RESUMEN
BACKGROUND: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.
Asunto(s)
Hepatitis Autoinmune , Tacrolimus , Humanos , Tacrolimus/efectos adversos , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/tratamiento farmacológico , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento , Inmunosupresores/efectos adversos , Ácido Micofenólico/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. METHODS: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. RESULTS: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). CONCLUSIONS: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. IMPACT AND IMPLICATIONS: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. TRIAL REGISTRATION NUMBER: #NCT02900443.
Asunto(s)
Azatioprina , Hepatitis Autoinmune , Humanos , Femenino , Masculino , Azatioprina/uso terapéutico , Ácido Micofenólico/efectos adversos , Hepatitis Autoinmune/tratamiento farmacológico , Estudios Prospectivos , Resultado del Tratamiento , Inmunosupresores/efectos adversos , Prednisolona/efectos adversos , Inducción de RemisiónRESUMEN
BACKGROUND: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. METHODS: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. DISCUSSION: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. TRIAL REGISTRATION: EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016.
Asunto(s)
Enfermedad Hepática en Estado Terminal , Hepatitis Autoinmune , Adulto , Humanos , Ácido Micofenólico/efectos adversos , Azatioprina/efectos adversos , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/tratamiento farmacológico , Calidad de Vida , Inmunosupresores/efectos adversos , Resultado del Tratamiento , Índice de Severidad de la Enfermedad , Prednisolona/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND AND AIMS: Epidemiological data on autoimmune hepatitis (AIH) are scarce. In this study, we determined the clinical and epidemiological characteristics of AIH patients in the Netherlands (16.7 million inhabitants). METHODS: Clinical characteristics were collected from 1313 AIH patients (78% females) from 31 centers, including all eight academic centers in the Netherlands. Additional data on ethnicity, family history and symptoms were obtained by the use of a questionnaire. RESULTS: The prevalence of AIH was 18.3 (95% confidential interval [CI]: 17.3-19.4) per 100,000 with an annual incidence of 1.1 (95% CI: 0.5-2) in adults. An incidence peak was found in middle-aged women. At diagnosis, 56% of patients had fibrosis and 12% cirrhosis in liver biopsy. Overall, 1% of patients developed HCC and 3% of patients underwent liver transplantation. Overlap with primary biliary cirrhosis and primary sclerosing cholangitis was found in 9% and 6%, respectively. The clinical course did not differ between Caucasian and non-Caucasian patients. Other autoimmune diseases were found in 26% of patients. Half of the patients reported persistent AIH-related symptoms despite treatment with a median treatment period of 8 years (range 1-44 years). Familial occurrence was reported in three cases. CONCLUSION: This is the largest epidemiological study of AIH in a geographically defined region and demonstrates that the prevalence of AIH in the Netherlands is uncommon. Although familial occurrence of AIH is extremely rare, our twin data may point towards a genetic predisposition. The high percentage of patients with cirrhosis or fibrosis at diagnosis urges the need of more awareness for AIH.
Asunto(s)
Carcinoma Hepatocelular/epidemiología , Hepatitis Autoinmune/epidemiología , Neoplasias Hepáticas/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Antiinflamatorios/uso terapéutico , Anticuerpos Antinucleares/sangre , Pueblo Asiatico/estadística & datos numéricos , Población Negra/estadística & datos numéricos , Niño , Preescolar , Fatiga/etiología , Femenino , Hepatitis Autoinmune/diagnóstico , Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/genética , Humanos , Inmunoglobulina G/sangre , Inmunosupresores/uso terapéutico , Incidencia , Ictericia/etiología , Cirrosis Hepática/epidemiología , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Prevalencia , Estudios Retrospectivos , Factores Sexuales , América del Sur/etnología , Encuestas y Cuestionarios , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS: We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS: We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 × 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 × 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 × 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 × 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 × 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.
Asunto(s)
Autoinmunidad/genética , Hepatitis Autoinmune/genética , Complejo Mayor de Histocompatibilidad/genética , Polimorfismo de Nucleótido Simple , Proteínas Adaptadoras Transductoras de Señales , Adulto , Proteínas Adaptadoras de Señalización CARD/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Alemania , Cadenas HLA-DRB1/genética , Hepatitis Autoinmune/inmunología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Persona de Mediana Edad , Países Bajos , Fenotipo , Proteínas/genética , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: Single nucleotide polymorphisms (SNP) in the Cytotoxic T lymphocyte antigen-4 gene (CTLA-4) have been associated with several autoimmune diseases including autoimmune Hepatitis (AIH). In this chronic idiopathic inflammatory liver disease, conflicting results have been reported on the association with a SNP at position +49 in the CTLA-4 gene in small patient cohorts. Here, we established the role of this SNP in a sufficiently large cohort of AIH patients. METHODS: The study population consisted of 672 AIH patients derived from academic and regional hospitals in the Netherlands and was compared with 500 controls selected from the 'Genome of the Netherlands' project cohort. Genotype frequencies were assessed by PCR for patients and by whole genome sequencing for controls. RESULTS: No significant differences in allele frequencies were found between patients and controls (G Allele: 40% vs 39%, P = 0.7). Similarly, no significant differences in genotype frequencies between patients and controls were found. Finally, there was no relation between disease activity and the G allele or AG and GG genotypes. CONCLUSION: The Cytotoxic T Lymphocyte Antigen-4 +49 A/G polymorphism does not represent a major susceptibility risk allele for AIH in Caucasians and is not associated with disease severity at presentation.
Asunto(s)
Antígeno CTLA-4/genética , Predisposición Genética a la Enfermedad/genética , Hepatitis Autoinmune/genética , Polimorfismo de Nucleótido Simple/genética , Población Blanca/genética , Análisis de Varianza , Frecuencia de los Genes , Genotipo , Humanos , Países Bajos , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADNRESUMEN
BACKGROUND & AIMS: Current treatment strategies in autoimmune hepatitis (AIH) include long-term treatment with corticosteroids and/or azathioprine. Here we determined the risk of relapse after drug withdrawal in patients in long-term remission and factors associated with such a relapse. METHODS: A total of 131 patients (out of a cohort including 844 patients) from 7 academic and 14 regional centres in the Netherlands were identified in whom treatment was tapered after at least 2 years of clinical and biochemical remission. Relapse was defined as alanine-aminotransferase levels (ALT) three times above the upper limit of normal and loss of remission as a rising ALT necessitating the reinstitution of drug treatment. RESULTS: During follow-up, 61 (47%) patients relapsed and 56 (42%) had a loss of remission. In these 117 patients, 60 patients had fully discontinued medication whereas 57 patients were still on a withdrawal scheme. One year after drug withdrawal, 59% of the patients required retreatment, increasing to 73% and 81% after 2 and 3 years, respectively. Previous combination therapy of corticosteroids and azathioprine, a concomitant autoimmune disease and younger age at time of drug withdrawal were associated with an increased risk of relapse. Subsequent attempts for discontinuation after initial failure in 32 patients inevitably resulted in a new relapse. CONCLUSIONS: This retrospective analysis indicates that loss of remission or relapse occurs in virtually all patients with AIH in long-term remission when immunosuppressive therapy is discontinued. These findings indicate a reluctant attitude towards discontinuation of immunosuppressive treatment in AIH patients.
Asunto(s)
Hepatitis Autoinmune/tratamiento farmacológico , Hepatitis Autoinmune/epidemiología , Inmunosupresores/efectos adversos , Síndrome de Abstinencia a Sustancias/epidemiología , Adolescente , Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Adulto , Anciano , Azatioprina/administración & dosificación , Azatioprina/efectos adversos , Niño , Femenino , Estudios de Seguimiento , Hepatitis Autoinmune/inmunología , Humanos , Inmunosupresores/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de Riesgo , Síndrome de Abstinencia a Sustancias/inmunología , Adulto JovenRESUMEN
UNLABELLED: With early posttransplant bone loss, orthotopic liver transplantation (OLT) recipients experience a high rate of fracturing and some avascular necrosis (AVN), but little is known about the incidence of and predictive factors for these skeletal complications. We studied 360 consecutive patients who underwent transplantation for primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and assessed both vertebral and nonvertebral (rib, pelvic, and femur) fractures in a protocolized fashion. Before OLT, 20% of the patients had experienced fracturing, and 1.4% of the patients had experienced AVN. Following OLT, there was a sharp increase in fracturing, with a 30% cumulative incidence of fractures at 1 year and 46% at 8 years after transplantation. In contrast to previous studies, there was a similar incidence of posttransplant vertebral and nonvertebral fractures. The greatest risk factors for posttransplant fracturing were pretransplant fracturing and the severity of osteopenia and posttransplant glucocorticoids. Nine percent of the liver recipients experienced AVN after OLT, and this correlated with pretransplant and posttransplant lipid metabolism, bone disease (bone mineral density and fracturing), and posttransplant glucocorticoids. A novel association between cholestasis and AVN was also identified, the mechanism for which is not known. CONCLUSION: Fortunately, recent years have seen an increase in the bone mass of liver recipients and, along with this, less fracturing and less AVN. Nonetheless, 25% of patients undergoing OLT for chronic cholestatic liver disease still develop de novo fractures after OLT; this situation demands an ongoing search for effective therapeutic agents for these patients.
Asunto(s)
Colangitis Esclerosante/complicaciones , Fracturas Óseas/etiología , Cirrosis Hepática Biliar/complicaciones , Trasplante de Hígado/efectos adversos , Osteonecrosis/etiología , Adulto , Enfermedades Óseas Metabólicas/complicaciones , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/fisiopatología , Colangitis Esclerosante/cirugía , Femenino , Estudios de Seguimiento , Fracturas Óseas/fisiopatología , Glucocorticoides/efectos adversos , Glucocorticoides/uso terapéutico , Humanos , Incidencia , Cirrosis Hepática Biliar/cirugía , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Análisis Multivariante , Osteonecrosis/fisiopatología , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Fracturing after liver transplantation (OLT) occurs due to the combination of preexisting low bone mineral density (BMD) and early posttransplant bone loss, the risk factors for which are poorly defined. The prevalence and predictive factors for hepatic osteopenia and osteoporosis, posttransplant bone loss, and subsequent bone gain were studied by the long-term posttransplant follow-up of 360 consecutive adult patients with end-stage primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Only 20% of patients with advanced PBC or PSC have normal bone mass. Risk factors for low spinal BMD are low body mass index, older age, postmenopausal status, muscle wasting, high alkaline phosphatase and low serum albumin. A high rate of spinal bone loss occurred in the first 4 posttransplant months (annual rate of 16%) especially in those with younger age, PSC, higher pretransplant bone density, no inflammatory bowel disease, shorter duration of liver disease, current smoking, and ongoing cholestasis at 4 months. Factors favoring spinal bone gain from 4 to 24 months after transplantation were lower baseline and/or 4-month bone density, premenopausal status, lower cumulative glucocorticoids, no ongoing cholestasis, and higher levels of vitamin D and parathyroid hormone. Bone mass therefore improves most in patients with lowest pretransplant BMD who undergo successful transplantation with normal hepatic function and improved gonadal and nutritional status. Patients transplanted most recently have improved bone mass before OLT, and although bone loss still occurs early after OLT, these patients also have a greater recovery in BMD over the years following OLT.
Asunto(s)
Densidad Ósea/fisiología , Trasplante de Hígado , Osteoporosis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
This article discusses the clinical importance of hepatic osteopenia, the identification of risk factors for the individual patient, and the selection of patients, timing, and methods for diagnostic screening. General supportive measures to maximize bone health should be used in all patients at risk. In addition, for the patient with established osteoporosis, specific therapeutic measures may be justified, despite the lack of adequate randomized trials of these agents in patients with hepatic osteopenia.
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Hepatopatías/complicaciones , Osteoporosis/etiología , Densidad Ósea , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/terapia , Difosfonatos/uso terapéutico , Terapia de Reemplazo de Estrógeno , Femenino , Humanos , Trasplante de Hígado , Masculino , Osteoporosis/diagnóstico , Osteoporosis/terapia , Factores de RiesgoAsunto(s)
Glándulas Suprarrenales/lesiones , Insuficiencia Suprarrenal/etiología , Hemorragia/complicaciones , Traumatismo Múltiple/complicaciones , Heridas no Penetrantes/complicaciones , Accidentes de Tránsito , Insuficiencia Suprarrenal/sangre , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/tratamiento farmacológico , Hormona Adrenocorticotrópica , Cuidados Críticos/métodos , Diagnóstico Diferencial , Tratamiento de Urgencia/métodos , Fluidoterapia/métodos , Hemorragia/diagnóstico , Hemorragia/cirugía , Humanos , Hidrocortisona/sangre , Hidrocortisona/uso terapéutico , Masculino , Persona de Mediana Edad , Traumatismo Múltiple/diagnóstico , Traumatismo Múltiple/cirugía , Recuperación de la Función , Resucitación/métodos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Heridas no Penetrantes/diagnóstico , Heridas no Penetrantes/cirugíaRESUMEN
Bone loss occurs early after orthotopic liver transplantation (OLT) in all liver transplant recipients and leads to postoperative fractures, especially in cholestatic patients with the lowest bone mass. Little is known about the underlying changes in bone metabolism after OLT or about the etiology of these changes. Histomorphometric analysis of bone biopsies, a method that allows assessment of bone volume, resorption, and formation, has shown improved bone metabolism at 4 months after OLT. It has further suggested that accelerated posttransplant bone loss occurs in the first 1-2 months after OLT, probably by an additional insult to bone formation. This study attempts to correlate the histomorphometric bone changes in paired bone biopsies (OLT and 4 months after OLT) of 33 patients undergoing OLT for chronic cholestatic liver disease with the many clinical and biochemical changes in these patients over the same period. Cumulative steroid dosage early after OLT is shown to be important, presumably by decreasing bone formation rates. The actual effect of calcineurin inhibitors on this early phase of bone loss is less clear, although posttransplant histomorphometric findings suggest that tacrolimus-treated patients have an earlier recovery of bone metabolism and trabecular structure compared with cyclosporine patients. Other factors important in the recovery of bone metabolism after the early phase of bone loss are recovery of liver and gonadal function and better calcium balance.
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Huesos/metabolismo , Trasplante de Hígado/fisiología , Densidad Ósea , Resorción Ósea/inmunología , Huesos/efectos de los fármacos , Ciclosporina/farmacología , Ciclosporina/uso terapéutico , Femenino , Glucocorticoides/administración & dosificación , Humanos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Trasplante de Hígado/inmunología , Vértebras Lumbares/fisiología , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Prednisona/administración & dosificación , Tacrolimus/farmacología , Tacrolimus/uso terapéuticoRESUMEN
UNLABELLED: Thirty-three patients with cholestatic liver disease underwent histomorphometric assessment of paired bone biopsy specimens at time of orthotopic liver transplantation (OLT) and 4 months thereafter. At 4 months after OLT, bone metabolism improved, with bone formation increasing to normal and no change in bone resorption. Early post-transplant bone loss may be attributed to an additional insult to bone formation early after transplantation. INTRODUCTION: Patients with advanced liver disease, especially chronic cholestasis, often have osteopenia, which worsens early after orthotopic liver transplantation (OLT) before starting to recover. The changes in bone metabolism leading to this rapid loss of bone after OLT, and to its recovery, are poorly defined. MATERIALS AND METHODS: In thirty-three patients with advanced chronic cholestatic liver disease, tetracycline-labeled bone biopsy specimens were analyzed prospectively at time of OLT and at 4 months after OLT, as part of a randomized trial to study the efficacy of calcitonin on post-transplant bone loss. Hierarchical cluster analysis of histomorphometric parameters was performed in an attempt to establish the functional grouping of individual histomorphometric parameters before and after OLT. RESULTS AND CONCLUSIONS: Results showed that from the time of OLT to 4 months after OLT, bone mineral density of the lumbar spine and histomorphometric parameters of bone volume decreased, consistent with early post-transplant bone loss. Histomorphometric resorption parameters were increased before OLT, with no change after OLT. Histomorphometric formation parameters increased from low values before OLT to normal values at 4 months after OLT, with the exception of mean wall thickness values, which further decreased after OLT, suggesting an additional insult to bone formation during the study period. Histomorphometric changes after OLT were similar in female and male patients, pre- and postmenopausal women, and in patients treated and not treated with calcitonin. Hierarchical cluster analysis suggested that before OLT, bone resorption was functioning independently of bone formation, but that by 4 months after OLT, their coupled relationship had improved. Therefore, despite post-transplant bone loss, by 4 months after OLT, bone metabolism had improved, with increased bone formation and more coupled bone balance, as suggested by hierarchical cluster analysis.
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Densidad Ósea/efectos de los fármacos , Resorción Ósea/prevención & control , Calcitonina/uso terapéutico , Colestasis Intrahepática/cirugía , Trasplante de Hígado/fisiología , Adulto , Biopsia , Desarrollo Óseo/efectos de los fármacos , Huesos/anatomía & histología , Huesos/efectos de los fármacos , Huesos/patología , Análisis por Conglomerados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Posmenopausia , Complicaciones PosoperatoriasRESUMEN
Non-anastomotic biliary stricture (NAS) formation is a major complication of liver transplantation. We prospectively determined the time to development of responsiveness to treatment, and clinical outcomes following NAS formation. In addition, an extensive analysis of the association of recipient, donor, and clinical variables with NAS formation was performed. A total of 749 consecutive patients was studied in a prospective, protocol-based fashion. Seventy-two patients (9.6%) developed NAS at a mean of 23.6 +/- 34.2 weeks post-transplantation. Non-anastomotic biliary stricture formation resolved in only 6% of affected patients. Although patient survival was not affected, retransplantation and graft loss rates were significantly greater in recipients who developed NAS. In contrast to previous reports, a pretransplant diagnosis of HCV was associated with a low frequency of NAS formation. The incidence of NAS was independently associated with pretransplant diagnoses of PSC and autoimmune hepatitis. Hepatic artery thrombosis, and prolonged warm and cold ischemia times were also independent risk factors for NAS formation. We conclude that NAS developed in approximately 10% of primary liver transplant recipients. A pretransplant diagnosis of autoimmune hepatitis has been identified as a novel independent risk factor for NAS formation. Development of NAS significantly attenuates graft but not patient survival.
Asunto(s)
Atresia Biliar/fisiopatología , Sistema Biliar/fisiopatología , Hepatopatías/complicaciones , Trasplante de Hígado , Adulto , Atresia Biliar/epidemiología , Sistema Biliar/anomalías , Humanos , Persona de Mediana EdadRESUMEN
Despite the clinical importance of cholestatic osteopenia, little is known about its pathophysiologic mechanism. By tetracycline-labeled histomorphometric analysis of bone biopsies taken at the time of liver transplantation, we prospectively evaluated bone resorption and formation in 50 consecutive patients with advanced primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Histomorphometric analysis confirmed low bone volume parameters, consistent with the mean T-score of the lumbar spine of -1.9 by dual energy x-ray absorptiometry. Dynamic (bone formation rates, adjusted apposition rates) and static (osteoid markers, osteoblast number) parameters of bone formation were decreased in cholestatic patients with no abnormalities in mineralization. Increased osteoclast numbers and increased eroded surface areas suggested increased bone resorption, and this was supported in female patients by increased trabecular separation and decreased trabecular number. Male cholestatic patients, however, did not have significant increases in resorption parameters, although they were as osteopenic as female patients and had low bone formation markers. Bone histomorphometric changes were similar in PBC and PSC, suggesting an etiologic effect of chronic cholestasis rather than the individual diseases. Cancellous bone volume and osteoid markers correlated with bone mineral density measurements but no correlations were found between histomorphometric parameters and biochemical markers of bone metabolism. In conclusion, cholestatic osteopenia appears to result from a combination of decreased bone formation and increased resorption, especially in female patients, but the relative importance of these two abnormalities and their actual etiology remain to be elucidated.