RESUMO
Shwachman-Diamond syndrome (SDS) is one of the more common inherited bone marrow failure syndromes, characterized by neutropenia, occasional thrombocytopenia, and anemia. Bone marrow evaluation reveals an increased number of monocytes and mature B cells along with decreased granulocytes. However, little is known about the subpopulations of peripheral blood cells, and few previous publications have been based on a small number of patients. Here, we report a comprehensive immunophenotypic analysis from a cohort of 37 SDS patients who display impairment mostly in the myeloid compartment with a deficiency also in the number of B cells and CD4/CD8 double-negative T cells.
Assuntos
Linfócitos B/imunologia , Doenças da Medula Óssea/sangue , Doenças da Medula Óssea/imunologia , Insuficiência Pancreática Exócrina/sangue , Insuficiência Pancreática Exócrina/imunologia , Imunofenotipagem/métodos , Leucócitos Mononucleares/imunologia , Lipomatose/sangue , Lipomatose/imunologia , Adolescente , Adulto , Doenças da Medula Óssea/patologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Insuficiência Pancreática Exócrina/patologia , Feminino , Seguimentos , Humanos , Lactente , Lipomatose/patologia , Masculino , Prognóstico , Síndrome de Shwachman-Diamond , Adulto JovemRESUMO
Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients (n = 403) treated with anti-PD-1 (n = 356) or anti-CTLA-4 (n = 47) were divided into a case group (radiologic evidence of PA); control group matched by age, gender, and previous lines of treatment; and colitis group (ICI-induced colitis). Quantitative pancreatic volumetry was used for calculation of the decrease in pancreatic volume over time (atrophy rate). Thirty-one patients (7.7%) developed PA compared with 41 matched controls (P = 0.006). Four patients developed EPI, all from the anti-PD-1-treated group, which resolved with oral enzyme supplementation. The atrophy rate did not correlate with EPI (P = 0.87). EPI-related diarrhea presented at a median of 9 months, whereas the diarrhea of anti-PD-1-induced colitis patients (n = 22) was presented at a median of 2 months (P = 0.029). ICI-induced PA is irreversible and can result in EPI. EPI should be suspected in cases of late-onset steroid-resistant diarrhea with features of steatorrhea and treated with oral enzyme supplements.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Pâncreas/patologia , Idoso , Atrofia/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/terapia , Estudos de Casos e Controles , Insuficiência Pancreática Exócrina/induzido quimicamente , Insuficiência Pancreática Exócrina/imunologia , Feminino , Humanos , Ipilimumab/efeitos adversos , Neoplasias Pulmonares/terapia , Masculino , Melanoma/terapia , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/imunologia , Estudos RetrospectivosAssuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Insuficiência Pancreática Exócrina/induzido quimicamente , Ipilimumab/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Insuficiência Pancreática Exócrina/diagnóstico por imagem , Insuficiência Pancreática Exócrina/imunologia , Humanos , Ipilimumab/administração & dosagem , Masculino , Melanoma/tratamento farmacológico , Melanoma/imunologia , Melanoma/patologia , Receptor de Morte Celular Programada 1/imunologiaRESUMO
Immune function abnormalities have been reported in patients with Fanconi anemia (FA), dyskeratosis congenita (DC) and, rarely, in Shwachman-Diamond syndrome (SDS), and Diamond-Blackfan anemia (DBA), but large systematic studies are lacking. We assessed immunological parameters in 118 patients with these syndromes and 202 unaffected relatives. We compared the results in patients with reference values, and with values in relatives after adjusting for age, sex, corticosteroid treatment, and severe bone marrow failure (BMF). Adult patients (≥18 years) with FA had significantly lower immunoglobulins (IgG, IgA and IgM), total lymphocytes, and CD4 T cells than reference values or adult relatives (P < 0.001); children with FA had normal values. Both children and adults with FA had lower B- and NK cells (P < 0.01) than relatives or reference values. Patients with DC had essentially normal immunoglobulins but lower total lymphocytes than reference values or relatives, and lower T-, B-, and NK-cells; these changes were more marked in children than adults (P < 0.01). Most patients with DBA and SDS had normal immunoglobulins and lymphocytes. Lymphoproliferative responses, serum cytokine levels, including tumor necrosis factor-α and interferon-γ, and cytokine levels in supernatants from phytohemagglutinin-stimulated cultures were similar across patient groups and relatives. Only patients with severe BMF, particularly those with FA and DC, had higher serum G-CSF and Flt3-ligand and lower RANTES levels compared with all other groups or relatives (P < 0.05). Overall, immune function abnormalities were seen mainly in adult patients with FA, which likely reflects their disease-related progression, and in children with DC, which may be a feature of early-onset severe disease phenotype.
Assuntos
Anemia de Diamond-Blackfan/diagnóstico , Doenças da Medula Óssea/diagnóstico , Disceratose Congênita/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Anemia de Fanconi/diagnóstico , Hemoglobinúria Paroxística/diagnóstico , Lipomatose/diagnóstico , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Anemia Aplástica , Anemia de Diamond-Blackfan/tratamento farmacológico , Anemia de Diamond-Blackfan/imunologia , Anemia de Diamond-Blackfan/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Doenças da Medula Óssea/congênito , Doenças da Medula Óssea/tratamento farmacológico , Doenças da Medula Óssea/imunologia , Transtornos da Insuficiência da Medula Óssea , Estudos de Casos e Controles , Criança , Pré-Escolar , Citocinas/biossíntese , Citocinas/imunologia , Disceratose Congênita/tratamento farmacológico , Disceratose Congênita/imunologia , Disceratose Congênita/patologia , Insuficiência Pancreática Exócrina/congênito , Insuficiência Pancreática Exócrina/tratamento farmacológico , Insuficiência Pancreática Exócrina/imunologia , Família , Anemia de Fanconi/tratamento farmacológico , Anemia de Fanconi/imunologia , Anemia de Fanconi/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos/biossíntese , Fator Estimulador de Colônias de Granulócitos/imunologia , Hemoglobinúria Paroxística/congênito , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/imunologia , Humanos , Imunoglobulinas/biossíntese , Lactente , Interferon gama/biossíntese , Interferon gama/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Lipomatose/congênito , Lipomatose/tratamento farmacológico , Lipomatose/imunologia , Masculino , Proteínas de Membrana/biossíntese , Proteínas de Membrana/imunologiaRESUMO
Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder with exocrine pancreatic insufficiency, bone marrow failure and skeletal abnormalities. Patients frequently present failure to thrive, susceptibility to infections and short stature. A persistent or intermittent neutropenia occurs in 88-100% of patients. Bone marrow biopsy usually reveals a hypoplastic specimen with varying degrees of hypoplasia and fat infiltration. Some patients may develop myeloblastic syndrome and acute myeloblastic leukemia. The genetic defect in SDS has been identified in 2002. The osteoporosis is increased in patients with SDS, and also, bone malformations are included among the primary characteristics of the syndrome. The severity and location change with age and sexes. The typical characteristics include the following: secondary ossification centers delayed appearance, metaphysis enlargement and irregularity (very common in childhood, particularly in coastal and femur), growth cartilage progressive thinning and irregularity (possibly asymmetric growth), generalized osteopenia with cortical thinning. We describe a clinical case regarding an SDS patient with severe bone abnormalities and treated surgically for corrective osteotomy. The persistent or intermittent neutropenia that characterized this disease and the consequent risk of infection is a contraindication for short stature correction and limbs lengthening.
Assuntos
Doenças da Medula Óssea/patologia , Insuficiência Pancreática Exócrina/patologia , Lipomatose/patologia , Deformidades Congênitas das Extremidades Inferiores/cirurgia , Osteotomia/métodos , Tíbia/cirurgia , Adolescente , Antibioticoprofilaxia , Doenças da Medula Óssea/imunologia , Pré-Escolar , Contraindicações , Nanismo/genética , Insuficiência Pancreática Exócrina/imunologia , Fixadores Externos , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Hospedeiro Imunocomprometido , Lenograstim , Lipomatose/imunologia , Locomoção , Deformidades Congênitas das Extremidades Inferiores/genética , Masculino , Neutropenia/tratamento farmacológico , Neutropenia/genética , Procedimentos Ortopédicos , Osteotomia/instrumentação , Fenótipo , Cuidados Pré-Operatórios , Proteínas Recombinantes/uso terapêutico , Síndrome de Shwachman-Diamond , Tíbia/patologiaRESUMO
BACKGROUND: The inherited bone marrow failure syndromes (IBMFS) include Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome (SDS). Previous studies reported decreased neutrophil chemotaxis in patients with SDS; there are no reports of neutrophil function in other IBMFS. In this study we examined neutrophil respiratory burst function in IBMFS patients. PROCEDURE: Samples from 43 IBMFS patients and 61 healthy family members were collected, shipped, and analyzed within 24 hr. We also studied samples from 12 healthy control persons immediately after collection. Neutrophils were stimulated with phorbol 12-myristate acetate (PMA) and N-formyl-methyonyl-leucyl-phenylalanine (fMLP), and respiratory burst analyzed by reduction of dihydro-rhodamine and cytochrome c. RESULTS: There was no significant difference in the degree of fMLP or PMA-driven respiratory burst activity between each of the IBMFS subgroups and their respective family members. There was also no difference in respiratory burst activity between any IBMFS, pooled group of all healthy family members and healthy controls. CONCLUSIONS: Neutrophil respiratory burst activity from IBMFS patients does not differ from that of healthy family members and controls.
Assuntos
Anemia Hipoplástica Congênita/imunologia , Disceratose Congênita/imunologia , Neutrófilos/metabolismo , Explosão Respiratória , Doenças da Medula Óssea/imunologia , Estudos de Casos e Controles , Insuficiência Pancreática Exócrina/imunologia , Humanos , Lipomatose , Síndrome de Shwachman-DiamondRESUMO
Shwachman-Diamond syndrome is a rare clinical condition consisting of exocrine pancreatic dysfunction, various degree of pancytopenia, and metaphyseal dysplasia. The majority of Shwachman-Diamond syndrome cases result from mutations in the Shwachman-Bodian-Diamond Syndrome gene. To date, type 1 diabetes mellitus has only been reported in 4 independent cases presenting with Shwachman-Diamond syndrome, 3 of them with molecular confirmation of the diagnosis. We describe 2 unrelated patients with clinical and molecular features typical of Shwachman-Diamond syndrome and type 1 diabetes mellitus. In addition, we report the occurrence rate of type 1 diabetes mellitus in the Italian registry for Shwachman-Diamond syndrome, which is low (3.23%) but increased at least 30-fold over the type 1 diabetes mellitus occurrence rate in the general population. No evidence of a direct correlation between Shwachman-Diamond syndrome and type 1 diabetes mellitus have been reported, therefore the presence of both diseases in the same patient might be a chance association, however we suggest that the defects in immune regulation of Shwachman-Diamond syndrome might play a role in the development of type 1 diabetes mellitus.
Assuntos
Doenças da Medula Óssea/complicações , Diabetes Mellitus Tipo 1/complicações , Insuficiência Pancreática Exócrina/complicações , Lipomatose/complicações , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/imunologia , Relação CD4-CD8 , Diabetes Mellitus Tipo 1/etiologia , Insuficiência Pancreática Exócrina/genética , Insuficiência Pancreática Exócrina/imunologia , Feminino , Heterozigoto , Humanos , Sistema Imunitário/fisiopatologia , Lactente , Itália/epidemiologia , Lipomatose/genética , Lipomatose/imunologia , Masculino , Mutação , Prevalência , Proteínas/genética , Sistema de Registros , Síndrome de Shwachman-DiamondRESUMO
OBJECTIVES: Autoimmune pancreatitis (AIP) is better described than before, but there is still no international consensus for definition, diagnosis, and treatment. Our aims were to analyze the short- and long-term outcome of patients with focus on pancreatic endocrine and exocrine functions, to search for predictive factors of relapse and pancreatic insufficiency, and to compare patients with type 1 and type 2 AIP. METHODS: All consecutive patients followed up for AIP in our center between 1999 and 2008 were included. Two groups were defined: (a) patients with type 1 AIP meeting HISORt (Histology, Imaging, Serology, Other organ involvement, and Response to steroids) criteria; (b) patients with definitive/probable type 2 AIP including those with histologically confirmed idiopathic duct-centric pancreatitis ("definitive") or suggestive imaging, normal serum IgG4, and response to steroids ("probable"). AIP-related events and pancreatic exocrine/endocrine insufficiency were looked for during follow-up. Predictive factors of relapse and pancreatic insufficiency were analyzed. RESULTS: A total of 44 patients (22 males), median age 37.5 (19-73) years, were included: 28 patients (64%) with type 1 AIP and 16 patients (36%) with type 2 AIP. First-line treatment consisted of steroids or pancreatic resection in 59 and 27% of the patients, respectively. Median follow-up was 41 (5-130) months. Steroids were effective in all treated patients. Relapse was observed in 12 patients (27%), after a median delay of 6 months (1-70). Four patients received azathioprine because of steroid resistance/dependence. High serum IgG4 level, pain at time of diagnosis, and other organ involvement were associated with relapse (P<0.05). At the end point, pancreatic atrophy was observed in 35% of patients. Exocrine and endocrine insufficiencies were present in 34 and 39% of the patients, respectively. At univariate analysis, no factor was associated with exocrine insufficiency, although female gender (P=0.04), increasing age (P=0.006), and type 1 AIP (P=0.001) were associated with the occurrence of diabetes. Steroid/azathioprine treatment did not prevent pancreatic insufficiency. Type 2 AIP was more frequently associated with inflammatory bowel disease than type 1 AIP (31 and 3%, respectively), but relapse rates were similar in both groups. CONCLUSIONS: Relapse occurs in 27% of AIP patients and is more frequent in patients with high serum IgG4 levels at the time of diagnosis. Pancreatic atrophy and functional insufficiency occur in more than one-third of the patients within 3 years of diagnosis. The outcome of patients with type 2 AIP, a condition often associated with inflammatory bowel disease, is not different from that of patients with type 1 AIP, except for diabetes.
Assuntos
Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Insuficiência Pancreática Exócrina/imunologia , Pancreatite/imunologia , Pancreatite/terapia , Adulto , Idoso , Doenças Autoimunes/patologia , Biópsia por Agulha , Estudos de Coortes , Terapia Combinada , Insuficiência Pancreática Exócrina/patologia , Insuficiência Pancreática Exócrina/terapia , Feminino , Seguimentos , Humanos , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pancreatectomia/métodos , Ductos Pancreáticos/patologia , Testes de Função Pancreática , Pancreatite/patologia , Prednisolona/uso terapêutico , Recidiva , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
Autoimmune pancreatitis (ALP) represents a distinct form of chronic pancreatitis initially described in Japan but now reported worldwide. AIP often presents with obstructive jaundice/pancreatic mass as well as pancreatic exocrine and endocrine insufficiency. Histologically, it is characterised by a lymphoplasmacytic infiltrate with fibrosis. The disease responds readily to steroids in 70-80% of cases. Given the absence of unified diagnostic criteria, the diagnosis of AIP proves difficult. In particular, distinguishing ALP from pancreatic or biliary cancer remains a challenging task. In order to avoid unnecessary resections for an otherwise benign and easily treatable condition, it is urgent to refine diagnostic criteria and to reach an international consensus.
Assuntos
Doenças Autoimunes/diagnóstico , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/epidemiologia , Diagnóstico Diferencial , Europa (Continente)/epidemiologia , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/imunologia , Glucocorticoides/uso terapêutico , Humanos , Icterícia Obstrutiva/diagnóstico , Icterícia Obstrutiva/imunologia , Pancreatite Crônica/tratamento farmacológico , Pancreatite Crônica/epidemiologia , Resultado do TratamentoRESUMO
AIM: To review the gastrointestinal mucosal histological features of biopsies from children with Shwachman-Diamond syndrome (SDS) examined at a single specialist centre. METHODS: Search of a clinical database was performed to identify SDS cases and their gastrointestinal biopsies were reviewed for morphological parameters such as crypt:villous ratio, crypt hyperplasia and abnormal inflammatory infiltrates. Histological sections were also immunostained with CD4, CD20 and HLA-DR to determine the nature of the inflammatory infiltrate. RESULTS: 15 SDS cases were included, 7 (47%) of which showed morphologically normal duodenal villous architecture, whereas 8 (53%) showed varying degrees of enteropathic histological features ranging from villous blunting to partial villous atrophy and duodenitis. 11/15 (73%) showed some degree of duodenal inflammation, including increased lamina propria density of plasma cells, macrophages and eosinophils. CONCLUSION: Varying degrees of duodenal inflammatory enteropathic features are present in more than 50% of symptomatic children with SDS. This suggests that, in addition to pure pancreatic exocrine failure, an enteropathic component may contribute to symptoms in some cases, and be potentially responsive to appropriate therapy.
Assuntos
Duodeno/patologia , Atrofia , Biópsia , Doenças da Medula Óssea/imunologia , Doenças da Medula Óssea/patologia , Linfócitos T CD4-Positivos/imunologia , Criança , Duodenite/imunologia , Duodenite/patologia , Duodenoscopia , Duodeno/imunologia , Insuficiência Pancreática Exócrina/imunologia , Insuficiência Pancreática Exócrina/patologia , Antígenos HLA-DR/metabolismo , Humanos , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Lipomatose , Síndrome de Shwachman-DiamondRESUMO
Although it has been reported that cystic fibrosis and coeliac disease can coexist, a clear relationship between the two diseases has never been firmly established. Our case concerns a 56-year-old man with cystic fibrosis (delta F508/N1303J). Over the last two years he had been complaining about diarrhoea and meteorism. The serum level of tissue transglutaminase was elevated. Duodenoscopy showed a typical pattern for coeliac disease. This was confirmed by the biopsy. After three months on a gluten-free diet the symptoms had disappeared. In the literature there are some hypotheses to explain the coexistence of cystic fibrosis and coeliac disease. Due to pancreatic insufficiency in patients with cystic fibrosis the mucosa of the bowel may have more contact with the complete gluten protein. In addition, malnutrition might contribute to some additional mucosal damage. Both mechanisms might induce an inappropriate immune response to dietary gluten. In the literature all cystic fibrosis patients with coeliac disease were diagnosed with both diseases in childhood with a maximum latency between both diseases of 26 months. It seems unlikely that manifest coeliac disease remained undiagnosed in our patient since childhood. The long time gap between the diagnosis of cystic fibrosis and the first symptoms of the celiac disease in our patient could support the above-mentioned pathophysiological hypotheses.
Assuntos
Doença Celíaca/etiologia , Fibrose Cística/complicações , Autoanticorpos/sangue , Doença Celíaca/diagnóstico , Doença Celíaca/imunologia , Fibrose Cística/diagnóstico , Fibrose Cística/imunologia , Duodenoscopia , Duodeno/patologia , Insuficiência Pancreática Exócrina/complicações , Insuficiência Pancreática Exócrina/diagnóstico , Insuficiência Pancreática Exócrina/imunologia , Proteínas de Ligação ao GTP , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Glutamina gama-Glutamiltransferase , Transglutaminases/sangueRESUMO
A young woman with the HLA phenotype A1, A2, B5, B8, DR3, DR4 developed RA, idiopathic thrombocytopenic purpura (ITP), pernicious anaemia (PA), Hashimoto's thyroiditis (HT), systemic sclerosis (SS), pancreatic exocrine insufficiency (PEI) and coeliac disease (CD) before dying from vasculitic complications. A family study revealed RA, PA and insulin-dependent diabetes mellitus (IDDM) amongst her first degree relatives. Her case emphasizes the clinical and immunogenetic links between the autoimmune diseases.