial therapy.

Tubular dysfunction is a hallmark of severe leptospirosis. Antimicrobial therapy is thought to interfere on renal involvement. We evaluated the expression of a proximal tubule type-3 Na+/H+ exchanger (NHE3) and a thick ascending limb Na+-K+-2Cl(-) cotransporter (NKCC2) in controls and treated hamsters. Animals infected by a serovar Copenhageni isolate, were treated or not with ampicillin (AMP) and/or N-acetylcysteine (NAC). Leptospiral antigen(s) and expression of renal transporters were evaluated by immunohistochemistry, and serum thiobarbituric acid (TBARS) was quantified. Infected hamsters had high amounts of detectable leptospiral antigen(s) in target tissues while renal expression of NHE3 and NKCC2 decreased. Ampicillin treatment was associated with minimal or no detection of leptospiral antigens, normal expression of NHE3 and NKCC2 transporters, and reduced levels of TBARS. NAC effect was restricted to lowering TBARS. Early and late AMP treatment rescued tubular defects in severe leptospirosis disease, and there was no evidence of benefit from antioxidant therapy.

Prevalence of celiac disease in an urban area of Brazil with predominantly European ancestry.

AIM: To determine the prevalence of celiac disease in a group of volunteer blood donors at a blood bank in the city of Curitiba, Brazil through detection of the serum marker immunoglobulin A (IgA) antitransglutaminase antibody. METHODS: Blood samples collected from 2086 healthy subjects at the Paraná State Center for Hematology and Hemotherapy in Curitiba were submitted to ELISA testing for the IgA antitransglutaminase antibody. Positive samples received IgA antiendomysium antibody test through indirect immunofluorescence using human umbilical cord as substrate. Subsequently, patients who were positive on both tests underwent small bowel (distal duodenum) biopsy. RESULTS: Six subjects, four males and two females, tested positive for the two serum markers. Five of the six were submitted to intestinal biopsy (one declined the procedure). Biopsy results revealed changes in the distal duodenum mucosa (three classified as Marsh IIIb lesions and two as Marsh II lesions). Most donors diagnosed having celiac disease presented multiple symptoms (gastrointestinal tract complaints). One donor reported having a family history of celiac disease (in a niece). CONCLUSION: Among apparently healthy blood donors, the prevalence of biopsy-confirmed celiac disease was approximately 1:417, similar to that seen in European countries.

Histologic study of colonic mucosa in patients with chronic diarrhea and normal colonoscopic findings.

BACKGROUND: There are controversies about the importance of biopsies of normal colon mucosa in the investigation of patients with chronic diarrhea. STUDY: Colonic and terminal ileum biopsies of 167 patients were reviewed. In 5 patients, used as controls, colonoscopy was done due to family history of colon cancer. RESULTS: The 5 patients without symptoms had no histologic abnormalities. The histologic findings in 162 patients with chronic diarrhea were as follows: 110 patients (67.9%) with normal histology, microscopic colitis not otherwise specified, and isolated small granulomas; 17 (10.5%) patients had findings of borderline diagnostic significance, including possible collagenous colitis, some features of lymphocytic colitis and melanosis coli; and 35 (21.6%) patients, with diagnostic significant histologic findings as collagenous colitis, lymphocytic colitis, minimal change microscopic colitis, eosinophilic colitis, pericrypt eosinophilic enterocolitis, intestinal spirochetosis, schistosomiasis, and Crohn's disease. Of the 52 patients with either borderline or significant diagnostic abnormalities, in 8 (15.4%) the diagnosis was done only with a proximal study (ascending, transverse, or descending colons). CONCLUSIONS: Histologic lesions of possible diagnostic value could exist in 32.1% of chronic diarrhea patients with normal colonoscopy, which can justify, in certain cases, mucosa biopsies, which might contribute for a more precise etiologic diagnosis; also, the distribution of these histologic changes has pointed out the importance of having all colon segments biopsied.