Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver transplantation is now widely recognised as an effective treatment option for patients with advanced liver disease. Many units now achieve greater than 85% survival at 1 year, with the majority of patients having a high quality of life. The maintenance of a high quality of life requires careful clinical management to ensure that the continued maintenance of excellent liver graft function is not achieved at the expense of immunosuppressive drug complications or morbidity. Acute liver rejection will occur in between 30 to 45% of patients, although with modern immunosuppressive protocols, usually combining one of the calcineurin agents, either cyclosporin or tacrolimus, with both azathioprine and corticosteroids (prednisolone) ensures that relatively few grafts are lost from severe acute rejection. While the incidence and severity of acute rejection may be one factor in raising the risk of chronic rejection, it may not be the principal one in many patients. It is important to recognise that the frequency of rejection also varies with the primary underlying liver disease, with patients with hepatitis B or alcoholic liver disease having relatively low rejection rates, compared with patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC), which range between 20 to 70%. Chronic rejection will account for some 5% of grafts lost in the first 3 to 5 years. Indeed, there is some evidence that the incidence of chronic rejection is actually declining over the past few years. While the reason for this apparent decline is uncertain, and it could relate to better immunosuppression management, or more likely to the growing recognition that chronic graft dysfunction may be due to recurrent liver disease, such as autoimmune hepatitis, PBC, PSC, or recurrent hepatitis C. The differentiation of recurrent primary liver disease from chronic rejection can prove to be very difficult in clinical practice. Thus, the clinician must carefully monitor liver and graft function, evaluate any biochemical changes, and try to reach a clear diagnosis before considering any modification of immunosuppressive schedules.
 ...
PMID:Chronic rejection of the liver: the role of immunosuppression. 1803 74

Tacrolimus is a potent immunosuppressant medication with a low therapeutic index. We report a case of mutism with persistent dysarthria in a patient receiving tacrolimus-based immunosuppression following allogeneic liver transplantation. A 59-year-old female patient with end-stage liver disease secondary to primary sclerosing cholangitis underwent successful allogeneic liver transplantation. The patient was started on tacrolimus for prevention of allograft rejection and subsequently developed complete mutism. Following consultation of the medical toxicology service, tacrolimus was discontinued and the patient's mutism gradually improved. However, the patient still has moderate dysarthria more than 2 years after tacrolimus discontinuation. The Naranjo probability scale revealed a probable adverse reaction of mutism and dysarthria associated with tacrolimus therapy. Mutism is an uncommon complication of calcineurin inhibitors. Both cyclosporine and tacrolimus have been associated with mutism, though mutism may be more common in patients treated with tacrolimus. The mechanism of injury has not been delineated, although liver transplant patients and patients with preexisting hepatic encephalopathy or neurologic disease may be at increased risk for this complication. The mainstay of treatment is tacrolimus dose reduction or discontinuation, although benzodiazepine therapy may be beneficial in the treatment of this disorder. Clinicians should be aware of the potential adverse effects associated with calcineurin inhibitor toxicity in transplant patients and should advocate for aggressive and rapid treatment of this serious adverse drug effect.
 ...
PMID:Mutism and persistent dysarthria due to tacrolimus-based immunosuppression following allogeneic liver transplantation. 2053 6

Autoimmune hepatitis (AIH) is an immune-mediated liver disorder characterised by female preponderance, elevated transaminase and immunoglobulin G levels, seropositivity for autoantibodies and interface hepatitis. Presentation is highly variable, therefore AIH should be considered during the diagnostic workup of any increase in liver enzyme levels. Overlap/variant forms of the disease, presenting with concomitant features of primary biliary cirrhosis or primary sclerosing cholangitis are increasingly recognised. AIH is exquisitely responsive to immunosuppressive treatment, which should be instituted promptly to prevent rapid deterioration and promote remission and long-term survival. Difficult-to-treat or non-responsive patients should be treated with mycophenolate mofetil or, failing that, calcineurin inhibitors. Persistent failure to respond or lack of adherence to treatment result in end-stage liver disease. These patients, and those with fulminant liver failure (encephalopathy grade II-IV) at diagnosis, will require liver transplantation. The pathogenesis of AIH is not fully understood, although there is mounting evidence that genetic susceptibility, molecular mimicry and impaired immunoregulatory networks contribute to the initiation and perpetuation of the autoimmune attack. Liver damage is thought to be mediated primarily by CD4(pos) T-cells, although recent studies support the involvement of diverse populations, including Th17 cells. Animal models faithfully representing the human condition are needed to unravel the contribution of innate and adaptive, effector and regulatory immune responses. A deeper understanding of the pathogenesis of AIH is likely to contribute to the development of novel treatments, such as the adoptive transfer of autologous expanded antigen-specific regulatory T-cells, which ultimately aim to restore tolerance to liver-derived antigens.
 ...
PMID:Autoimmune hepatitis: a comprehensive review. 2321 32