RESUMEN
Thiopurine-methyltransferase (TPMT) and nudix-hydrolase-15 (NUDT15) are enzymes relevant to the metabolism of thiopurine medications, used to treat immunologic disorders and malignancies. Standard dosing administered in the setting of TPMT/NUDT15 dysfunction can cause excessive cytotoxic metabolites and life-threatening complications. We describe an adolescent with high-risk B-cell acute lymphoblastic leukemia (ALL) whose TPMT/NUDT15 status was unknown due to lack of insurance approval for genetic testing. He subsequently developed myelosuppression and severe veno-occlusive disease (VOD) after receiving 6-mercaptopurine (6-MP). Our patient provides an example of a very rare 6-MP-related toxicity and the potential benefit of TPMT/NUDT15 screening before initiating thiopurine therapy.
Asunto(s)
Antimetabolitos Antineoplásicos , Enfermedad Veno-Oclusiva Hepática , Mercaptopurina , Humanos , Mercaptopurina/efectos adversos , Mercaptopurina/administración & dosificación , Masculino , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Enfermedad Veno-Oclusiva Hepática/patología , Adolescente , Antimetabolitos Antineoplásicos/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Metiltransferasas/genéticaRESUMEN
BACKGROUND AND AIM: Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. MATERIAL AND METHODS: Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS + CZ (MCT + CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48 h after MCT administration. Postoperative survival rates were evaluated (n = 9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. RESULTS: The cumulative 10-day postoperative survival rate was significantly higher in the SOS + CZ group than in the SOS group (88.9% vs 33.3%, P = 0.001). Total SOS scores were significantly lower in the SOS + CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS + CZ group than in the SOS group on POD 1 (86.1 ± 8.2% vs 63.8 ± 9.3%, P = 0.003). CONCLUSION: Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.
Asunto(s)
Cilostazol , Modelos Animales de Enfermedad , Hepatectomía , Enfermedad Veno-Oclusiva Hepática , Inhibidores de Fosfodiesterasa 3 , Animales , Enfermedad Veno-Oclusiva Hepática/prevención & control , Enfermedad Veno-Oclusiva Hepática/etiología , Enfermedad Veno-Oclusiva Hepática/patología , Cilostazol/farmacología , Hepatectomía/efectos adversos , Masculino , Inhibidores de Fosfodiesterasa 3/farmacología , Inhibidores de Fosfodiesterasa 3/uso terapéutico , Pronóstico , Oxaliplatino/efectos adversos , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/tratamiento farmacológico , Tasa de Supervivencia , Ratas , Tetrazoles/administración & dosificación , Tetrazoles/farmacología , Neoplasias Colorrectales/patología , Hígado/patología , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids (PA-HSOS) is a complication of drug-induced liver damage. Few studies have examined the relationship between pathological changes and clinical circumstances in PA-HSOS. The Drum Tower Severity Scoring System (DTSS) was developed using prognostic indicators from clinical treatment outcomes. We hypothesized that the severity of pathological damage is consistent with DTSS. AIMS: We aimed to improve our understanding and assessment of vascular liver injury disease histopathology by studying larger sample sizes of human histopathological samples. We also wanted to confirm the link between histopathological findings and DTSS. METHODS: The study included 62 patients with PA-HSOS who underwent transjugular liver biopsy. Their hepatic pathological tissues were evaluated. Analyses of linear regression and Spearman's correlation were employed to examine the relationship between DTSS and pathological characteristics. RESULTS: Clinical performance and the DTSS score were used to determine histopathological severity. The sinusoidal congestion area (SCA), central venous endothelial injury (CVEI), and fibrinoid exudation in congestion foci (FECF) were significant indicators. SCA was linearly related to the DTSS score. CONCLUSION: Our findings show that hepatic pathological characteristics correlate with DTSS scores in PA-HSOS. SCA, CVEI, and FECF may be helpful for determining PA-HSOS severity.
Asunto(s)
Enfermedad Veno-Oclusiva Hepática , Hígado , Alcaloides de Pirrolicidina , Índice de Severidad de la Enfermedad , Humanos , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Enfermedad Veno-Oclusiva Hepática/patología , Alcaloides de Pirrolicidina/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Hígado/patología , Adulto , Anciano , Estudios Retrospectivos , Biopsia , Modelos LinealesRESUMEN
Hepatic sinusoidal obstruction syndrome (HSOS) via exposure to pyrrolizidine alkaloids (PAs) is with high mortality and there is no effective treatment in clinics. Bear bile powder (BBP) is a famous traditional animal drug for curing a variety of hepatobiliary diseases such as cholestasis, inflammation, and fibrosis. Here, we aim to evaluate the protective effect of BBP against HSOS induced by senecionine, a highly hepatotoxic PA compound. Our results showed that BBP treatment protected mice from senecionine-induced HSOS dose-dependently, which was evident by improved liver histology including reduced infiltration of inflammatory cells and collagen positive cells, alleviated intrahepatic hemorrhage and hepatic sinusoidal endothelial cells, as well as decreased conventional serum liver function indicators. In addition, BBP treatment lowered matrix metalloproteinase 9 and pyrrole-protein adducts, two well-known markers positively associated with the severity of PA-induced HSOS. Further investigation showed that BBP treatment prevents the development of liver fibrosis by decreasing transforming growth factor beta and downstream fibrotic molecules. BBP treatment also alleviated senecionine-induced liver inflammation and lowered the pro-inflammatory cytokines, in which tauroursodeoxycholic acid played an important role. What's more, BBP treatment also decreased the accumulation of hydrophobic bile acids, such as cholic acid, taurocholic acid, glycocholic acid, as well. We concluded that BBP attenuates senecionine-induced HSOS in mice by repairing the bile acids homeostasis, preventing liver fibrosis, and alleviating liver inflammation. Our present study helps to pave the way to therapeutic approaches of the treatment of PA-induced liver injury in clinics.
Asunto(s)
Animales , Ratones , Bilis , Ácidos y Sales Biliares , Células Endoteliales/metabolismo , Enfermedad Veno-Oclusiva Hepática/patología , Inflamación/patología , Cirrosis Hepática/tratamiento farmacológico , Polvos , Alcaloides de Pirrolicidina/efectos adversos , UrsidaeRESUMEN
ABSTRACT Purpose: To investigate the underlying mechanism of hepatic sinusoidal obstruction syndrome (HSOS) induced by Gynura segetum by measuring autophagy in mouse models. Methods: The model group was administered G. segetum (30 g/kg/d) by gavage, while the normal control group was administered an equal volume of saline daily for five weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic histopathological examinations, and Masson staining were performed to evaluate liver injury. Liver intercellular adhesion molecule-1 (ICAM-1) and P-selectin were evaluated by immunohistochemistry. Hepatocellular apoptosis was assessed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Protein expression levels of autophagy markers were measured using Western blot analysis. Results: Gynura segetum was found to significantly induce liver injury compared with control mice, as evidenced by the increase of serum transaminases, a decrease in triglyceride levels, and histopathological changes in mice. Gynura segetum remarkably induced hepatocellular apoptosis and upregulated the expressions of ICAM-1 and P-selectin and also downregulated the protein expression levels of LC3, Atg12 and cytoplasmic polyadenylation element binding protein. Conclusions: Our results suggested that G. segetum induced liver injury with HSOS, and it was partly due to its ability to impair the autophagy pathway.
Asunto(s)
Animales , Ratones , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Enfermedad Veno-Oclusiva Hepática/patología , Medicamentos Herbarios Chinos , Autofagia , Apoptosis , Hígado/patologíaRESUMEN
This study investigated the value of computed tomography (CT) in the diagnosis and treatment of hepatic veno-occlusive disease (HVOD) caused by Sedum aizoon (SA). The clinical manifestations, treatment results, imaging findings, and histological findings of the liver were analyzed in 39 patients with HVOD caused by SA. Hepatomegaly, liver dysfunction, abdominal effusion, and geographic density changes on liver CT scans were found in all 39 patients. The pathological findings of histological liver examination included swelling and point-like necrosis of liver cells, significant expansion and congestion of the sinuses, endothelial swelling, and wall thickening with incomplete lumen occlusion of small liver vessels. CT geographic density changes were confirmed by histological examination of the liver in 18 patients. Sixteen patients with small amounts of ascites that started within 4 weeks of treatment recovered completely or significantly improved after symptomatic and supportive treatment. However, only 43.75% of the patients with larger amounts of ascites improved following symptomatic and supportive treatment. In conclusion, liver CT examination is a valuable, safe, and noninvasive tool for the diagnosis of HVOD caused by SA. In selected cases, liver CT examination may replace liver biopsy and histological analysis.
Asunto(s)
Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medicamentos Herbarios Chinos/envenenamiento , Enfermedad Veno-Oclusiva Hepática , Circulación Hepática/efectos de los fármacos , Sedum/envenenamiento , Ascitis/etiología , Biopsia , China , Enfermedad Veno-Oclusiva Hepática/etiología , Enfermedad Veno-Oclusiva Hepática/patología , Necrosis , Estudios Retrospectivos , Sedum/clasificación , Tomografía Computarizada por Rayos XRESUMEN
No abstract available.
Asunto(s)
Femenino , Humanos , Persona de Mediana Edad , Antineoplásicos/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Enfermedad Veno-Oclusiva Hepática/patología , Neoplasias Hepáticas/tratamiento farmacológico , Compuestos Organoplatinos/efectos adversos , Tomografía Computarizada por Rayos XRESUMEN
O objetivo do presente trabalho é avaliar as alteraçöes enzimáticas do efluente hepático e a funçäo mitocondrial do fígado como indicadores da síndrome de bloqueio ao efluxo venoso do fígado (BEVF). Foram estudados 14 cäes mestiços de ambos os sexos com peso variando de 16 a 20 Kg, submetidos a transplante ortotópico de fígado sendo sete doadores e sete receptores. Após a anastomose da veia cava supra-hepática perfundiu-se o fígado com 300ml de soluçäo de cloreto de sódio a 0,9//) (SF) pela veia porta, colhendo-se o efluente hepático (EH) pela veia cava infra-hepática em 4 frascos de 20ml, para dosagens de DHL, AST e ALT. Amostras de tecido hepático foram colhidas no início da operaçäo do doador (D1) imediatamente antes do implante (D@), 15 minutos (R1) e 60 minutos (R2) após a reperfusäo hepática no receptor. Nos animais com BEVF os níveis de DHL, ALT e AST no EH foram significativamente superiores aos controles. A respiraçäo mitocondrial hepática em todos os tempos estudados, foi significativamente maior e efetiva nos controles do que nos animais com BEVF. O BEVF foi confirmado pelo exame anatomopatológico que mostrou necrose hepatocelular, alargamento sinusoidal e destruiçäo da veia centro-lobular
Asunto(s)
Animales , Masculino , Femenino , Perros , Enfermedad Veno-Oclusiva Hepática/patología , Trasplante de Hígado/efectos adversos , Hígado/enzimología , Hígado/patología , Mitocondrias Hepáticas/fisiologíaRESUMEN
Fulvine, a toxic constituent of the herb Crotolaria fulva, has been incriminated as the causative factor of veno-occlusive disease of the liver (V.O.D.), which is endemic in Jamaica. In an attempt to elucidate further the pathogenesis of the disease, hepatic veno-occlusive lesions were induced in Wistar rats following treatment with fulvine (5-20 mg/kg body weight). The livers of these animals were examined with an electron-microscope 24, 48 or 72 hours later, using standard techniques. Rough endoplasmic reticulum was reduced 24 hours following treatment and the channel system disrupted into a system of vesticles. After 48 hours, smooth endoplasmic reticulum showed considerable increase and displayed progressive dilation and balooning. Mitochondrial changes (swelling, decrease of the internal matrix density and loss of cristae) were detected. Liver cells revealed degenerative cytoplasm and damaged cell membranes. Sinusoidal walls appeared intermittently naked, and swollen microvilli projected into dilated perisinusoidal spaces. The alterations became pronounced 72 hours after treatment. Fulvine caused a decrease in the number of mitochondria, further disorganization of mitochondrial structure, and conspicuous nuclear changes. The sinusoids, lined by swollen endothelial cells and necrotic hepatocytes, appeared distended with erythrocytes. Following breakdown of the space of Disse, the hepatocytes were usually obsreved to be in direct contact with blood. These early ultrastructural findings in the pathogenesis of V.O.D. support our previously reported histo-chemical observations of differences in hepatic enzymatic activities and is indicative of primary hepatocellular damages. The venovascular damage. The venovascular changes represent, in our opinion, a more advanced stage in the pathogenesis of the disease, and as such there is no primary veno-occlussive process (AU)
Asunto(s)
Humanos , 21003 , Ratas , Hepatopatías/patología , Enfermedad Veno-Oclusiva Hepática/patología , JamaicaRESUMEN
The case histories of four children in a family of seven are presented. The eldest of the four, a girl, presented in 1961 at age 4 1/2 years with evidence of liver disease and portal hypertension. A liver biopsy was not performed. This child died in 1964 of hepatorenal failure and unfortunately permission for autopsy was refused. The second affected child, a boy, presented at age 2 years with hepatosplenomegaly and jaundice and a needle biopsy of his liver revealed a histological picture consistent with post V.O.D. cirrhosis. He has remained fairly well since, although signs of cirrhosis persist. In June 1966 two female siblings age 1 year and 2 years respectively, presented at the same time with acute abdominal swelling. Liver biopsies confirmed the clinical diagnosis of acute V.O.D. and their subsequent progress is briefly reviewed. The case history of a boy who has had two proven episodes of acute V.O.D. is presented. This child was first admitted in January 1958 at age 1 year and five months, with acute abdominal swelling. A liver biopsy revealed histological evidence of acute V.O.D. His clinical condition settled and repeat biopsy in March 1958 showed no residual liver disease. He remained well after this until he had an episode of obstructive jaundice in 1960 which subsided spontaneously. In 1965 he was readmitted with a history of acute abdominal swelling and after two months during which time his ascites gradually subsided, a liver biopsy was performed and this showed subacute V.O.D. A final biopsy was done in September 1966 and this showed only minimal increase of fibrous tissue. A brief note on the aetiology of V.O.D. is submitted(AU)
Asunto(s)
Lactante , Preescolar , Niño , Humanos , Femenino , Masculino , Enfermedad Veno-Oclusiva Hepática/patología , Jamaica , Biopsia con AgujaRESUMEN
Veno-occlusive disease of the liver is a recently established disease entity. Its etiology, pathology, and symptomatology, and natural history are discussed on the basis of 99 cases of this disease so far authenticated at the University College of the West Indies. In the surgical literature the disease is added to the list of causes of intra-hepatic portal hypertension, and the cases of 4 patients are presented in detail in whom portacaval anastomoses were performed for the decompression of esophageal varices. The surgical implications of this disease have been stated and some of the difficulties enountered in the treatment of portal hypertension in infants and children outlined (Summary)
Asunto(s)
Humanos , Preescolar , Niño , Adulto , Masculino , Femenino , Enfermedad Veno-Oclusiva Hepática/cirugía , Cirrosis Hepática , Venas Hepáticas , Enfermedad Veno-Oclusiva Hepática/mortalidad , Enfermedad Veno-Oclusiva Hepática/patología , Factores de Edad , Várices Esofágicas y Gástricas , Hemorragia Gastrointestinal , Autopsia , Radiografía , Pruebas de Función HepáticaRESUMEN
The case of a cow suffering from veno-occlusive disease of the liver is reported. The condition has hitherto not been observed in animals in this island. The resemblance of the morbid anatomical findings in this cowand in our human patients is most striking. We feel that this observation greatly supports the hypothesis of an aetiological agent of vegetable origin. Field studies are being conducted to shed further light on the incidence and possible aetiology of this disease in animals. (AU)
Asunto(s)
21003 , Enfermedad Veno-Oclusiva Hepática/veterinaria , Senecio jacobaea/toxicidad , Jamaica , Enfermedad Veno-Oclusiva Hepática/etiología , Enfermedad Veno-Oclusiva Hepática/patología , Plantas Tóxicas , Bovinos , Hígado/patologíaRESUMEN
Three cases of veno-occlusive disease of the liver recently seen in Barbados are described. The clinical features and pathology are similar to those reported from Jamaica. They were associated with administration ofbush tea made from Crotalaria Retusa. It is suggested that this is further evidence that V.O.D. is probably the non-specific reaction of the liver to a number of toxins, herbal and/or bacterial. (AU)
Asunto(s)
Humanos , Preescolar , Masculino , Femenino , Enfermedad Veno-Oclusiva Hepática/etiología , Enfermedad Veno-Oclusiva Hepática/patología , Medicina Tradicional , Barbados , Hígado/patologíaRESUMEN
Extended pathological-anatomical data gleaned from 19 autopsies on patients with veno-occlusive disease of the liver are presented. The condition is frequently observed in Jamaican infants and children and less frequently in adults. Repeated attacks lead to a diffuse non-portal type of cirrhosis. Grossly the cirrhosis is indistinguishable from the portal type of Laennec's cirrhosis but the condition should not be regarded as a result of protein-malnutrition alone, nor as an after effect of kwashiorkor earlier in life. The pivotal lesion is obstruction of the smaller and medium sized branches of the hepatic vein. In the acute phase this mostly presents the picture described by earlier investigators as endophlebitis hepatica obliterans. Thrombosis is notably rare. The possibility is advanced that Duguid's concept of organizing arterial mural thrombi could explain the picture of "endophlebitis" in this condition, but so far this cannot be substantiated as it has not been demonstrated histologically that the endophlebitic thickening are either thrombi or mural despositions of constituents from the blood which have become organised. Available data suggest a toxic substance in "bush-teas" as a possible aetiologic factor. Concurrent substance of fatty change in the liver and of pancreatic pathology, both identical to the lesions observed in protein-under-nutrition, suggest that the latter may be an important co-factor. The result of dietary studies done Rhodes (1955) are also in conformity with this concept. (AU)
Asunto(s)
Humanos , Lactante , Preescolar , Niño , Adolescente , Adulto , Persona de Mediana Edad , Masculino , Femenino , Enfermedad Veno-Oclusiva Hepática/patología , Hígado/patología , Cirrosis Hepática/etiología , Autopsia , JamaicaRESUMEN
The clinical features of veno-occlusive disease of the liver (V.O.D.) in Jamaica are described, with details of four cases occurring in adults. The mechanisms of hepatomegaly and ascites formation are briefly considered. It is thought that in acute cases they are the mechanical results of hepatic congestion produced by occlusion of the hepatic venous radicles. A comparison has been drawn with the experimental ascites produced by ligation of the thoracic inferior vena cava in animals. Treatment with a high-protein diet and fluid and salt restriction is suggested. The difficulty in assessing response to treatment is stressed.(AU)
Asunto(s)
Humanos , Adolescente , Adulto , Persona de Mediana Edad , Masculino , Femenino , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Enfermedad Veno-Oclusiva Hepática/patología , Pruebas de Función Hepática , Ascitis , Hepatomegalia , Biopsia , Autopsia , Enfermedad Veno-Oclusiva Hepática/dietoterapia , Enfermedad Veno-Oclusiva Hepática/tratamiento farmacológico , Deanol/administración & dosificación , Dieta Hiposódica , Proteínas en la Dieta , JamaicaRESUMEN
The histological findings of 148 biopsies and 12 autopsies on 93 infants are given. No selection was made, beyond the addition of a miscallenous control group to the group of patients with clinical hepatic disease. Patients with hepatic disease were divided into three groups: (1) Kwashiorkor-marasmus(39 cases) (2) Veno-occlusive disease (12 cases) (3) Cirrhosis (8 cases). In discussing group (1) points of difference with the features of the disease elsewhere in the world are emphasised. It is of interest to note that liver cell necrosis was not uncommon, while pancreatic fibrosis was seen in only 2 out of 9 cases autopsied. Group (2) represents a clinical syndrome, apparently quite common in Jamaica, of which, however the underlying histology and aetiology may be varied. In the present study, attention is drawn to endophlebitic occlusion of hepatic veins and it is held that a non-portal fibrosis results, which sometimes progresses towards a cirrhosis. It is suggested that the condition is not solely based on malnutrition and the analogy with certain conditions in humans and in experimental animals as reported in the literature, points to one or more additional toxic factors, as yet unknown. The discussion of group (3) mentions some of the problems of tropical cirrhosis of the liver that await a solution. The control group (4) was considered to emphasise the opinion expressed by other workers in tropical countries that the children seem to establish themselves surprisingly well on a low dietetic level. (Summary)
Asunto(s)
Humanos , Lactante , Preescolar , Hepatopatías/patología , Enfermedad Veno-Oclusiva Hepática/patología , Cirrosis Hepática/patología , Trastornos de la Nutrición del Niño/patología , Biopsia , Hígado/patologíaRESUMEN
Of 100 patients studied clinically and by means of needle biopsies of the liver, 5 showed nonportal fibrosis associated with obliteration of branches of the hepatic veins, a condition hitherto not reported from Jamaica. In four of these, a cirrhosis with distortion of the normal lobular architecture had developed. The Table presents data regarding the incidence and age distribution of this condition within the group studied. The patients presented with signs of cirrhosis, in particular hepatomegaly, ascites, hematemesis from esophageal varices in one case, but no jaundice. It is held that the obliteration of the hepatic vein branches is a very early, and possibly an initial, phase of the disease. It is essentially the result of a subendothelial, i.e., intimal, thickening of the vassel wall caused by a primary obliterating endophlebitis. A centrilobular necrosis of liver cells preceding the changes observed was not demonstrated but cannot be excluded. The relation to various possibly allied conditions reported in the literature is discussed. The analogy to Scenecio poisoning is striking, but there also seems to be close similarity with infantile cirrhosis in India. The etiology is undetermined; however, our observations have given renewed interest in the possible role played by "bush tea" in undernourished persons. (Summary)