Histoplasmose em pacientes imunodeprimidos: estudo de 18 casos observados em Uberlândia, MG / Histoplasmosis in immunodepressed patients: a study of eighteen cases observed in Uberlândia, Minas Gerais State, Brazil

Os autores descrevem dezoito casos de histoplasmose observados em pacientes imunodeprimidos, sendo 17 com SIDA e um associado à cirrose hepática alcoólica. O diagnóstico de histoplasmose foi obtido através do isolamento do fungo em cultura de LCR, sangue e medula óssea ou por exame histopatológico obtido por biópsia ou necrópsia. A idade média dos pacientes foi de 35,8 anos, sendo 13 (72,2 por cento) do sexo masculino. Em geral a doença mostrou-se disseminada com acometimento por ordem de freqüência de: pele (38,8 por cento), medula óssea (27,7 por cento), mucosa nasofaringeana (22,2 por cento), pulmäo (22,2 por cento), cólon (11,1 por cento), SNC (5,5 por cento) e esôfago (5,5 por cento). Adenomegalia (50 por cento), hepatomegalia (77,7 por cento) e esplenomegalia (61,1 por cento) também foram observados com muita freqüência. Hematologicamente observou-se mais comumente pancitopenia (33,3 por cento). Onze dos 18 pacientes receberam tratamento, sendo 9 com anfotericina B e 2 com itraconazol; 8 obtiveram boa resposta clínica e todos receberam terapia de manutençäo com anfotericina B ou derivado triazólico. Este trabalho enfatiza a importância desta micose em pacientes imunodeprimidos, particularmente em pacientes com SIDA onde a infecçäo tende a acometer o sistema macrofágico-linfóide e o tegumento cutâneo.

[Histoplasmosis in immunodepressed patients: study of 18 cases seen in Uberlândia, MG]. / Histoplasmose em pacientes imunodeprimidos: estudo de 18 casos observados em Uberlândia, MG.

The diagnosis of histoplasmosis was made by isolation of Histoplasma capsulatum from cerebrospinal fluid (CSF), blood and bone marrow or by histopathologic (biopsy or post mortem) examination. The mean age of the patients was 35.8 years; 13 patients were male (72.2%). The disease was disseminated, with the following distribution:skin (38.8%), bone marrow (27.7%), nasopharyngeal mucosa (22.2%), lungs (22.2%), colon (11.1%), central nervous system (5.5%) and esophagus (5.5%). Adenomegaly (50%), hepatomegaly (77.7%) and splenomegaly (61.1%) were frequently seen. The most common hematologic abnormality was pancytopenia (33.3%) of the patients. Eleven patients were treated, 9 with amphotericin B and 2 with itraconazole. Eight had good clinical improvement and all of them were given amphotericin B or a triazolic as maintenance therapy. This study emphasize the importance of this mycosis in immunodepressed patients, specially AIDS patients, in whom the infection tends to invade the macrophagic-lymphoid system and preferentially the cutaneous tegument.

[Major histocompatibility system as a risk factor for alcoholic liver disease]. / El sistema mayor de histocompatibilidad como factor de riesgo de la enfermedad hepática alcohólica.

Several associations between alleles of the major histocompatibility system and alcoholic liver disease have been described. However, these are weak and change from one population to another. The aim of this work was to search for a possible genetic risk factor for alcoholic liver disease among Chilean alcoholics. We studied blood groups, serum proteins and HLA antigens in 39 alcoholic cirrhotics, 104 asymptomatic alcoholics and 44 non alcoholic controls. Asymptomatic alcoholics were also subjected to a percutaneous liver biopsy that showed moderate to severe histological liver damage in 46 subjects (44%). No differences in the studied genetic markers, were found among the four groups. It is concluded that this study does not confirm previously reported associations between genetic markers and alcoholic liver disease.

Alteraçöes imunitárias na cirrose hepática alcoólica / Immunologic changes in alcoholic liver cirrhosis

A cirrose hepática alcoólica cursa com alteraçöes imunitárias que podem ser atribuídas à hepatopatia em si, ao alcool e à desnutriçäo do paciente. Tais alteraçöes envolvem a imunidade celular e humoral, caracterizando-se por aumento de imunoglobulinas, diminuiçäo da resposta cutânea tardia e da resposta linfoproliferativa aos mitógenos, diminuiçäo de proteínas do sistema complemento (C3 C4) e queda (IL2 e çIF), ou elevaçäo (IL1, TNF, IL6, E IL8) de citoquinas. Paralelamente à imunossupressäo sistêmica comum a todos os pacientes, há uma imunoestimulaçäo, a nível hepático, com provável predisposiçäo genética, que norteia as características do curso da auto-agressäo hepática, em cada paciente. A imunossupressäo sistêmica poderia ser responsabilizada pelas infecçöes periódicas e neoplasias que invariavelmente acometem estes pacientes e pode ser fundamentada, genericamente, na exaustäo da defesa sistêmica: a) pelo menor clearance de bactérias e/ou toxinas; b) pela menor produçäo hepática de componentes do sistema complemento; c) pela deficiência de citoquinas (IL2 e çIF), e d) pela deficiência de nutrientes antioxidantes e/ou participantes dos mecanismos da defesa imune. A imunoestimulaçäo hepática, responsável pela autoagressäo e perpetuaçäo da doença, é caracterizada pela migraçäo preferencial de linfócitos T citotóxicos e de neutrófilos, ao fígado, estimulados por fatores, como os corpos de Mallory, acetaldeído ou mesmo autoanticorpos. Além disso, a elevaçäo local das citoquinas, (IL1, TNF, IL6 E IL8) poderia responder pela maior quimiotaxia aos fagócictos (IL8) ou por parte do dano hepático (TNF) facilitado pela menor defesa antioxidante do fígado cirrótico. As possíveis intervençöes atenuadoras ou revertedoras destas alteraçöes imunitárias passam, obrigatoriamente, pela retirada do álcool e recuperaçäo nutricional do paciente, particularmente nos aspectos protéico-energético e antioxidante. Ainda necessitando de maiores estudos, há a possibilidade do uso de anticorpos monoclonais contra as citoquinas de açäo catabólica

El sistema mayor de histocompatibilidad como factor de riesgo de la enfermedad hepática alcohólica / Major histocompatibility system as a risk factor of alcoholic hepatic disease

Several associations between alleles of the major histocompatibility system and alcoholic liver disease have been described. However, these are weak and changes from one population to another. The aim of this work was to search for a possible genetic risk factor for alcoholic liver disease among chilean alcoholics. We studied blood groups, serum proteins and HLA antigens in 39 alcoholic cirrhotics, 104 asymptomatic alcoholics and 44 non alcoholic controls. Asymptomatic alcoholics were also subjected to a percutaneous liver biopsy that showed moderate to severe histological liver damage in 46 subjects (44 percent). No differences in the studied genetic markers, were found among the four groups. It is concluded that this study does not confirm previously reported associations between genetic markers and alcoholic liver disease

[Immunologic changes in alcoholic liver cirrhosis]. / Alterações imunitárias na cirrose hepática alcoólica+.

The alcoholic liver cirrhosis usually causes overall immunological changes which might be attributed to either the hepatic disease itself, to ethanol action and/or to malnourishment of the patient. These immune abnormalities comprise both cellular and humoral immunity, consisting of increased immunoglobulin levels, depressed late-skin response to antigens, lowered proliferative response of lymphocytes to mitogens, lower plasma levels of complement proteins (C3 and C4) and by either lower (IL2 and gamma IF) or increased (IL1, TNF, IL6 and IL8) cytokine levels. Parallel to the systemic immune suppression found in most patients, there is also a concomitant local, genetically based, immune stimulation at the liver level which leads to hepatic self-aggression. The systemic immune-suppression could be responsible for periodical infections or neoplasia found in these patients. The possible factors for the immune exhaustion are: a) lower hepatic clearance of toxins and/or bacteria; b) lower hepatic synthesis of complement components; c) cytokines (IL2 and gamma IF) deficiencies, and d) deficiencies of nutrients related to the antioxidant and/or immune defense mechanisms. The immune stimulation of the liver self aggression is characterized by the preferential migration of cytotoxic T cell and neutrophils to the liver, following stimulatory factors such as Mallory bodies, acetaldehyde and/or antibodies. Moreover, the local increase of cytokines (IL1, TNF, IL6 and IL8) levels would be liable for the local phagocyte chemotaxy (IL8) or part of liver injury (TNF) eased by the lower antioxidant defense of the cirrhotic liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibición de rosetas E en la enfermedad hepática alcohólica / E rosette inhibition in alcoholic liver disease

Hemos estudiado la formación de Rosetas E y su inhibición en pacientes alcoholistas crónicos, con y sin cirrosis hepática. Los individuos fueron separados en 3 grupos: normales (n=21); alcoholistas sin lesión hepática (n=15) y alcoholistas con cirrosis (n=26). Se realizaron Test de Inhibición de Rosetas E, utilizando suero de los individuos en estudio, enfrentados con linfocitos de individuos sanos, efectuando 4 ensayos simultáneos: I.I. -S/A; I.I. -C/A; I.E. -S/A y I.E. -C/A. Analizados estadísticamente los resultados, observamos diferencias altamente significativas entre los pacientes con cirrosis y los controles, así como entre los cirróticos y los alcoholistas sin lesión hepática. Los ensayos que utilizaron la I.E. fueron los más eficientes para discriminar los grupos de individuos en estudio, siendo los que utilizan el suero no absorbido, los de mejor diferenciación. Con esta técnica observamos que 20/21 de los individuos control presentan inhibición inferior al 15//, y que todos los individuos con inhibición superior al 30// fueron cirróticos con sólo 2 excepciones. Proponemos la existencia de factores solubles en suero que provocan inhibición de la formación de rosetas E

Inhibición de rosetas E en la enfermedad hepática alcohólica / E rosette inhibition in alcoholic liver disease

Hemos estudiado la formación de Rosetas E y su inhibición en pacientes alcoholistas crónicos, con y sin cirrosis hepática. Los individuos fueron separados en 3 grupos: normales (n=21); alcoholistas sin lesión hepática (n=15) y alcoholistas con cirrosis (n=26). Se realizaron Test de Inhibición de Rosetas E, utilizando suero de los individuos en estudio, enfrentados con linfocitos de individuos sanos, efectuando 4 ensayos simultáneos: I.I. -S/A; I.I. -C/A; I.E. -S/A y I.E. -C/A. Analizados estadísticamente los resultados, observamos diferencias altamente significativas entre los pacientes con cirrosis y los controles, así como entre los cirróticos y los alcoholistas sin lesión hepática. Los ensayos que utilizaron la I.E. fueron los más eficientes para discriminar los grupos de individuos en estudio, siendo los que utilizan el suero no absorbido, los de mejor diferenciación. Con esta técnica observamos que 20/21 de los individuos control presentan inhibición inferior al 15//, y que todos los individuos con inhibición superior al 30// fueron cirróticos con sólo 2 excepciones. Proponemos la existencia de factores solubles en suero que provocan inhibición de la formación de rosetas E (AU)

[E rosette inhibition in alcoholic liver disease]. / Inhibición de rosetas E en la enfermedad hepática alcohólica.

Various studies performed in chronic alcoholic patients have demonstrated immunologic alterations, which have been described more often in patients with alcoholic hepatitis or liver cirrhosis. We have observed that the serum of some patients with alcoholic liver cirrhosis produces the inhibition of E rosette formation by T lymphocytes. This observation induced us to study E rosette formation and its probable inhibition by the serum of chronic alcoholic patients. Subjects were split into three groups: Group 1: n = 21. Normal individuals. Group 2: n = 15. Chronic alcoholic patients without cirrhosis. Group 3: n = 26. Chronic alcoholic patients with histologically demonstrated liver cirrhosis. E rosette and E rosette inhibition (TIRE) sera tests were performed utilizing subject's sera tested against lymphocytes of normal individuals not related to group 1. The results found are listed in detail in Table 1 (mean = -SD) and Figure 1 (median), for each of the test groups. We applied unifactorial variance analysis and observed highly significant differences between the groups studied in all tests performed. It was found that tests that utilized I.E. discriminate most efficiently among the three groups of patients and that those which utilize unabsorbed assay serum (S/A) yield the best differentiation. Using this last assay it was observed that 20/21 control individuals showed less than 15% inhibition. On this basis, we decided to separate the results into 15% regular intervals (Table 3). Inhibition above 30% was found only in cirrhotic patients with the exception of one individual of the control group and one non-cirrhotic alcoholic patient with no alcoholic liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Enfermedad alcohólica del hígado (EHA)

Alcohol consumption with all its severe organic complications has become one of the leading causes of morbidity and mortality in United States. In the metropolitan areas, alcohol consumption is the third cause of death between people aged 30 to 64. Latest estimates have shown that 20 percent of the total cost of health care is related to alcohol. Liver disease secondary to alcohol has been studied extensively and all its clinico-pathological consequences described. Alcoholic hepatitis characterized by anorexia, jaundice, hepatomegaly, fever, mental changes, leukocytosis and neutrophilia has been described associated to elevated bilirubin, low albumin, high AST levels and prolonged prothrombin time; histologically the picture has the following microscopic findings: degenerative changes of liver cells such as "ballooning" mainly around the terminal hepatic veins, acute and chronic inflammatory infiltrates and latest, pericellular fibrosis in the centrolobular area. Some patients develop sclerosing hyaline necrosis consistent in collapse of hepatocytes, alcoholic hyaline accumulation, neutrophilic inflammation and severe fibrosis leading to a functional obstruction of the hepatic veins, portal hypertension, ascitis and liver failure. A characteristic cytosqueletic abnormality is the Mallory Body that for many authorities constitutes the hallmark of alcoholic hepatitis. Recently the role of megamitochondrias in this entity has been unveiled showing that patients with increased number have better prognosis that the group with few megamitochondrias. Finally a significant role for cellular immunity, cytoquines, histocompatibility antigens and malnutrition has been found determinant in order to explain progression of disease after alcohol discontinuation, and prognosis after nutritional therapy.

HLA Gm systems and susceptibility to alcoholic cirrhosis: a study of mixed-race subjects.

The fact that only a small percentage of excessive drinkers develop cirrhosis may be due to a genetic susceptibility to the disease. In order to identify possible genetic risk factors for cirrhosis, we studied mixed-race (Negroid-Caucasian) inhabitants of the French West Indies and compared: (1) the frequency of 51 HLA-A, -B, -C and -DR antigens in 41 subjects with alcoholic cirrhosis and in two control groups consisting of 41 excessive drinkers free of liver disease and 51 healthy non-drinkers; and (2) the frequency of Gm and Km haplotypes in the same groups. Analysis of the Gm system also determined the patients' ethnic origins. The frequency of the HLA-A2 antigen was significantly higher in the cirrhotic patients than in the control group of excessive drinkers (chi 2 = 4.47; P less than 0.05), while that of the HLA-B15 antigen was significantly lower (chi 2 = 5.14; P less than 0.05). The frequency of the Cw4 antigen was significantly higher in the cirrhotics than in the non-drinkers (chi 2 = 5.59; P less than 0.05). However, these differences did not persist when the number of comparisons was taken into account. The frequency of Gm and Km haplotypes was not significantly different in the three groups. In conclusion, complementary studies are required to determine the value of the Gm-Km system as a marker of susceptibility to alcoholic cirrhosis. Our results do not identify an association between HLA antigens and cirrhosis specific to a negroid ethnic group and support the notion that such an association is weak.

Cell-mediated immunity in alcoholic liver cirrhosis

Se efectuaron estudios de inmunidad mediada por células en 25 pacientes con cirrosis hepática alcohólica (CA) activa e inactiva. Fueron observadas diversas alteraciones inmunológicas: aumento de los linfocitos B y disminución de los linfocitos T. Sólo en los enfermos con CA activa la relación H/S era más baja que los valores normales. Los linfocitos NK (Leu 7 +) y la función citotóxica natural killer estaban aumentados; sin embargo el índice NK/Leu 7 estaba disminuido. En los enfermos con CA activa la proliferación blástica a la PHA estaba descendida. Se observó un déficit de la función supresora inducida por Con A en los pacientes con CA. En los cocultivos alogeneicos de linfocitos supresores de los pacientes y células efectoras normales, se observó un descenso de la función supresora T-T con respecto a los cultivos autólogos normales. No se encontraron diferencias cuando los linfocitos de normales fueron inducidos con Con A y se cocultivaron con linfocitos efectores de los enfermos. Estos resultados indican que los linfocitos de los pacientes con CA presentan anomalías en la inducción de supresión por Con A

Cell-mediated immunity in alcoholic liver cirrhosis

Se efectuaron estudios de inmunidad mediada por células en 25 pacientes con cirrosis hepática alcohólica (CA) activa e inactiva. Fueron observadas diversas alteraciones inmunológicas: aumento de los linfocitos B y disminución de los linfocitos T. Sólo en los enfermos con CA activa la relación H/S era más baja que los valores normales. Los linfocitos NK (Leu 7 +) y la función citotóxica natural killer estaban aumentados; sin embargo el índice NK/Leu 7 estaba disminuido. En los enfermos con CA activa la proliferación blástica a la PHA estaba descendida. Se observó un déficit de la función supresora inducida por Con A en los pacientes con CA. En los cocultivos alogeneicos de linfocitos supresores de los pacientes y células efectoras normales, se observó un descenso de la función supresora T-T con respecto a los cultivos autólogos normales. No se encontraron diferencias cuando los linfocitos de normales fueron inducidos con Con A y se cocultivaron con linfocitos efectores de los enfermos. Estos resultados indican que los linfocitos de los pacientes con CA presentan anomalías en la inducción de supresión por Con A (AU)

HLA y cirrosis: la importancia de los antígenos de histocompatibilidad en el desarrollo de una cirrosis alcohólica / HLA and cirrhosis: the importance of HLA antigens in the course of alcoholic cirrhosis

Se presenta una investigación tendiente a aclarar la posible existencia de una relación entre la estructura antígena HLA de un individuo y la eventualidad de que éste desarrolle o no una cirrosis al ingerir alcohol en forma crónica. A estos efectos se integró un equipo multidisciplinario conformado por clínicos, genetistas, psiquiatras y patólogos, integrantes de 4 Cátedras de la Facultad de Medicina. Se diseño un trabajo prospectivo de investigación que se desarrolló en el transcurso de los años 1982 a 1984. Se estudiaron 47 alcoholistas portadores de una Cirrosis Portal, 19 alcoholistas No Cirróticos y 250 testigos sanos. Los cirróticos fueron biopsiados para confirmar histopatológicamente la enfermedad y los alcoholistas no cirróticos fueron biopsiados para confirmar que no la tuvieran. En todos los grupos se determinaron los antígenos de histocompatibilidad indicados en la Tabla I. Se efectuaron los cálculos estadísticos que incluyeron X con corrección de Yates, probabilidad corregida, y el cálculo del riesgo relativo (R.R), (este último especificado en la Tabla II). En el grupo de alcoholistas cirróticos, se comprobó una asociación positiva con el HLA Bw40, con un valor estadístico muy significativo: Pc<0,005; RR=3,93. (Tabla IV). No se comprobó predominancia de este antígeno en los etilistas no cirróticos (Tabla V). Se concluye que la presencia del HLA Bw40 aumenta casi 4 veces el riesgo de desarrollar una cirrosis en los pacientes que ingieren alcohol en forma crónica. Su presencia no influye estadísticamente en nuestra serie en el riesgo de que un individuo se convierta en alcoholista. Esta investigación, de comprobarse en series mayores, que este equipo de trabajo está desarrollando, permitirá en el futuro determinar criterios de prevención de la cirrosis alcohólica

HLA y cirrosis: la importancia de los antígenos de histocompatibilidad en el desarrollo de una cirrosis alcohólica / HLA and cirrhosis: the importance of HLA antigens in the course of alcoholic cirrhosis

Se presenta una investigación tendiente a aclarar la posible existencia de una relación entre la estructura antígena HLA de un individuo y la eventualidad de que éste desarrolle o no una cirrosis al ingerir alcohol en forma crónica. A estos efectos se integró un equipo multidisciplinario conformado por clínicos, genetistas, psiquiatras y patólogos, integrantes de 4 Cátedras de la Facultad de Medicina. Se diseño un trabajo prospectivo de investigación que se desarrolló en el transcurso de los años 1982 a 1984. Se estudiaron 47 alcoholistas portadores de una Cirrosis Portal, 19 alcoholistas No Cirróticos y 250 testigos sanos. Los cirróticos fueron biopsiados para confirmar histopatológicamente la enfermedad y los alcoholistas no cirróticos fueron biopsiados para confirmar que no la tuvieran. En todos los grupos se determinaron los antígenos de histocompatibilidad indicados en la Tabla I. Se efectuaron los cálculos estadísticos que incluyeron X con corrección de Yates, probabilidad corregida, y el cálculo del riesgo relativo (R.R), (este último especificado en la Tabla II). En el grupo de alcoholistas cirróticos, se comprobó una asociación positiva con el HLA Bw40, con un valor estadístico muy significativo: Pc<0,005; RR=3,93. (Tabla IV). No se comprobó predominancia de este antígeno en los etilistas no cirróticos (Tabla V). Se concluye que la presencia del HLA Bw40 aumenta casi 4 veces el riesgo de desarrollar una cirrosis en los pacientes que ingieren alcohol en forma crónica. Su presencia no influye estadísticamente en nuestra serie en el riesgo de que un individuo se convierta en alcoholista. Esta investigación, de comprobarse en series mayores, que este equipo de trabajo está desarrollando, permitirá en el futuro determinar criterios de prevención de la cirrosis alcohólica (AU)

[The importance of HLA antigens in alcoholic cirrhosis]. / HLA y cirrosis. La importancia de los antígenos de histocompatibilidad en el desarrollo de una cirrosis alcoholica.

The existence of a relationship between HLA and the possibility of the development of an alcoholic cirrhosis is researched in this paper. This work was done from 1982 to 1984, by the staff of four clinics of the Medicine School of the University of Uruguay. We studied 47 alcoholics with portal cirrhosis, 19 non-cirrhotic alcoholics and 250 healthy nonalcoholic controls. We confirmed with liver biopsy the cirrhosis in the first group and in the second, liver biopsy was performed in order to assure that they had no cirrhosis. Table I shows the histocompatibility antigens which were tested in the 3 groups. Levels of significance were obtained from exact Fisher test with Yates correction for discontinuity; Pc (corrected P) and RR (relative risk) were also determined. In the alcoholics with portal cirrhosis, the HLABW40 showed a Pc less than 0,005 (RR = 3,93). In the non-cirrhotic alcoholics no significative association was found. We conclude that the carrier of the genetic marker HLABW40, has almost 4 times more chances to develop a cirrhosis as consequence of chronic alcoholic abuse. The presence of this marker, in our patients, has no association with the possibility that an individual becomes an alcoholic abuser. We think that if this data are confirmed in a wider study, some guidelines for the prevention of alcoholic cirrhosis may be established.