INTRODUCTION — For liver transplant recipients, the goal of immunosuppression is to reduce the risk of graft rejection while minimizing the risk of recurrent liver disease and adverse effects related to immunosuppression (eg, infection). Immunosuppressive agents are initiated at the time of transplant and continued long-term as maintenance therapy. In most liver transplant centers, tacrolimus is the cornerstone of long-term immunosuppression, but the availability of alternative therapies allows for customizing the drug regimen.
對於肝臟移植病人來說，免疫抑制的目標是降低植體排斥的風險，同時最大程度地降低復發肝病的風險以及與免疫抑制相關的不良反應（例如感染）。免疫抑制劑在移植時開始使用，並作為維持治療長期持續。在多數肝臟移植中心， Tacrolimus 是長期免疫抑制的基礎，但替代療法的利用允許定製藥物治療方式。

This topic will discuss initiating immunosuppression following liver transplantation and maintaining long-term immunosuppressive therapy.
本專題將討論肝臟移植後啟動免疫抑制和維持長期免疫抑制治療。

The following transplant issues are discussed separately:

●Diagnosis and treatment of acute T-cell mediated (cellular) rejection. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft" and "Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft".)
急性 T 細胞媒介的（細胞）排斥反應的診斷和治療。 (請參閱「成人肝臟移植：同種異體肝植體急性T細胞媒介的(細胞)排斥反應的症狀和診斷」和「成人肝移植：同種異體肝植體急性T細胞媒介的(細胞)排斥反應的治療」 .)

●Long-term management of liver transplant recipients including health maintenance and complications of immunosuppression. (See "Liver transplantation in adults: Long-term management of transplant recipients".)
肝臟移植病人的長期治療，包括健康維護和免疫抑制併發症。 (請參閱「成人肝臟移植：移植病人的長期治療」)

●Infectious complications following liver transplantation. (See "Infectious complications in liver transplantation".)
肝臟移植後的感染性併發症。 (參閱「肝臟移植中的感染併發症」)

PATHOPHYSIOLOGY OF ACUTE REJECTION — Organ rejection is a multistep process that includes the following (figure 1 and figure 2):
器官排斥是一個多步驟的過程，包括以下步驟（圖 1 和圖 2）：

●Signal I: Alloantigen recognition – Alloantigen recognition requires presentation of a foreign alloantigen along with a host major histocompatibility complex (MHC) molecule. Presentation is done by an antigen-presenting cell (APC). The antigen, bound to an MHC molecule, binds to the T-cell receptor. This is the first of three signals that are required for T-cell maturation and can be aborted by antilymphocyte antibodies.
訊號 I：同種異體抗原辨識 – 同種異體抗原辨識需要呈​​現外源同種異體抗原以及宿主主要組織相容性複合體 (MHC) 分子。呈現由抗原呈現細胞（APC）完成。與 MHC 分子結合的抗原與 T 細胞受體結合。這是 T 細胞成熟所需的三個訊號中的第一個，可以抗淋巴球抗體中。

●Signal II: Lymphocyte activation (costimulation) – T-cell activation requires costimulation, a process in which a number of ligands on the APC bind to a variety of T-cell receptors, including CD28, CD154, CD2, CD11a, and CD54. The T-cell receptor complex is internalized and binds to immunophilin. Immunophilin stimulates calcineurin, which activates nuclear factor of T-cell activation (NFAT) by removing pyrophosphate. The activated NFAT then translocates to the nucleus where it drives transcription of interleukin (IL)-2 and other cytokines. Two immunophilin targets, cyclophilin and FK-binding protein, are targets of cyclosporine and tacrolimus, respectively. Both agents block calcineurin and are known collectively as calcineurin inhibitors. (See 'Calcineurin inhibitors' below.)
訊號 II：淋巴球活化（共刺激）－T 細胞活化需要共刺激，在此過程中，APC 上的許多配體與各種 T 細胞受體結合，包括 CD28、CD154、CD2、CD11a 和 CD54。 T 細胞受體複合體被內化並與親免素結合。親免素刺激鈣調神經磷酸酶，後者通過清除 Pyrophosphate 來活化 T 細胞活化核因子 (NFAT)。然後，活化的 NFAT 會移位到細胞核，操作 IL (IL)-2 和其他細胞激素的轉錄。兩個親免素目標，親環素和 FK 結合蛋白，分別是 Cyclosporine 和 Tacrolimus 的標靶。這兩種藥物均可阻斷鈣調磷酸酶，統稱為鈣調磷酸酶抑制劑(Calcineurin Inhibitor)。 (參閱下文『鈣調神經磷酸酶抑制劑’)

●Signal III: Clonal expansion – Newly synthesized IL-2 is secreted by T cells and binds to IL-2 receptors on the cell surface in an autocrine fashion, stimulating a burst of cell proliferation. Basiliximab, a monoclonal antibody against the IL-2 receptor, blocks this signal. Sirolimus, which binds to the downstream mechanistic target of rapamycin (mTOR), also acts at this step. Finally, the proliferation burst can be inhibited at the level of DNA synthesis by azathioprine and mycophenolate. (See 'Alternatives to systemic glucocorticoids' below and 'Use of mechanistic target of rapamycin (mTOR) inhibitors' below.)
訊號 III：克隆擴張－新合成的 IL-2 由 T 細胞分泌，並以自分泌方式與細胞表面的 IL-2 受體結合，刺激細胞增生。 Basiliximab 是一種針對 IL-2 受體的單株抗體，可阻斷此訊號。與 Rapamycin 下游機轉標靶 (mTOR) 結合的 Sirolimus 也在這一步發揮作用。最後， Azathioprine 和 Mycophenolate 能在 DNA 合成層面抑制增生爆發。 (請參閱下文『全身性類固醇的替代藥物』及『 Rapamycin (mTOR)機械標靶抑制劑的使用』)

●Graft inflammation – T-cell proliferation is associated with cell-mediated cytotoxicity and secretion of cytokines, chemokines, and adhesion molecules. The secreted mediators recruit additional inflammatory cells to the graft. The result is an inflammatory milieu with additional toxic and vasoactive mediators. Glucocorticoids and anti-thymocyte globulin are therapies that inhibit this step. (See 'Glucocorticoids' below and "Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft", section on 'Therapy for nonresponders'.)
植體發炎－T 細胞增生與細胞媒介的細胞毒性以及細胞激素、趨化因子和凝集分子的分泌有關。分泌的介質將額外的發炎細胞招募到植體中。結果是產生具有額外毒性和血管活性介質的發炎環境。類固醇和抗胸腺細胞球蛋白是抑制此步驟的療法。 (請參閱下文‘類固醇’和“成人肝臟移植：同種異體肝植體急性 T 細胞媒介的(細胞)排斥的治療”，關於‘無反應者的治療’一節)

GENERAL PRINCIPLES

Goals — All liver transplant recipients receive immunosuppression following transplantation. The goal of immunosuppression is to lower the risk of rejection, while minimizing the risk of adverse drug effects and recurrent liver disease.
目標 — 所有肝臟移植病人在移植後均接受免疫抑制。免疫抑制的目標是降低排斥反應的風險，同時最大程度地降低藥物不良反應和復發肝病的風險。

Transplant expertise — Multiple specialists are involved in the care of liver transplant recipients immediately after transplant (eg, transplant surgeon, transplant hepatologist, clinical pharmacist). After several months, the transplant center typically continues to manage the immunosuppressive agents, treat recurrent liver disease, and manage biliary complications. In addition, the transplant center may also manage adverse effects related to immunosuppression (eg, kidney disease).
移植專業知識 — 多位專家在移植後立即參與肝臟移植病人的照護（例如移植外科醫師、移植肝病學家、臨床藥師）。幾個月後，移植中心通常會繼續使用免疫抑制劑、治療復發肝病並處理膽道併發症。此外，移植中心還可以與免疫抑制相關的不良反應（例如腎臟疾病）。

Drug interactions — Some immunosuppressive agents have drug interactions that may necessitate dose adjustments (table 1). Both calcineurin inhibitors (CNIs) and mechanistic target of rapamycin (mTOR) inhibitors are metabolized by CYP3A4, a member of the cytochrome P450 enzyme system. This creates the potential for other drugs that inhibit or induce CYP34A to cause drug-drug interactions that may result in toxic or subtherapeutic drug levels that are associated with increased risk of rejection. As examples, antifungal agents and some antibiotics inhibit CYP3A4 (table 2).
藥物交互作用 — 有些免疫抑制劑具有藥物交互作用，可能需要調整劑量(表 1)。鈣調神經磷酸酶抑制劑 (CNI) 和 Rapamycin 機械標靶 (mTOR) 抑制劑均由細胞色素 P450 酶系統成員 CYP3A4 代謝。這使得其他抑制或誘導 CYP34A 藥物有可能引起藥物間交互作用，並因此可能產生有毒或低於治療藥物水平，並因此增加排斥風險。例如，抗黴菌藥物和一些抗生素會抑制 CYP3A4（表 2）。

Consultation with a clinical pharmacist may help with identifying and managing interactions through dose adjustments. For more information on potential drug-drug interactions, refer to the drug interactions program within UpToDate.
諮詢臨床藥師可能有助於透過劑量調整來辨識與控制交互作用。有關潛在藥物交互作用的更多資訊，請參閱 UpToDate 中藥物交互作用計劃。

INITIAL THERAPY

General approach — For most liver transplant recipients, the immunosuppressive regimen is center-specific and informed by the drug's mechanism of action, the available published evidence, and clinical experience.
一般方法 — 對於多數肝臟移植病人來說，免疫抑制治療方式是針對特定中心的，並根據藥物的作用機轉、現有已發表的證據和臨床經驗區分。

We typically use an initial regimen consisting of triple immunosuppression with the following agents [1]:
我們通常使用由三重免疫抑制和以下藥物組成的起始治療方式[1]：

●A glucocorticoid (see 'Glucocorticoids' below)

●A calcineurin inhibitor (CNI; usually tacrolimus) (see 'Calcineurin inhibitors' below)
鈣調磷酸酶抑制劑(Calcineurin Inhibitor)（CNI；通常是 Tacrolimus ）（請參閱下文『鈣調磷酸酶抑制劑(Calcineurin Inhibitor)』）

●An antimetabolite (usually mycophenolate) (see 'Antimetabolite agents' below)
抗代謝藥（通常為 Mycophenolate ）（請參閱下文『抗代謝藥』）

We maximize the level of immunosuppression in the early post-transplant period (ie, during the first three months post-transplant) when the risk of rejection is greatest. As an example, we administer a glucocorticoid intravenously immediately post-transplant and continue it for several days until transitioning to an oral glucocorticoid that is then gradually tapered over the next several weeks to months.
我們在移植後早期（即移植後的前三個月）最大程度地提升免疫抑制水平，此時排斥風險最大。例如，我們在移植後立即靜脈注射類固醇，並持續幾天，直到轉換至口服類固醇，然後在接下來的幾周到幾個月內逐漸減量。

We use drug trough levels to titrate the dose of some immunosuppressive agents (eg, CNIs). We target higher drug levels earlier in the post-transplant course. As the duration of time after transplant increases, we aim for lower drug levels in patients without acute T-cell mediated (cellular) rejection. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft".)
分析藥物最低濃度來調整一些免疫抑制劑（例如，CNI）。我們在移植後過程的早期階段就以較高藥物水平為目標。隨著移植後時間的延長，我們的目標是在沒有急性 T 細胞媒介的（細胞）排斥的病人中降低藥物濃度。 (參閱「成人肝臟移植：同種異體肝臟植體急性T細胞媒介的(細胞)排斥反應的症狀和診斷」)

In general, all liver transplant recipients receive lifelong immunosuppression because the lack of immunosuppression routinely results in graft rejection and graft loss. To transition from the initial to a long-term maintenance regimen, we typically reduce the doses of the immunosuppressants. (See 'Maintenance therapy' below.)
一般而言，所有肝臟移植病人都會接受終生免疫抑制，因為缺乏免疫抑制通常會造成植體排斥和植體減少。為了從起始維持治療方式轉換至長期維持治療方式，我們通常會減少免疫抑制劑。 (參閱下文‘維持治療’)

For most recipients, we do not include an mTOR inhibitor as part of the long-term immunosuppressive regimen. However, we may use an mTOR inhibitor as an alternative agent for selected patients (eg, those intolerant of CNIs due to toxicity). (See 'When and how to modify maintentance therapy' below.)
對於多數接受者，我們不將 mTOR 抑制劑作為長期免疫抑制治療方式的一部分。然而，我們可以使用 mTOR 抑制劑作為選定病人（例如，因毒性而無法耐受 CNI 的病人）的替代藥物。 (參閱下文『何時及如何調整維持治療』)

Glucocorticoids — Systemic glucocorticoids are the cornerstone of the initial immunosuppressive regimen after transplant because they suppress antibody and complement binding, upregulate expression of interleukin (IL)-10, and downregulate T cell synthesis of IL-2, IL-6, and interferon-gamma [2-4].
類固醇— 全身性類固醇是移植後起始免疫抑制治療方式的基礎，因為它們抑制抗體和補體結合，提高 IL-(IL)-10 的表現，並減少T 細胞IL-2、IL-6 和干擾素-γ 的合成[2-4]。

Dosing and administration — Glucocorticoid regimens vary among transplant centers, and consensus on dosing is lacking. We administer methylprednisolone in a bolus dose beginning with 1000 mg intravenously intraoperatively, followed by four days of gradually decreasing the methylprednisolone dose, and then transitioning to oral prednisone. We then gradually taper the prednisone dose with the goal of discontinuing it by approximately six months posttransplant.
劑量與給藥 — 不同移植中心的類固醇治療方式各不相同，且缺乏劑量共識。我們以術中靜脈注射 1000 mg 開始推注 Methylprednisolone ，隨後四天逐漸減少 Methylprednisolone 劑量，然後過渡為口服 Prednisone 。然後，我們逐漸減少 Prednisone 劑量，目標是在移植後約六個月內停止使用。

An example of a glucocorticoid dosing protocol following liver transplantation is provided in the table (table 3).
表中提供了肝臟移植後類固醇處方的範例（表 3）。

Some transplant centers administer higher doses of glucocorticoids during the first four days post-transplant, followed by a more rapid glucocorticoid taper to achieve a prednisone dose of 5 mg daily by one-month post-transplant. Beginning at 6 to 12 months post-transplant, prednisone is then slowly tapered by reducing the dose in 1 mg increments every 1 to 2 months until it is discontinued. Based on clinical experience, a slow, gradual glucocorticoid taper lowers the risk of acute cellular rejection or an underlying disease flare (eg, autoimmune hepatitis).
有些移植中心在移植後的前四天內給予較高劑量的類固醇，然後較快地逐漸減量類固醇，以在移植後一個月內達到每日 5 mg， Prednisone 劑量。從移植後 6 至 12 個月開始， Prednisone 逐漸減量，每 1 至 2 個月減少 1 mg 劑量，直到停藥。根據臨床經驗，緩慢、逐漸減量類固醇可降低急性細胞排斥或潛在疾病發作（例如自體免疫性肝炎）的風險。

Alternatively, some centers may continue a low-dose oral glucocorticoid indefinitely (eg, prednisone 5 mg daily).
或者，一些中心可能會無緊急地繼續使用低劑量口服類固醇（例如，每日 5 mg Prednisone ）。

Managing glucocorticoid-related toxicity — A major complication of glucocorticoids is increased susceptibility to infection, especially oral candidiasis, cytomegalovirus (CMV), Aspergillus, Pneumocystis jirovecii (previously referred to as P. carinii), and bacterial pathogens [5]. Other potential problems include impaired wound healing, hyperglycemia, hypertension, peptic ulcer disease, psychiatric conditions (eg, depression), visual changes, and osteopenia. (See "Major adverse effects of systemic glucocorticoids".)
處理類固醇相關的毒性— 類固醇的一個主要併發症是對感染的感受性增加，尤其口腔念珠感染、巨細胞病毒(CMV)、麴菌、耶氏肺囊蟲(以前稱為卡氏肺孢子蟲)和細菌病原體[5]。其他潛在問題包括傷口癒合受損、高血糖、高血壓、消化性潰瘍病、精神疾病（如憂鬱症）、視力變化和骨質減少。 (參閱「全身性類固醇的主要不良反應」)

The approach to managing glucocorticoid-related toxicity includes monitoring blood glucose levels and infection prophylaxis, and these issues are discussed separately. (See "Liver transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection of the liver allograft", section on 'Managing glucocorticoid-related toxicity' and "Infectious complications in liver transplantation".)
管理類固醇相關毒性的方法包括監測血糖和預防感染，這些問題請參閱其他專題。 (請參閱“成人肝臟移植：同種異體肝臟植體急性T細胞媒介的(細胞)排斥反應的治療”，關於‘處理類固醇相關毒性’一節和“肝臟移植中的感染併發症”)

Whether the benefits of withdrawing glucocorticoids outweigh the potential risks is uncertain. Thus, the decision to withdraw glucocorticoids is informed by patient characteristics (eg, risk factors for graft rejection) as well as transplant center-specific protocols. In a meta-analysis of 16 trials comparing early glucocorticoid avoidance or withdrawal with glucocorticoid-containing immunosuppression in 1347 liver transplant recipients, there were no statistically significant differences in rates of mortality, graft loss, or infections between the groups [6]. Glucocorticoid avoidance or withdrawal was associated with increased risk of acute cellular rejection (relative risk [RR] 1.33, 95% CI 1.08-1.64) and glucocorticoid-resistant rejection (RR 2.14, 95% CI 1.13-4.02). However, glucocorticoid avoidance or withdrawal was associated with lower risks of diabetes mellitus (RR 0.81, 95% CI 0.66-0.99) and hypertension (RR 0.76, 95% CI 0.65-0.90).
停用類固醇的效益是否大於潛在風險仍不清楚。因此，撤回類固醇的決定取決於病人之特性（例如植體排斥的危險因子）以及移植中心特定的治療方式。有1篇統合分析中，對1347 名肝臟移植病人的早期類固醇避免或戒斷與含類固醇的免疫抑制劑進行比較，結果顯示，各組之間的死亡率、器官移植失敗或感染率沒有統計上的顯著差異[6]。避免或戒斷類固醇與急性細胞排斥風險增加（相對風險[RR] 1.33，95% CI 1.08-1.64）和類固醇抗藥性排斥風險增加（RR 2.14，95% CI 1.13-4.02）相關。然而，避免或戒斷類固醇與降低糖尿病（RR 0.81，95% CI 0.66-0.99）和高血壓（RR 0.76，95% CI 0.65-0.90）風險有關。

Alternatives to systemic glucocorticoids — Although initial immunosuppressive therapy after liver transplant typically includes systemic glucocorticoids, other agents are available for patients intolerant of glucocorticoids:
全身性類固醇的替代方案 — 雖然肝臟移植後的起始免疫抑制治療通常包括全身性類固醇，但對於類固醇無法耐受的病人也可以使用其他藥物：

●Monoclonal antibodies – Monoclonal antibodies against specific cell surface proteins such as the IL-2 receptor are not typically used as first-line immunosuppressive agents in liver transplantation. However, they have important roles as glucocorticoid- or CNI-sparing agents [7]. (See 'Alternatives to calcineurin inhibitors' below.)
單株抗體 – 針對特定細胞表面蛋白（例如 IL-2 受體）的單株抗體通常不會用作肝臟移植中的第一線免疫抑制劑。然而，它們作為類固醇或 CNI 保留劑扮演重要角色 [7]。 (參閱下文『鈣調神經磷酸酶抑制劑的替代’)

Basiliximab is a monoclonal antibody against the IL-2 receptor on activated T cells. Blockade of the IL-2 receptor prevents T-cell proliferation.
Basiliximab 是一種針對活化 T 細胞上 IL-2 受體的單株抗體。阻斷 IL-2 受體可防止 T 細胞增生。

For liver transplant recipients who do not tolerate glucocorticoids, we administer intravenous (IV) basiliximab 20 mg, intraoperatively, and 20 mg on postoperative day 4. This regimen is similar to basiliximab use for inducing immunosuppression in kidney transplant recipients. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Basiliximab'.)
對於無法耐受類固醇的肝臟移植病人，我們在術中靜脈注射(IV) Basiliximab 20 mg，並在術後第4 天給予20 mg。腎臟移植病人中誘導免疫抑制的使用類似。 (請參閱“成人腎臟移植：免疫抑制劑誘導治療”，關於‘ Basiliximab ’一節)

●Budesonide – Budesonide is a glucocorticoid with limited systemic effects because of high first-pass hepatic extraction from portal venous blood. We do not use budesonide for initial immunosuppression because data from clinical studies are limited and because its modest serum concentrations are less effective for downregulating effector T cells in peripheral lymph nodes [8,9]. In a study comparing a budesonide-based regimen in 20 liver transplant recipients with a prednisone-based regimen in recipients who were matched for age, sex, autoimmune liver disease and use of anti-thymocyte globulin, budesonide was associated with lower rates of new-onset diabetes mellitus (0 versus 15 percent) and infection (0 versus 30 percent) at six months after transplant [9]. (See "Overview of budesonide therapy for adults with inflammatory bowel disease", section on 'Pharmacology'.)
Budesonide – Budesonide 是一種類固醇，由於門靜脈血的肝臟首渡效應較高，因此全身影響有限。我們未使用 Budesonide 進行起始免疫抑制，因為臨床試驗的數據有限，而且其適度的血中濃度對於減少周邊淋巴結中的影響T細胞效果較差[8,9]。有1篇研究中，對20 名肝移植病人對 Budesonide 的治療方式與年齡、性別、自體免疫性肝病和抗胸腺細胞球蛋白的使用相匹配的病人對 Prednisone 的治療方式進行比較， Budesonide 與較低的新生生率相關。 (參閱“ Budesonide 治療成人發炎性腸道疾病的簡要介紹”，關於‘藥理學’一節)

Calcineurin inhibitors — For most liver transplant recipients, CNI therapy is initiated postoperatively and continued as the cornerstone of long-term maintenance therapy. We typically use tacrolimus as the first-line CNI because studies demonstrated that tacrolimus resulted in lower risk of acute cellular rejection and mortality compared with cyclosporine [10-14]. Tacrolimus is better tolerated overall and does not lower mycophenolate levels, although tacrolimus has been associated with higher rates of new onset diabetes mellitus. In a meta-analysis of 16 trials including 3813 liver transplant recipients, tacrolimus resulted in lower risk of mortality and graft loss in the first year post-transplant compared with cyclosporine (RR 0.85, 95% CI 0.73-0.99 and RR 0.73, 95% CI 0.61-0.86, respectively) [10]. However, the risk of new onset diabetes mellitus was higher with tacrolimus (RR 1.38, 95% CI 1.01-1.86).
鈣調神經磷酸酶抑制劑 — 對於多數肝臟移植病人來說，CNI 治療是在術後開始的，並作為維持治療的基礎繼續進行。我們通常使用 Tacrolimus 作為第一線 CNI，因為研究證明，與 Cyclosporine 相比， Tacrolimus 可降低急性細胞排斥和死亡率的風險 [10-14]。雖然 Tacrolimus 與較高的新生糖尿病發生率有關，但 Tacrolimus 整體耐受性較佳，並且不會降低 Mycophenolate 水平。有1篇針對16 項試驗（包括3813 名肝臟移植病人）進行的統合分析中，與 Cyclosporine 相比， Tacrolimus 在移植後第一年可降低死亡和植體減少的風險（ RR 0.85，95% CI 0.73-0.99 和RR 0.73，95% CI 分別為 0.61-0.86）[10]。然而，使用 Tacrolimus 時新生生糖尿病風險增加（RR 1.38，95% CI 1.01-1.86）。

CNIs selectively inhibit calcineurin, thereby impairing the transcription of the T cell mitogen IL-2 and other cytokines. By inhibiting cytokine gene transcription, CNIs suppress effector T cell proliferation and T cell-dependent B cell activation. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Calcineurin inhibitors'.)
CNI 選擇性抑制鈣調神經磷酸酶，進而損害 T 細胞有絲分裂原 IL-2 和其他細胞激素的轉錄。透過抑制細胞激素基因轉錄，CNI 抑制影響 T 細胞增生和 T 細胞依賴型 B 淋巴球活化。 (請參閱“成人腎臟移植：免疫抑制劑治療”，關於‘鈣調神經磷酸酶抑制劑’一節)

Tacrolimus (commonly-used)

Pharmacology — Tacrolimus inhibits IL-2 and interferon-gamma production and is 100 times more potent than cyclosporine. Oral bioavailability varies widely (5 to 67 percent), and an oral dose of 0.15 mg/kg results in a peak drug concentration of 0.4 to 3.7 ng/mL. Tacrolimus is metabolized in the liver by CYP3A4 and is not removed by dialysis. (See "Pharmacology of calcineurin inhibitors", section on 'Mechanism of action'.)
藥理 — Tacrolimus 可抑制 IL-2 和干擾素 γ 的產生，其療效比 Cyclosporine 強 100 倍。口服生體可用率差異很大（5％~67％），0.15mg/kg的口服劑量造成藥物最高(Peak)濃度為0.4-3.7ng/mL。 Tacrolimus 在肝臟中經由 CYP3A4 代謝，不會經由透析清除。 (參閱“鈣調神經磷酸酶抑制劑的藥理學”，關於‘作用機轉’一節)

Dosing and administration — There is wide variation in dosing between centers, although for most patients the recipient's kidney function informs the timing and dosing of initial tacrolimus therapy:
劑量與用法 — 雖然對於多數病人來說，接受者的腎功能決定了起始 Tacrolimus 治療的時間和劑量，但不同中心之間的劑量存在很大差異：

●No kidney impairment – We typically start with a low dose of 2 mg by mouth every 12 hours on postoperative day 1 and adjust the dosing to achieve a trough level of 8 to 12 ng/mL by the end of the first week post-transplant.
無腎損傷－我們通常在術後第一天每 12 小時口服 2 mg，低劑量開始，並在移植後第一週結束時調整劑量以達到 8 至 12 ng/ml的最低濃度。

●Kidney impairment – For patients who meet criteria for perioperative acute kidney injury (table 4) and/or chronic kidney disease (table 5) and who did not receive a combined liver-kidney transplant, we either delay initiation of tacrolimus until at least postoperative day 2 or use an alternative agent such as basiliximab. (See 'Alternatives to systemic glucocorticoids' above and "Definition and staging criteria of acute kidney injury in adults" and "Definition and staging of chronic kidney disease in adults".)
腎功能不全– 對於符合手術全期急性腎損傷（表4）和/或慢性腎臟病（表5）標準且未接受肝腎聯合移植的病人，我們 or 將 Tacrolimus 的開始使用延遲到至少術後一天2 或使用替代藥物，例如 Basiliximab 。 (參閱上文『全身性類固醇的替代藥物』和「成人急性腎損傷的定義和分期標準」和「成人慢性腎臟病的定義和分期」)

For patients with kidney impairment who are starting tacrolimus, we begin with 2 mg every 12 hours and adjust the dosing to achieve a lower target trough level of ≤8 ng/mL until their kidney injury improves.
對於開始使用 Tacrolimus 的腎功能不全病人，我們從每 12 小時 2 mg 開始，並調整劑量來達到 ≤8 ng/mL 的較低最低目標濃度水平，直到腎損傷改善。

For all patients, we typically obtain drug trough levels daily during the post-transplant hospitalization (table 6), and subsequent monitoring is discussed below. (See 'Monitoring' below.)
對於所有病人，我們通常在移植後住院期間每日搜集藥物最低（表 6），隨後的監測將在下面討論。 （請參閱下文『監測』。）

Observational data suggested that achieving target tacrolimus trough levels in the early post-transplant period was associated with improved outcomes. In a study of 493 liver transplantation recipients who were treated with tacrolimus as their primary immunosuppressive agent, a tacrolimus level >7 ng/mL at the time of a protocol liver biopsy (mean of six days after transplantation) was associated with lower rates of moderate or severe rejection compared with drug levels <7 ng/mL (24 versus 41 percent) [15]. Compared with achieving tacrolimus trough levels between 7 and 10 ng/mL within 15 days after transplant, trough levels outside the target range were associated with higher risk of graft loss after a median follow-up of seven years (trough level <7 ng/mL: RR 2.32, 95% CI 1.28-4.16, and trough level 10 to 15 ng/mL: RR 2.17, 95% CI 1.16-4.03).  
觀察數據證明，在移植後早期達成目標 Tacrolimus 最低與改善結果相關。有1篇對493 名接受 Tacrolimus 作為主要免疫抑制劑治療的肝移植病人的研究中，在治療方式肝臟組織切片時（移植後六天的平均值） Tacrolimus 水平>7 ng/mL與較低的中度免疫抑制劑發生率相關。與移植後15 天內 Tacrolimus 最低濃度達到7 至 10 ng/mL 相比，中位追蹤七年後，超出目標範圍的最低濃度與植體流失風險增加相關（最低濃度<7 ng/ mL) ：RR 2.32，95% CI 1.28-4.16，最低(Trough) 10 至 15 ng/mL：RR 2.17，95% CI 1.16-4.03）。

Cyclosporine — Cyclosporine is an alternative CNI for patients who have experienced or are at risk for tacrolimus-associated toxicity. (See 'Calcineurin inhibitor (CNI)-related toxicity' below.)
Cyclosporine — Cyclosporine 是一種替代 CNI，適用於經歷過 Tacrolimus 相關毒性或有 Tacrolimus 相關毒性風險的病人。 (參閱下文『鈣調神經磷酸酶抑制劑(CNI)相關毒性’)

Pharmacology — Cyclosporine, a peptide derived from the fungus Cylindrocarpon lucidum, is a potent immunosuppressive agent [16]. It inhibits T-cell activation by binding intracellular cyclophilin, thus reducing calcineurin activation. Without calcineurin, the nuclear factor of activated T cells (NFAT) does not translocate to the nucleus and does not cause production of IL-2 and other cytokines. This markedly diminishes T-cell response to class I and class II antigens resulting in a significant reduction in rejection.
藥理學 — Cyclosporine 是一種從黴菌 Cylindrocarpon lucidum 中萃取的 Peptides ，是一種有效的免疫抑制劑[16]。它透過結合細胞內親環蛋白來抑制 T 細胞活化，並因此減少鈣調神經磷酸酶的活化。如果沒有鈣調神經磷酸酶，活化 T 細胞的核因子 (NFAT) 不會轉位到細胞核，也不會造成 IL-2 和其他細胞激素的產生。這顯著減弱了 T 細胞對 I 類和 II 類抗原的反應，大幅減少排斥反應。

Formulations and dosing — Cyclosporine is available in modified and unmodified formulations (table 7). Modified cyclosporine is a microemulsion formulation that does not depend on bile salts for its absorption and, thus, has increased bioavailability and more consistent absorption. The microemulsion formulation is preferred for liver transplant recipients who may have alterations in production and delivery of bile salts into the gut due to biliary complications, drug-induced cholestasis, or acute cellular rejection.
劑型與劑量 — Cyclosporine 有改良劑型及未改良劑型（表 7）。改良 Cyclosporine 是一種微乳液製劑，其吸收不依賴膽鹽，因此具有較高的生體可用率和更一致的吸收。微乳製劑是肝臟移植病人的首選，他們可能會因為膽道併發症、藥物引起的膽汁淤積或急性細胞排斥而造成膽鹽的產生和輸送到腸道中改變。

The typical starting dose for microemulsion cyclosporine is 1 to 2 mg/kg every 12 hours. We typically obtain drug trough levels daily during the post-transplant hospitalization, and subsequent monitoring is discussed below. (See 'Monitoring' below.)
微乳 Cyclosporine 的典型起始劑量為每 12 小時 1 至 2 mg/kg。我們通常在移植後住院期間每日搜集藥物最低，隨後的監測將在下面討論。 （請參閱下文『監測』。）

Because nonmodified oral cyclosporine depends upon bile salts for absorption, it has inconsistent bioavailability and gastrointestinal absorption patterns that limit its use. The formulations of cyclosporine are discussed in more detail separately. (See "Pharmacology of calcineurin inhibitors", section on 'Cyclosporine'.)
由於未經改變結構口服 Cyclosporine 依賴膽鹽吸收，因此其生體可用率和胃腸道吸收模式不一致，限制了其使用。 Cyclosporine 的製劑將單獨更詳細地討論。 (參閱“鈣調神經磷酸酶抑制劑的藥理學”，關於‘ Cyclosporine ’一節)

Monitoring — The frequency of monitoring CNI trough levels varies depending on the duration of time post-transplant and transplant center protocol. We typically use the following monitoring schedule:
監測 — 監測 CNI 最低濃度的頻率會根據移植後的用藥天數和移植中心治療方式而改變。我們通常會使用以下監測計劃：

●Immediate post-transplant period of hospitalization: Daily CNI trough level

●Following hospital discharge until achieving target drug level with stable dose: Twice weekly CNI level
出院後直到以穩定劑量達成目標藥物濃度：每週兩次 CNI 水平

●After achieving stable dose: Weekly CNI levels for one month, then once monthly thereafter
達到穩定劑量後：一個月每週一次 CNI 水平，然後每月一次

In addition, we check drug levels if the transplant recipient develops an acute illness or starts a new medication with potential for interaction (table 1).
此外，如果移植病人出現急性疾病或開始使用可能出現交互作用的新藥物，我們會檢查藥物濃度（表 1）。

When measuring CNI levels, we also measure electrolytes, magnesium, and serum creatinine. We check blood pressure daily during hospitalization and with each outpatient follow-up visit.
在測量 CNI 水平時，我們也測量電解質、鎂和 Scr 。我們在住院期間和每次門診追蹤時每日檢查血壓。

The target trough levels vary among transplant center protocols and may be individualized based on etiology of liver disease (eg, targeting the lower end of the range for recipients with a nonimmune etiology such as those with nonalcohol-associated fatty liver disease, viral hepatitis, or alcohol-related liver disease):
最低目標濃度值因移植中心治療方式而異，並且可以根據肝病病因進行個別化（例如，針對具有非免流行性疾病因的病人（例如有非酒精相關性脂肪肝病、病毒性肝炎或酒精相關性肝病）：

●Tacrolimus – Target tacrolimus levels are listed in the table (table 6).

●Cyclosporine – During the first three to six months after transplantation, target cyclosporine trough levels range from 200 to 250 ng/mL. Between 6 and 12 months post-transplant, target trough levels range from 80 to 120 ng/mL.
Cyclosporine – 移植後的前三至六個月內，目標 Cyclosporine 最低濃度範圍為 200 至 250 ng/mL。移植後 6 至 12 個月期間，最低目標濃度值範圍為 80 至 120 ng/mL。

Monitoring drug trough levels facilitates the goal of using the least amount of immunosuppression that prevents rejection but also minimizes the risk of long-term dose-related complications of CNIs, including kidney toxicity, hypertension, and post-transplant lymphoproliferative disorders (PTLD). (See 'Adverse effects' below and "Pharmacology of calcineurin inhibitors", section on 'Side effects'.)
監測藥物最低(Trough)有助於達到使用最少量的免疫抑制的目標，並因此防止排斥反應，同時也最大程度地降低CNI 長期劑量相關併發症的風險，包括腎毒性、高血壓和移植後淋巴增生性疾病(PTLD)。 (參閱下文‘不良反應’和“鈣調神經磷酸酶抑制劑的藥理學”，關於‘副作用’一節)

Adverse effects — The side effects of tacrolimus and cyclosporine are generally similar and include nephrotoxicity, hypertension, hyperkalemia, hypomagnesemia, and neurologic toxicity.
不良反應 — Tacrolimus 和 Cyclosporine 的副作用通常相似，包括腎毒性、高血壓、高血鉀、低血鎂和神經毒性。

For patients on CNI therapy, we avoid potassium-sparing diuretics (eg, spironolactone, amiloride) and any potentially nephrotoxic drugs (table 1). For more detailed information on potential drug-drug interactions, refer to the drug interactions program.
對於接受 CNI 治療的病人，我們避免使用保鉀利尿劑（例如 Spironolactone 、 Amiloride ）以及導致潛在的腎毒性藥物（表 1）。有關潛在藥物交互作用的更多詳細資料，請參閱藥物交互作用計劃。

Neurologic toxicity may include altered mental status, polyneuropathy, dysarthria, myoclonus, seizures, hallucinations, and cortical blindness [17]. Other adverse effects include hyperlipidemia, gingival hyperplasia, and hirsutism.
神經系統毒性可能包括精神狀態改變、多神經病變變、構音障礙、肌陣攣、癲癇發作、幻覺和皮質視覺喪失[17]。其他不良反應包括高血脂、牙齦增生和多毛症。

Nephrotoxicity and other adverse effects related to CNIs are discussed in more detail separately:
與 CNI 相關的腎毒性和其他不良反應將單獨更詳細地討論：

●(See "Cyclosporine and tacrolimus nephrotoxicity".)

●(See "Kidney function and non-kidney solid organ transplantation", section on 'Liver transplantation'.)
(參閱“腎功能和非腎臟實體器官移植”，關於‘肝臟移植’一節)

●(See "Pharmacology of calcineurin inhibitors", section on 'Side effects'.)

Alternatives to calcineurin inhibitors — For patients with pretransplant kidney disease in whom we wish to limit the use of CNIs, we generally use antibody preparations in the immediate post-transplant period. We use basiliximab, a IL-2 receptor inhibitor that reduces proliferation and maturation of activated T cells [7].
鈣調神經磷酸酶抑制劑的替代方案 — 對於我們希望限制使用 CNI 的移植前腎臟病病人，我們通常在移植後立即使用抗體製劑。分析 Basiliximab ，一種 IL-2 受體抑制劑，可減少活化 T 細胞的增生和成熟 [7]。

Dosing and administration for basiliximab in liver transplantation is based on dosing recommendations in kidney transplant recipients, and this is discussed separately. (See "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Basiliximab' and 'Alternatives to systemic glucocorticoids' above.)
肝臟移植中 Basiliximab 的劑量與用法是根據腎臟移植病人的劑量建議，這樣的結果請參閱其他專題。 (請參閱“成人腎臟移植：免疫抑制劑誘導治療”，關於‘ Basiliximab ’一節和‘全身性類固醇的替代藥物’)

The use of IL-2 receptor inhibitors for initial immunosuppression in liver transplant recipients is supported by data from clinical trials and observational studies [7,18-21]. In a trial comparing an induction regimen of basiliximab, glucocorticoids, and mycophenolate with standard triple agent regimen (ie, glucocorticoid, tacrolimus, and mycophenolate) in 89 liver transplant recipients, there were no significant differences in patient survival, graft dysfunction, infection rate or type, or wound healing between regimens [21]. However, the rate of developing kidney impairment was lower with the regimen containing basiliximab (7 versus 19 percent).
臨床試驗和觀察性研究的數據支持使用IL-2受體抑制劑對肝臟移植病人進行起始免疫抑制[7,18-21]。有1篇針對89 名肝臟移植病人進行的試驗中，將 Basiliximab 、類固醇和 Mycophenolic acid 的誘導治療方式與標準三種藥治療方式（即類固醇、 Tacrolimus 和 Mycophenolic acid ）進行比較，結果顯示，病人存活時間率、植體功能障礙、感染率或感染率並未達統計顯著差異。然而，含有 Basiliximab 的治療方式中，腎損傷發生率較低（7% vs 19%）。

Antimetabolite agents — Antimetabolite agents (eg, mycophenolate mofetil [MMF], mycophenolic sodium, azathioprine) inhibit the proliferation of T and B lymphocytes by interfering with DNA synthesis from nucleic acids. Antimetabolite agents may be used in combination with a CNI or as CNI- or glucocorticoid-sparing agents.
抗代謝藥物 — 抗代謝藥物（例如 Mycophenolate mofetil [MMF]、 Mycophenolate sodium 、 Azathioprine ）透過干擾核酸合成 DNA 來抑制 T 和 B 淋巴球的增生。抗代謝劑可與 CNI 併用或作為 CNI 或類固醇節省劑。

Although published evidence of superiority over azathioprine is lacking, MMF is the first-line antimetabolite agent in most liver transplant centers [22]. An important exception is that we do not use MMF or mycophenolate sodium in females of childbearing potential because of teratogenicity, unless they are on long-acting contraception, have undergone a surgical sterilization procedure, or have infertility. We use azathioprine in such patients because long-term safety data demonstrated that azathioprine does not have adverse effects on fertility or pregnancy outcomes. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases" and "Safety of rheumatic disease medication use during pregnancy and lactation".)
雖然缺乏已發表的優於 Azathioprine 的證據，但 MMF 是多數肝臟移植中心的第一線抗代謝藥物 [22]。一個重要的例外是，我們不會在有生育能力的女性中使用MMF 或 Mycophenolate sodium ，因為它們具有致畸性，除非她們正在採取長效避孕措施、接受過結紮手術或有不孕症。我們在這樣的病人中使用 Azathioprine ，因為長期安全性數據證明 Azathioprine 不會對生育或懷孕結局產生不良反應。 (請參閱「 Mycophenolate ：治療風濕性疾病的使用和不良反應簡要介紹」和「孕期和哺乳風濕性疾病藥物使用的安全性」)

Mycophenolate (commonly-used) — Mycophenolate is widely used for preventing rejection in transplant recipients:
Mycophenolate （常用）－ Mycophenolate 廣泛用於預防移植病人的排斥反應：

●Pharmacology – Mycophenolic acid (MPA) is produced by several species of the fungus Penicillium. While MPA is poorly absorbed, two oral prodrugs with superior gut absorption are available in the United States: the 2-morpholinoethyl ester, mycophenolate mofetil (MMF, CellCept), and mycophenolate sodium (Myfortic). Both drugs are converted to antiproliferative MPA in the liver and eliminated predominantly by glucuronidation and urinary excretion [23].
藥理學 – Mycophenolate (MPA) 由多種青黴屬黴菌產生。雖然MPA 的吸收性較差，但美國有兩種具有良好腸道吸收能力的口服前藥：2-嗎啉乙酯、 Mycophenolate mofetil （MMF，CellCept）和 Mycophenolate sodium （Myfortic） 。兩種藥物在肝臟中轉化為抗增生 MPA，並主要透過葡萄醣醛酸化和尿液排洩清除[23]。

MPA inhibits inosine monophosphate dehydrogenase (IMPDH), the rate limiting step in purine synthesis, preventing formation of guanosine monophosphate (GMP). Cells depleted of GMP cannot synthesize guanine triphosphate (GTP) or deoxy-guanine triphosphate (d-GTP) for DNA synthesis and, therefore, cannot replicate. Most mammalian cells can maintain GMP levels through the purine salvage pathway. However, lymphocytes lack a key enzyme of the guanine salvage pathway (hypoxanthine-guanine phosphoribosyltransferase) and cannot compensate for the MPA-induced block. As a result, MPA selectively inhibits the proliferation of both B and T lymphocytes [24].
MPA 抑制 Inosine 單磷酸去氫酶 (IMPDH)，這是嘌呤合成的限速步驟，並因此阻止單磷酸鳥苷 (GMP) 的形成。缺乏 GMP 的細胞無法合成鳥嘌呤三磷酸 (GTP) 或去氧鳥嘌呤三磷酸 (d-GTP) 來合成 DNA，因此無法複製。多數哺乳動物細胞可以透過嘌呤補救途徑維持 GMP 水平。然而，淋巴球缺乏鳥嘌呤補救途徑的關鍵酵素（次 Xanthine -鳥嘌呤磷酸核糖轉移酶），無法補償 MPA 誘導的阻斷。因此，MPA 選擇性抑制 B 淋巴球和 T 淋巴球的增生 [24]。

●Safety – The most common adverse effects are bone marrow suppression and gastrointestinal symptoms, including abdominal pain, ileus, nausea, vomiting, and oral ulcerations. These symptoms are generally dose-related and improve with temporary or permanent dose reduction.
安全性－最常見的不良反應是骨髓抑制和胃腸道症狀，包括腹痛、腸阻塞、噁心、嘔吐和口腔潰瘍。這些症狀通常與劑量相關，並可透過暫時或永久降低劑量而改善。

Mycophenolate is not associated with either neurotoxicity or nephrotoxicity.

●Dosing – Typical dosing for MMF (Cellcept) is 1 g, orally, every 12 hours. Patients may tolerate the drug better when they initiate therapy with a dose of 250 to 500 mg every 12 hours and gradually increase to 1 g twice daily. Alternatively, MMF can be initially dosed at 500 mg four times daily. Mycophenolate sodium (Myfortic) is formulated as 360 mg tablets and is typically given as two tablets (720 mg) orally every 12 hours. Food may interfere with absorption of both drugs; thus, they should be taken one hour before or two hours after meals.
劑量 – MMF (Cellcept) 的典型劑量是每 12 小時口服 1 克。當病人開始每 12 小時 250 至 500 mg，劑量並逐漸增加至每日兩次 1 克時，病人可能會耐受性更好藥物。或者，MMF 最初可以以 500 mg QID給藥。 Mycophenolate sodium (Myfortic) 的配方為 360 mg 錠劑，通常每 12 小時口服兩顆（720 mg ）。食物可能會干擾兩種藥物的吸收；因此，應在飯前一小時或飯後兩小時服用。

●Monitoring – We measure a complete blood count in one week after starting therapy to evaluate for cytopenia. If there is no evidence of bone marrow suppression, we measure a complete blood count every eight weeks. We do not use serum mycophenolate concentrations to guide dosing adjustments.
監測－我們在開始治療後一週內測量全血球計數，以評估血球減少。如果沒有骨髓抑制的證據，我們每八週測量一次全血球數。我們未使用血清 Mycophenolate 濃度作出劑量調整。

●Efficacy – The use of immunosuppression regimens containing mycophenolate is supported by clinical trials and observational studies [25-29]. In a trial including 565 liver transplant recipients, mycophenolate therapy resulted in lower rates of biopsy-proven acute rejection or graft loss at six months post-transplant compared with azathioprine (38.5 versus 47.7 percent) [29]. In a study including 30 adult liver transplant recipients who were treated with an immunosuppressive regimen of tacrolimus and mycophenolate, patient and graft survival rates after two years were 87 and 84 percent, respectively [30].
功效－使用含有 Mycophenolate 的免疫抑制治療方式得到臨床試驗和觀察性研究的支持[25-29]。有1篇包含565 名肝臟移植病人的試驗中，與 Azathioprine 相比， Mycophenolate 治療經組織切片證實的移植後6 個月的急性排斥反應或器官移植失敗率較低（38.5％ vs 47.7％）[29]。有1篇包含30 名成年肝臟移植病人的研究中，他們接受了 Tacrolimus 和 Mycophenolate 的免疫抑制治療，兩年後病人和植體的存活率分別為87% 和84% [30]。

Data suggest that mycophenolate monotherapy may be an effective and safe maintenance regimen for selected recipients (eg, those with kidney impairment) [26,31,32]. In a trial comparing long-term MMF therapy alone with CNI-based immunosuppression in 150 liver transplant recipients, the rates of chronic rejection, patient survival, and graft survival were not significantly different after five years [31]. There was a nonsignificant trend toward higher rates of acute rejection with MMF alone (11 versus 3 percent), but all patients with acute rejection were successfully treated with glucocorticoid therapy. There were no significant differences between regimens in rates of de novo malignancy or other adverse cardiovascular, gastrointestinal, or neurologic effects. In a trial including 56 liver transplant recipients with CNI-related kidney injury, conversion to MMF monotherapy resulted in lower serum creatinine levels and improved glomerular filtration rates (GFR) after 12 months compared with CNI therapy [26].
數據證明， Mycophenolate 單一治療對於特定接受者（例如腎功能不全的病人）可能是有效且安全的維持治療方式[26,31,32]。有1篇對 150 名肝臟移植病人進行單獨長期 MMF 治療與根據 CNI 的免疫抑制進行比較的試驗中，五年後慢性排斥反應、病人存活時間率和植體存活率並未達統計顯著差異 [31]。單獨使用 MMF 時，急性排斥反應發生率沒有顯著增加的趨勢（11% 對 3%），但所有急性排斥反應病人均成功接受類固醇治療。各種治療治療方式之間的新生惡性腫瘤發生率或其他心血管、胃腸道或神經系統不良反應的發生率並未達統計顯著差異。有1篇納入56 名有CNI 相關腎損傷的肝臟移植病人的試驗中，與CNI 治療相比，轉為MMF 單一療法在12 個月後降低 Scr 水平並改善 eGFR (GFR) [26]。

Azathioprine — We use the antimetabolite azathioprine for patients who do not tolerate mycophenolate and for female patients who are pregnant or may become pregnant (ie, those without effective long-acting contraception, surgical sterilization, or infertility):
Azathioprine — 對於無法耐受 Mycophenolic acid 的病人以及懷孕或可能懷孕的女性病人（即沒有有效長效避孕、結紮手術或不孕症的病人），分析抗代謝藥物 Azathioprine ：

●Pharmacology – Azathioprine is a prodrug of 6-mercaptopurine, which is further metabolized into 6-thioguanine nucleotides (6-TGNs) that inhibit purine synthesis. By preventing de novo synthesis of purines, 6-mercaptopurine interferes with RNA and DNA synthesis required for replication of T and B cells.
藥理學 – Azathioprine 是 6-MP 的前藥，進一步代謝為抑制嘌呤合成的 6- Thioguanine 核苷酸 (6-TGN)。透過阻止嘌呤的重新合成新的，6-MP 會干擾 T 細胞和 B 淋巴球複製所需的 RNA 和 DNA 合成。

●Dosing – Azathioprine is typically given at a dose of 1.5 to 2.0 mg/kg daily, up to a maximum dose of 200 mg daily [33]. Assessing thiopurine methyltransferase metabolite (TPMT) enzyme activity reduces the risk of toxicity associated with absence of TPMT. In addition, measuring levels of 6-TGNs can help optimize dosing of azathioprine. Pretreatment testing prior to azathioprine use is discussed in detail separately. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Pretreatment evaluation'.)
劑量 – Azathioprine 的給藥劑量通常為每日 1.5 至 2.0 mg/kg，最高劑量為每日 200 mg [33]。評估 Thiopurines 甲基轉移酶代謝物 (TPMT) 酵素活性可降低與缺乏 TPMT 相關的毒性風險。此外，測量 6-TGN 水平有助於改良 Azathioprine 。使用 Azathioprine 之前的預防測試將請參閱其他專題。 (請參閱“ Thiopurines ：成人發炎性腸道疾病的治療前檢查和治療藥物監測方法”，關於‘治療前評估’一節)

●Safety – Adverse effects of azathioprine include bone marrow suppression, nausea, vomiting, pancreatitis, hepatotoxicity, and neoplasia. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Adverse effects'.)
安全性－ Azathioprine 的不良反應包括骨髓抑制、噁心、嘔吐、胰臟炎、肝毒性和腫瘤。 (參閱“ Azathioprine 用於風濕性疾病的藥理學和副作用”，關於‘不良反應’一節)

Azathioprine has been used safely during pregnancy. (See 'Pregnancy and lactation' below.)
Azathioprine 在懷孕期間可以安全使用。 (參閱下文『懷孕與授乳』)

Monitoring – The approach to laboratory and therapeutic drug monitoring with azathioprine therapy is discussed in detail separately. (See "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Routine laboratory monitoring' and "Thiopurines: Pretreatment testing and approach to therapeutic drug monitoring for adults with inflammatory bowel disease", section on 'Therapeutic drug monitoring'.)
監測－ Azathioprine 治療的實驗室和治療藥物監測方法將請參閱其他專題。 (請參閱“ Thiopurines ：成人發炎性腸道疾病的治療前測試和治療藥物監測方法”，關於'常規實驗室監測'一節和“ Thiopurines ：成人發炎性腸道疾病的治療前測試和治療藥物監測方法”，關於'常規實驗室監測'一節“治療藥物監測”。）

●Efficacy – Historically, azathioprine was used for immunosuppression in liver transplant recipients; however, data from randomized trials to support its efficacy are lacking.
功效－病史上， Azathioprine 用於肝臟移植病人的免疫抑制；然而，缺乏支持其功效的隨機試驗數據。

Investigational therapies — Other therapies have been examined for initial immunosuppression, but none has been sufficiently studied to be recommended for use:
研究性療法 — 其他療法已針對起始免疫抑制進行檢查，但尚未經過充分研究以建議使用：

●Rabbit anti-thymocyte globulin – Rabbit anti-thymocyte globulin (rATG) has been studied in liver transplant recipients in order to delay initiation of CNIs and potentially preserve kidney function. In a trial including 55 liver transplant recipients that compared rATG induction therapy plus initiating tacrolimus on postoperative day 10 with a standard tacrolimus regimen that was initiated on postoperative day 2, there were no significant differences in estimated glomerular filtration rate (GFR), biopsy-proven acute rejection, or infections between groups [34].
兔抗胸腺細胞球蛋白 – 在肝臟移植病人進行兔抗胸腺細胞球蛋白 (rATG)，以延遲 CNI 的啟動並可能保留腎功能。有1篇包含55 名肝臟移植病人的試驗中，將rATG 誘導治療加術後第10 天開始 Tacrolimus 與術後第2 天開始的標準 Tacrolimus 治療方式進行比較，組織切片證明 eGFR (GFR) 並未達統計顯著差異急性排斥反應或組間感染[34]。

MAINTENANCE THERAPY

General approach — Beyond the initial period of three months post-transplant, the risk of complications related to intensive immunosuppression outweighs the benefit because the risk of graft rejection decreases over time [35,36]. For most recipients with stable graft function and normal liver enzymes, lower doses of immunosuppressive agents are generally well tolerated. Factors informing individualized medication adjustments include the etiology of primary liver disease, recipient characteristics such as kidney function, time from transplant, center-specific protocols, and achieving CNI target trough levels.
一般方法 — 在移植後三個月的起始階段之後，與加強免疫抑制相關的併發症的風險超過了效益，因為植體排斥的風險隨時間而降低[35,36]。對於多數移植功能穩定且肝臟酵素正常的病人來說，較低劑量的免疫抑制劑通常具有良好的耐受性。個別化藥物調整的因素包括原發性肝病的病因、腎功能等病人特性、移植時間、中心特定治療方式以及達到 CNI 最低目標濃度水平。

As an example, an initial regimen consisting of a glucocorticoid, tacrolimus, and mycophenolate in a recipient who has stable graft function and no kidney disease is gradually transitioned to a maintenance regimen by continuing the gradual glucocorticoid taper, titrating the tacrolimus dose to a lower drug level range (table 6), and continuing mycophenolate at the fixed dose [37]. The maintenance regimen is usually achieved within six months post-transplant. (See 'Glucocorticoids' above and 'Calcineurin inhibitors' above.)
例如，移植功能穩定且無腎臟疾病的病人的初始治療治療方式由類固醇、 Tacrolimus 和 Mycophenolic acid 組成，透過繼續逐漸減量類固醇，將 Tacrolimus 劑量調整至較低藥物，逐漸轉換至維持治療治療方式水準範圍（表 6），以及繼續固定劑量的 Mycophenolate [37]。維持治療方式通常在移植後六個月內完成。 (參閱上文『類固醇』和『鈣調神經磷酸酶抑制劑』)

If liver enzymes begin to rise with dose and/or regimen adjustments, we return to the previously successful dose or regimen of immunosuppression. If the liver enzymes remain elevated, we obtain a liver biopsy to assess for features of acute cellular rejection or other cause of inflammation. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft".)
如果肝酵素隨著劑量和/或治療方式調整而開始升高，我們將返回到原本成功的免疫抑制劑量或治療方式。如果肝臟酵素仍然升高，我們將進行肝臟切片檢查以評估急性細胞排斥或其他發炎原因的特性。 (參閱「成人肝臟移植：同種異體肝臟植體急性T細胞媒介的(細胞)排斥反應的症狀和診斷」)

Duration of therapy — In general, liver transplant recipients receive lifelong immunosuppression because of the increased risk of rejection and graft loss after discontinuing immunosuppression.
治療持續時間 — 一般而言，肝臟移植病人接受終生免疫抑制，因為停止免疫抑制後排斥和植體減少的風險增加。

Some center-specific protocols for recipients transplanted for autoimmune liver disease use higher CNI trough levels, dual therapy with an antimetabolite, and/or maintenance glucocorticoid therapy to prevent rejection and recurrent autoimmune liver disease. However, data from a meta-analysis of two observational studies did not support long-term use of glucocorticoids to prevent rejection, graft loss, or patient mortality related to recurrent autoimmune hepatitis [38]. (See 'Calcineurin inhibitors' above.)
一些針對自體免疫性肝病移植病人的特定中心治療方式採用較高的 CNI 最低(Trough)、抗代謝物二合一治療和/或維持性類固醇治療，以預防排斥反應和復發自體免疫性肝病。然而，兩項觀察性研究的統合分析數據並不支持長期使用類固醇來預防與復發自體免疫性肝炎相關的排斥反應、植體減少或病人死亡[38]。 (參閱上文『鈣調神經磷酸酶抑制劑’)

Some data suggest that a few, highly selected recipients develop immune tolerance to the graft, usually after a prolonged, stable period (ie, years) of immunosuppression. These recipients may tolerate withdrawal of immunosuppression without developing rejection [39-41]. In contrast, there have been unpublished case reports of graft rejection and patient mortality among recipients who stopped immunosuppression without medical supervision, despite having stable graft function for many years post-transplant.
一些數據證明，少數經過精心挑選的病人通常會在長期穩定的免疫抑制期（即數年）之後對植體產生免疫耐受性。這些接受者可以耐受免疫抑制的撤消而不會發生排斥反應[39-41]。相較之下，雖然移植後多年植體功能穩定，但在沒有醫療監督的情況下停止免疫抑制的病人中，存在植體排斥和病人死亡的未發表個案報告。

Preliminary studies suggest that gradually weaning and discontinuing immunosuppression may be possible for a group of carefully selected liver transplant recipients [40,41]. In a study including 77 liver transplant recipients who met specific criteria (ie, history of either hepatitis C virus or nonimmune, nonviral liver disease; use of single-drug immunosuppression at one to two years post-transplant; stable kidney function; and absence of rejection on liver biopsy), gradual, systematic reduction of immunosuppression resulted in immunosuppressive doses of <50 percent of baseline doses in 52 recipients (68 percent) and complete withdrawal of immunosuppression for ≥1 year in 10 recipients (13 percent) [41]. However, attempts to discontinue long-term immunosuppression outside well-established protocols should be avoided until methods to select patients with graft immune tolerance are developed and validated.  
初步研究證明，對於一組精心挑選的肝臟移植病人來說，逐漸斷奶和停止免疫抑制是可能的[40,41]。有1篇研究中，包括77 名符合特定標準的肝臟移植病人（即， C型肝炎病毒或非免疫性非病毒性肝病病史；移植後一到兩年內使用單一藥物免疫抑制劑；穩定的腎功能；以及沒有肝臟切片排斥），逐漸、系統性地減少免疫抑制造成52 名病人(68%) 的免疫抑制劑量低於基準線劑量的50%，10 名病人(13%) 完全停止免疫抑制≥ 1 年[41]。然而，在開發和驗證選擇具有植體免疫耐受性的病人的方法之前，應避免嘗試在既定治療方式之外停止長期免疫抑制。

Studies of biomarkers may lead to the ability to predict whether a recipient is likely to develop immune tolerance and can tolerate withdrawal of immunosuppression; however, specific predictive models are not yet available.
對生物標記的研究可能有助於預測接受者是否有可能產生免疫耐受性以及能否耐受免疫抑制的撤消；然而，具體的預測模式無資料。

WHEN AND HOW TO MODIFY MAINTENTANCE THERAPY — In most liver transplant recipients, a stable maintenance immunosuppressive regimen is established within six months after transplantation. However, some recipients may require modification of the maintenance regimen due to complications, such as drug toxicity, acute cellular rejection, infection, or other clinical event, such as pregnancy or surgery. We discuss these special patient populations below.
多數肝臟移植病人在移植後六個月內建立穩定的維持免疫抑制治療方式。然而，有些接受者可能因併發症（例如藥物毒性、急性細胞排斥、感染或其他臨床事件（例如懷孕或手術））而需要調整維持治療方式。我們在下面討論這些特殊的病友。

It is important to emphasize that adjustments to the immunosuppressive regimen should be made in consultation with the recipient's transplant team.
需要強調的是，免疫抑制治療方式的調整應與病人移植團隊協商進行。

Calcineurin inhibitor (CNI)-related toxicity — Although CNIs are the cornerstone of maintenance immunosuppression in liver transplantation, some recipients do not tolerate these agents due to kidney injury or other adverse effects (eg, neurotoxicity, leukopenia). The risk of post-transplant kidney injury has been exacerbated by the MELD-based organ allocation system, which favors recipients with higher serum creatinine levels indicative of acute and/or chronic kidney injury. (See "Model for End-stage Liver Disease (MELD)".)
鈣調神經磷酸酶抑制劑(CNI) 相關毒性— 雖然CNI 是肝臟移植中維持免疫抑制的基礎，但有些病人因腎損傷或其他不良反應（如神經毒性、白血球減少症）而無法耐受這些藥物。根據 MELD 的器官分配系統擴大了移植後腎損傷的風險，該系統有利於 Scr 水平較高（證明存在急性和/或慢性腎損傷）的病人。 (參閱「末期肝病(MELD)模式」)

Modifying the existing regimen — Selecting a strategy to minimize the use of CNIs is based on the available published data, transplant center-specific protocols, clinical experience, and type and severity of CNI-related adverse effects [42] (see 'Use of mechanistic target of rapamycin (mTOR) inhibitors' below):
調整現有治療方式 — 選擇盡量減少 CNI 使用的策略是根據現有的已發表數據、移植中心特定治療方式、臨床經驗以及 CNI 相關不良反應的類型和嚴重程度[42](參閱“使用機械性藥物”) Rapamycin (mTOR) 抑制劑的標靶如下）：

●For patients with CNI-related kidney toxicity, we either lower the CNI dose and initiate a mechanistic target of rapamycin (mTOR) inhibitor or substitute an mTOR inhibitor for the CNI. The use of an mTOR inhibitor is supported by a pooled analysis of two trials including 772 liver transplant recipients that compared a regimen of everolimus plus lower dose tacrolimus (target level 3 to 5 ng/mL) with standard dose CNI therapy [43]. After 24 months, the everolimus-based regimen resulted in better kidney function, and there were no significant differences in rates of acute rejection, graft loss, or mortality between the groups.  
對於罹患 CNI 相關腎毒性的病人，我們 or 降低 CNI 劑量並啟動 Rapamycin (mTOR) 抑制劑的機轉目標， or 用 mTOR 抑制劑取代 CNI。 mTOR 抑制劑的使用得到了兩項試驗的彙整分析的支持，兩項試驗包括772 名肝移植病人，這個試驗將 Everolimus 加低劑量 Tacrolimus （目標3 至 5 ng/mL ）的治療方式與標準劑量CNI 療法進行比較[43]。 24 個月後，根據 Everolimus 的治療方式使腎功能得到改善，且各組之間的急性排斥反應、植體減少或死亡率並未達統計顯著差異。

●For patients with non-kidney-related adverse effects that can be attributed to CNI therapy, our approach takes into account the severity and timing of the adverse effects. As an example, if a patient experiences a severe adverse event such as seizure activity related to tacrolimus (despite achieving target trough levels), we discontinue tacrolimus. After seizure prophylaxis has been given, we may either reintroduce tacrolimus at a lower dose or switch to cyclosporine. For patients with less severe side effects (eg, nausea), we reduce the CNI dose by 25 to 50 percent.  
對於因 CNI 治療而出現非腎臟相關不良反應的病人，我們的方法會考慮不良反應的嚴重程度和發生時間。例如，如果病人經歷嚴重的不良事件，例如與 Tacrolimus 相關的癲癇發作活動（雖然達到了最低目標濃度值），我們會停止使用 Tacrolimus 。預防癲癇發作後，我們可以重複使用較低劑量的 Tacrolimus 或改用 Cyclosporine 。對於副作用較輕（例如噁心）的病人，我們將 CNI 劑量減少 25% 至 50%。

The optimal timing for initiating mTOR inhibitor therapy and reducing the dose or withdrawing the CNI is uncertain. However, we do not initiate mTOR inhibitors prior to postoperative day 30 after transplantation because of increased risk of hepatic artery thrombosis and poor wound healing in the early post-transplant period [44]. (See 'Use of mechanistic target of rapamycin (mTOR) inhibitors' below.)
開始 mTOR 抑制劑治療和降低劑量或撤回 CNI 的最佳時機仍不清楚。然而，我們不會在移植後第 30 天之前啟動 mTOR 抑制劑，因為移植後早期肝動脈血栓形成的風險增加且傷口癒合不良[44]。 (參閱下文‘ Rapamycin (mTOR)抑制劑機械標靶的使用’)

Use of mechanistic target of rapamycin (mTOR) inhibitors — The mTOR inhibitors used in liver transplantation include everolimus and sirolimus. Although mTOR inhibitors facilitate dose reduction or discontinuation of CNIs, mTOR inhibitors are associated with adverse events such as bone marrow suppression and poor wound healing [45-51]. As a result, mTOR inhibitors are used as second-line immunosuppressive agents. (See 'Modifying the existing regimen' above.)
Rapamycin 機械標靶 (mTOR) 抑制劑的使用 — 用於肝臟移植的 mTOR 抑制劑包括 Everolimus 和 Sirolimus 。雖然 mTOR 抑制劑有助於減少 CNI 劑量或停藥，但 mTOR 抑制劑與骨髓抑制和傷口癒合不良等不良事件有關[45-51]。因此，mTOR 抑制劑被使用於第二線免疫抑制劑。 (參閱上文‘調整現有治療方式’)

In addition, we generally do not initiate mTOR inhibitors earlier than 30 days post-transplant because of an increased risk of hepatic artery thrombosis and wound healing complications in the postoperative period [51,52]. The pharmacology, formulations, dosing, pharmacokinetics, drug interactions, and adverse effects associated with mTOR inhibitors are discussed in detail separately. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors".)
此外，我們通常不會在移植後 30 天之前開始使用 mTOR 抑制劑，因為術後肝動脈血栓形成和傷口癒合併發症的風險增加[51,52]。 mTOR抑制劑的藥理學、劑型、劑量、藥物動力學、藥物交互作用和不良反應將請參閱其他專題。 (參閱「 Rapamycin 目標(mTOR)抑制劑的哺乳動物(機轉)藥理學」)

Issues related to mTOR inhibitors in liver transplant recipients are summarized as follows [45,53]:
肝臟移植病人中與 mTOR 抑制劑相關的問題摘要如下 [45,53]：

●Pharmacology – mTOR inhibitors bind to the FK binding protein and presumably modulate the activity of intracellular mTOR to inhibit IL-2-mediated signal transduction necessary for proliferation of activated T- and B-cells. mTOR inhibitors are metabolized by CYP3A4, 3A5, and 2C8. As a result, there are risks of drug interactions with azoles, macrolides, antiepileptic agents, antiviral agents, and grapefruit juice (table 1).  
藥理學 – mTOR 抑制劑與 FK 結合蛋白結合，可能調節細胞內 mTOR 的活性，以抑制活化 T 細胞和 B 淋巴球增生所需的 IL-2 媒介的訊號傳導。 mTOR 抑制劑由 CYP3A4、3A5 和 2C8 代謝。因此，有與 Azole類、 Macrolide類、抗癲癇藥物、抗病毒藥物和葡萄柚汁發生藥物交互作用的風險（表 1）。

●Dosing – For liver transplant recipients who are converting from a CNI to mTOR inhibitor monotherapy, most transplant centers use everolimus with initial dosing of 1 mg twice daily and a target trough level of 6 ng/mL [54]. An alternative option is sirolimus with initial dosing of 1 to 2 mg daily and target trough level of 8 to 12 ng/mL.
劑量 – 對於從 CNI 轉為 mTOR 抑制劑單一療法的肝臟移植病人，多數移植中心使用 Everolimus ，起始劑量為 1 mg，每日兩次，最低目標濃度值為 6 ng/mL [54]。另一種選擇是 Sirolimus ，起始劑量為每日 1 至 2 mg，最低目標濃度濃度為 8 至 12 ng/mL。

●Monitoring – We monitor complete blood count, electrolytes, kidney function, glucose, and liver enzymes once a month. We check spot urine protein-to-creatinine ratio (calculator 1) at baseline, one month, six months, one year, and once yearly thereafter. We measure fasting lipids at baseline, at every three months for the first year, and then twice a year. We discontinue the mTOR inhibitor if the patient develops nephrotic range proteinuria (ie, protein excretion >3.5 g/24 hours) and/or severe hypertriglyceridemia (serum triglyceride level >500 mg/dL).  
監測－我們每月監測一次全血球計數、電解質、腎功能、血糖和肝臟酵素。我們在基準線、一個月、六個月、一年以及此後每年一次檢查現場尿蛋白與肌酸酐比率（計算器 1）。我們在基準線時測量空腹血脂，第一年每三個月測量一次，然後每年兩次。如果病人出現腎臟病範圍蛋白尿（即蛋白質排洩 >3.5 g/24 小時）和/或嚴重高三酸甘油脂血症（血清三酸甘油酯濃度 >500 mg/dL），我們將停用 mTOR 抑制劑。

●Adverse effects – The adverse effects of mTOR inhibitors have contributed to their positioning as second-line immunosuppressive agents [45-51].
不良反應－mTOR抑制劑的不良反應使其成為第二線免疫抑制劑[45-51]。

We avoid the use of mTOR inhibitors during the first 30 days after liver transplant because in the postoperative period mTOR inhibitors have been associated with hepatic artery thrombosis, delayed wound healing with incisional hernias, and graft loss [51].
我們避免在肝臟移植後的前 30 天內使用 mTOR 抑制劑，因為在術後期間，mTOR 抑制劑與肝動脈血栓形成、切口疝氣延遲傷口癒合和植體減少有關[51]。

Long-term adverse effects of mTOR inhibitors include hyperlipidemia, bone marrow suppression, mouth ulcers, skin rash, albuminuria, and pneumonia.
mTOR抑制劑的長期不良反應包括高血脂、骨髓抑制、口腔潰瘍、皮膚疹、蛋白尿和肺炎。

The dose-dependent nature of side effects of mTOR inhibitors is discussed separately. (See "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Adverse effects'.)
mTOR 抑制劑副作用的劑量依賴型請參閱其他專題。 (參閱“哺乳動物 Rapamycin 目標(mTOR)抑制劑的藥理學”，關於‘不良反應’一節)

●Efficacy – The beneficial effect of mTOR inhibitors on kidney function is supported by some clinical trials and observational studies, but the risk of adverse events remains a concern [52,55-62]. Overall, none of the studies have shown improvement in patient or graft survival with regimens that included mTOR inhibitors. In a trial including 188 liver transplant recipients who initially received basiliximab induction therapy and mycophenolate, patients were randomly assigned at four weeks post-transplant to receive either everolimus plus tapering doses of tacrolimus until discontinuation or a standard-dose tacrolimus regimen. After 24 weeks, the everolimus-based regimen resulted in improvement in estimated glomerular filtration rate (1.1 mL/min/1.73 m² versus -13.3 mL/min/1.73 m²) [52]. However, rates of biopsy-proven acute rejection were higher with the everolimus regimen (10 versus 2 percent). In a study including 140 liver transplant recipients, introducing everolimus in the early postoperative period (day 8) plus minimizing tacrolimus use was associated with higher rates of wound healing complications at three months compared with a standard dose tacrolimus-based regimen (18 versus 0 percent) [56].
功效－一些臨床試驗和觀察性研究支持mTOR抑制劑對腎功能的有幫助作用，但不良事件的風險仍令人擔憂[52,55-62]。整體而言，沒有一項研究顯示包含 mTOR 抑制劑的治療方式可以改善病人或植體的存活率。有1篇包括188 名最初接受 Basiliximab 誘導治療和 Mycophenolate 的肝移植病人的試驗中，病人在移植後4 週被隨機分派接受 Everolimus 加逐漸劑量的 Tacrolimus 直到停藥或接受標準劑量 Tacrolimus 治療方式。 24 週後，根據 Everolimus 的治療方式改善了 eGFR （1.1 mL/min/1.73 m ² 對比-13.3 mL/min/1.73 m ²

The timing of initiating mTOR inhibitors has also been linked to changes in recipient's kidney function. In a study including 1045 recipients who were switched from tacrolimus to everolimus, initiating everolimus at >12 months post-transplant was associated with lower rates of improved kidney function at 36 months compared with initiating everolimus within three months (21 versus 55 percent) [57]. These data may suggest that CNI-induced kidney disease is more reversible in its earlier stages. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Calcineurin inhibitor-related toxicity'.)
開始使用 mTOR 抑制劑的時機也與受體腎功能改變有關。有1篇納入1045 名從 Tacrolimus 轉為 Everolimus 的病人的研究中，與三個月內開始使用 Everolimus 相比，移植後12 個月以上開始使用 Everolimus 與36 個月時腎功能改善率較低相關（21% 對55%）[57 ]。這些數據可能證明 CNI 引起的腎臟疾病在早期階段更容易逆轉。 (請參閱“成人腎臟移植：免疫抑制劑治療”，關於‘鈣調神經磷酸酶抑制劑相關毒性’一節)

Pregnancy and lactation — Adjustments to maintenance immunosuppression during pregnancy and lactation are informed by the relative drug safety, the risk of rejection if the drug is discontinued, and the available data [63,64] (see "Safety of rheumatic disease medication use during pregnancy and lactation"):
懷孕與授乳— 懷孕和哺乳免疫抑制劑的調整取決於相對藥物安全性、停藥後的排斥風險以及現有數據[63,64](參閱“孕期風濕病藥物使用的安全性” )和哺乳”）：

●Pregnancy – For transplant recipients who are or may become pregnant, mycophenolate (ie, MMF or mycophenolate sodium) and mTOR inhibitors are contraindicated. Mycophenolate should be stopped at least six weeks prior to attempts at conceiving due to high reported rates of spontaneous abortion (45 percent) and risk of congenital anomalies such as orofacial, esophageal, cardiac, and kidney malformations [65-67]. If pregnancy occurs within six weeks of mycophenolate use, it should be reported to the Mycophenolate Risk Evaluation and Mitigation Strategy (Mycophenolate REMS).  
懷孕 – 對於已懷孕或可能懷孕的移植病人， Mycophenolate （即 MMF 或 Mycophenolate ）和 mTOR 抑制劑是禁忌的。由於自然流產率較高（45%）和先天性異常（如口腔臉部、食道、心臟和腎臟畸形）的風險，應在嘗試懷孕前至少六週停用 Mycophenolic acid [65-67]。如果在使用 Mycophenolate 後六週內發生懷孕，應向 Mycophenolate 風險評估和緩解策略（ Mycophenolate REMS）報告。

Mycophenolate can safely be switched to azathioprine without increased risk of graft rejection. Azathioprine is considered safe for use during pregnancy in both transplant and non-transplant populations [66,68].
Mycophenolic acid 可以安全地改用 Azathioprine ，而不會增加移植排斥的風險。 Azathioprine 在移植和非移植族群的懷孕期間使用是安全的[66,68]。

CNIs are considered to be safe during pregnancy based on data suggesting no increased risk of congenital anomalies [69]. While low birthweight and prematurity have been linked to CNI use, maternal comorbidities may have been confounding factors. Tacrolimus levels should be monitored every two to four weeks during pregnancy because the increase in circulating volume during pregnancy can lead to lower drug levels [70].
根據顯示先天性異常風險不會增加的數據，CNI 在懷孕期間是安全的 [69]。雖然低出生體重和早產與 CNI 的使用有關，但孕婦合併症可能是混雜因素。懷孕期間應每兩到四周監測一次 Tacrolimus 水平，因為懷孕期間血容量的增加可能產生藥物濃度降低[70]。

Professional society guidance supports the use of glucocorticoids during pregnancy and lactation [71]. Although earlier data suggested an increased risk of orofacial cleft for infants whose mothers were treated with glucocorticoids during pregnancy, subsequent studies did not find increased risk of this abnormality [72,73].
專業醫學會指導支持在懷孕與授乳間使用類固醇[71]。雖然早期數據證明，母親在懷孕期間接受類固醇治療的嬰兒發生口臉部裂的風險會增加，但隨後的研究並未發現這種異常的風險增加[72,73]。

Preconception counseling, timing of pregnancy, and pregnancy outcomes in liver transplant recipients are discussed separately. (See "Pregnancy in women with pre-existing chronic liver disease", section on 'Liver transplantation'.)
肝臟移植病人的孕前諮詢、懷孕時機和懷孕結局請參閱其他專題。 (參閱“已有慢性肝病女性的懷孕”，關於‘肝臟移植’一節)

●Lactation – Azathioprine, CNIs, and glucocorticoids are considered safe for breastfeeding because studies have shown low or undetectable drug levels in breast milk or infant serum [74-77]. However, mycophenolate and mTOR inhibitors should be avoided during breast feeding due to limited data on drug levels in breast milk and potential adverse effects on infants.
哺乳 – Azathioprine 、CNI 和類固醇對哺乳是安全的，因為研究顯示母乳或嬰兒血中藥物濃度較低或無法檢查到[74-77]。然而，由於母乳中藥物濃度的數據有限以及對嬰兒可能的不良影響，哺乳期間應避免使用 Mycophenolate 和 mTOR 抑制劑。

Patients undergoing non-transplant surgery — Most liver transplant recipients undergoing elective surgery do not require adjustment of maintenance immunosuppression. However, special considerations during the perioperative period include:
接受非移植手術的病人 — 多數接受常規性手術的肝臟移植病人不需要調整免疫抑制劑。然而，手術全期的特殊考量包括：

●Drug interactions – We carefully check for potential drug interactions with medications given perioperatively (eg, antimicrobials or antifungals). The recipient's transplant team should be consulted prior to making any changes to the immunosuppressive regimen. (See 'Drug interactions' above.)
藥物交互作用 – 我們仔細檢查與手術全期給予藥物（例如抗生素或抗黴菌藥物）之間有無潛在藥物交互作用。在對免疫抑制治療方式進行任何改變之前，應諮詢病人的移植團隊。 (參閱上文‘藥物交互作用’)

●Drug administration – The route of administration for immunosuppressant drugs may need to be modified if the patient cannot tolerate oral medication. However, intravenous administration of calcineurin inhibitors (CNIs) should be avoided because it is associated with a higher risk of kidney toxicity. We consult with a transplant pharmacist when adjusting the route of drug administration.
藥物給藥－如果病人無法耐受口服藥物，可能需要調整免疫抑制劑的給藥途徑。然而，應避免靜脈注射鈣調神經磷酸酶抑制劑（CNI），因為它會增加腎毒性的風險。在調整給藥途徑時，我們會諮詢移植藥師。

●Adjusting immunosuppressive drug doses – Dosing adjustments for the following drug classes may be indicated:
調整免疫抑制藥物劑量－可能需要調整以下藥物類別的劑量：

•mTOR inhibitors – We typically discontinue mTOR inhibitors at least one month prior to elective surgery because they are associated with poor wound healing. While the mTOR is being held, we usually use tacrolimus with or without an antimetabolite to maintain immunosuppression.
mTOR 抑制劑－我們通常在常規性手術前至少一個月停用 mTOR 抑制劑，因為它們與傷口癒合不良有關。在保留 mTOR 的同時，我們通常會使用 Tacrolimus （無論是否有抗代謝藥）來維持免疫抑制。

Urgent surgery should not be delayed due to use of an mTOR inhibitor; however, discontinuing the mTOR inhibitor after surgery is appropriate. For patients who undergo urgent surgery, selecting an alternative immunosuppressive agent involves input from the surgical and liver transplantation teams. (See 'Use of mechanistic target of rapamycin (mTOR) inhibitors' above and "Pharmacology of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors", section on 'Adverse effects'.)
不應因使用 mTOR 抑制劑而延遲緊急手術；然而，手術後停用 mTOR 抑制劑是適當的。對於接受緊急手術的病人，選擇替代免疫抑制劑需要手術和肝臟移植團隊的意見。 (參閱上文‘ Rapamycin 機械目標(mTOR)抑制劑的用途’和“哺乳動物 Rapamycin 目標(mTOR)抑制劑的藥理學”，關於‘不良反應’一節)

•Glucocorticoids – For recipients on glucocorticoid therapy, the need for perioperative glucocorticoid coverage is determined by the duration and dose of maintenance glucocorticoid therapy, the likelihood of underlying suppression of the hypothalamic-pituitary-adrenal (HPA) axis, and the surgical procedure. However, stress dose glucocorticoids are rarely necessary. Management of surgical patients taking glucocorticoids is discussed in more detail separately. (See "The management of the surgical patient taking glucocorticoids".)
類固醇– 對於接受類固醇治療的病人來說，手術全期類固醇涵蓋的需要取決於類固醇維持治療的用藥天數和劑量、下丘腦-腦下垂體-腎上腺(HPA) 軸潛在抑制的可能性以及手術過程。然而，很少需要壓力劑量的類固醇。服用類固醇的手術病人管理將單獨更詳細地討論。 (參閱「手術病人服用類固醇的治療」)

Patients who develop infection — For transplant recipients who develop infection, the approach to adjusting immunosuppression varies among transplant centers, but it is generally based on the severity of infection (see "Infection in the solid organ transplant recipient"):
發生感染的病人 — 對於發生感染的移植病人，不同移植中心調整免疫抑制的方法有所不同，但通常根據感染的嚴重程度(參閱“實體器官移植病人的感染”)：

●For patients with acute infection requiring hospitalization who have sepsis or organ dysfunction, we typically reduce the doses of antimetabolite and/or CNI, with the dosing adjustments guided by severity of illness and comorbidities (eg, kidney injury, myelosuppression).
對於罹患敗血症或器官功能障礙且需要住院的急性感染病人，我們通常會減少抗代謝藥物和/或CNI 的劑量，並根據疾病的嚴重程度和合併症（例如腎損傷、骨髓抑制）調整劑量。

●For patients with acute infection requiring hospitalization but who do not have sepsis or organ dysfunction, we usually reduce the dose of immunosuppressants if they are at higher risk of developing severe infection (eg, advanced age, comorbidities).
對於需要住院治療但沒有敗血症或器官功能障礙的急性感染病人，如果他們發生嚴重感染風險增加（例如高齡、合併症），我們通常會減少免疫抑制劑。

●For patients with uncomplicated, community-acquired infection (eg, cystitis, bronchitis), we usually do not adjust the maintenance regimen.
對於無併發症、社區型感染（如膀胱炎、支氣管炎）的病人，我們通常不會調整維持治療方式。

For recipients with an opportunistic infection, regardless of severity (eg, cytomegalovirus [CMV]), we typically decrease the CNI dose by 25 percent and/or decrease the antimetabolite dose by 25 to 50 percent. CMV viremia in solid organ transplant recipients is often a sign of excessive immunosuppression, and this is discussed separately. (See "Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients", section on 'Reduction of immunosuppression'.)
對於伺機性感染的病人，無論嚴重程度為何（例如巨細胞病毒 [CMV]），我們通常會將 CNI 劑量減少 25% 和/或將抗代謝藥物劑量減少 25% 至 50%。實體器官移植病人的巨細胞病毒血症通常是過度免疫抑制的徵兆，這樣的結果請參閱其他專題。 (請參閱“腎臟移植病人巨細胞病毒疾病的症狀、診斷和治療”，關於‘減少免疫抑制’一節)

For liver transplant recipients with COVID-19, adjustments to immunosuppression are individualized and based on COVID-19 severity, the specific regimen used, time post-transplant, and estimated risk of graft rejection [78-82]. These issues are discussed separately. (See "COVID-19: Issues related to solid organ transplantation", section on 'Active COVID-19 in solid organ transplant recipients'.)
對於罹患COVID-19 的肝臟移植病人，免疫抑制的調整是個別化的，並根據COVID-19 的嚴重程度、使用的具體治療方式、移植後時間和估計的植體排斥風險[78-82] 。這些問題請參閱其他專題。 (請參閱“COVID-19：與實體器官移植相關的問題”，關於‘實體器官移植病人中的活動性COVID-19’一節)

Some antimicrobial agents have the potential for drug interactions with immunosuppressive agents (table 1). For more detailed information on potential drug-drug interactions, refer to the drug interactions program within UpToDate.
一些抗生素可能與免疫抑制劑發生藥物交互作用（表 1）。有關潛在藥物交互作用的更多詳細資料，請參閱 UpToDate 中藥物交互作用計劃。

Patients with a new cancer — For recipients who develop a new cancer after liver transplantation, we typically reduce maintenance immunosuppression to optimize response to cancer treatment and to reduce the risk of infection. Optimal management of such patients requires a multidisciplinary team approach by oncology, transplant hepatology, and pharmacy. Adjusting maintenance immunosuppression in patients with a post-transplant malignancy is discussed separately. (See "Malignancy after solid organ transplantation" and "Malignancy after solid organ transplantation", section on 'Reduction in immunosuppression'.)
有新癌症的病人 — 對於肝臟移植後出現新癌症的病人，我們通常會減少免疫抑制劑，以改良對癌症治療的反應並降低感染風險。對這樣的病人的最佳管理需要腫瘤學、移植肝病學和藥學的跨領域團隊方法。移植後惡性腫瘤病人免疫抑制劑的調整請參閱其他專題。 (參閱“實體器官移植後的惡性腫瘤”和“實體器官移植後的惡性腫瘤”，關於‘免疫抑制的減少’一節)

Liver transplant recipients who are diagnosed with cancer can usually be managed with the same therapeutic protocols used to treat nontransplant patients with cancer. However, an important exception is immune checkpoint inhibitor (ICI) therapies (ie, cytotoxic T-lymphocyte antigen 4, programmed cell death 1 and programmed cell death 1 ligand antibodies), which have been associated with increased risk of graft rejection. In a systematic review of 83 solid organ transplant recipients who were treated with ICIs, allograft rejection was reported in 33 patients (40 percent) [83]. Whether there is an immunosuppressive strategy that will help mitigate risk of ICI-related rejection is uncertain without compromising the efficacy of ICIs. However, preliminary data suggested that mTOR inhibitors were associated with lower risk of rejection in transplant recipients receiving ICI therapy [84-86]. Selecting an immunosuppressive strategy in recipients with de novo cancer is individualized and informed by the estimated risk of graft rejection, risk of cancer-related mortality, the available evidence, and multidisciplinary input. (See "Malignancy after solid organ transplantation", section on 'Management'.)
被診斷為癌症的肝臟移植病人通常可以採用與治療非移植癌症病人相同的治療方式進行治療。然而，一個重要的例外是免疫檢查點抑制劑(ICI) 療法（即細胞毒性T 淋巴球抗原4、檢查細胞死亡1 和檢查細胞死亡1 配體抗體），這些療法與植體排斥風險呈正相關。在接受 ICI 治療的 83 名實體器官移植病人進行的系統性回顧中，33 名病人（40%）報告同種異體移植排斥反應[83]。有無一種免疫抑制策略能夠幫助降低 ICI 相關排斥風險而不會影響 ICI 的療效仍不清楚。然而，初步數據證明，mTOR 抑制劑與接受 ICI 治療的移植病人的排斥風險降低有關[84-86]。對有新生癌症的病人選擇免疫抑制策略是個別化的，並根據估計的植體排斥風險、癌症相關死亡率的風險、現有證據和跨領域團隊意見提供資訊。 (參閱“實體器官移植後的惡性腫瘤”，關於‘治療’一節)

Patients with recurrent hepatitis C virus — The availability of highly effective direct-acting antivirals (DAAs) has greatly reduced the need for HCV treatment after liver transplantation. However, for liver transplant recipients with HCV viremia, we typically use a DAA-based therapy that minimizes the risk of drug interaction with the immunosuppressive regimen [87-92]. Specific drug interactions are listed in the table (table 8). Drug interactions can also be checked through the drug interactions program included with UpToDate.
C型肝炎病毒復發病人 — 強效直接抗病毒藥物 (DAA) 的出現大大減少了肝臟移植後 HCV 治療的需求。然而，對於罹患 HCV 病毒血症的肝臟移植病人，我們通常使用根據 DAA 的治療，藉此降低藥物與免疫抑制治療方式交互作用的風險 [87-92]。具體藥物交互作用列於表中（表8）。藥物交互作用也可以透過 UpToDate 附帶藥物交互作用檢查進行檢查。

DAA regimens containing a protease inhibitor have the potential to increase drug levels of CNIs and mTOR inhibitors. Thus, CNI levels should be monitored closely after starting antiviral therapy (table 8). For patients receiving DAA therapy, we measure tacrolimus levels weekly for the first four weeks and every two to four weeks thereafter during treatment. In addition, the rate of tacrolimus clearance may increase as HCV replication declines. Management of HCV infection in liver transplant recipients is discussed separately. (See "Hepatitis C virus infection in liver transplant candidates and recipients", section on 'Post-transplant antiviral therapy'.)
含有蛋白酶抑制劑的 DAA 治療方式有可能增加 CNI 和 mTOR 抑制劑藥物含量。因此，開始抗病毒治療後應密切監測 CNI 水平（表 8）。對於接受 DAA 治療的病人，我們在前 4 週每週測量一次 Tacrolimus 水平，此後在治療期間每 2 至 4 週測量一次。此外，隨著 HCV 複製的下降， Tacrolimus 的清除率可能會增加。肝臟移植病人中HCV感染的處理請參閱其他專題。 (請參閱“肝臟等待移植病人和病人的C型肝炎病毒感染”，關於‘移植後抗病毒治療’一節)

Patients with hepatocellular carcinoma (HCC) — Some data have suggested that the mTOR inhibitor sirolimus suppresses tumor growth and may be beneficial for recipients with history of hepatocellular carcinoma (HCC) [93-97]. In a meta-analysis of three trials and 14 cohort studies including recipients with history of HCC, mTOR inhibitors were associated with increased likelihood of overall survival at five years post-transplant compared with no mTOR use (trials: RR 1.13, 95% CI 1.02-1.26 and cohort studies: RR 1.17, 95% 1.10-1.24) [97]. The clinical implications of these data remain unclear because most studies included in the meta-analysis were observational and subject to selection bias. Additionally, protocols for long-term immunosuppression at most transplant centers do not use sirolimus as monotherapy and typically add a second immunosuppressive agent when discontinuing CNI. (See 'Use of mechanistic target of rapamycin (mTOR) inhibitors' above and "Overview of treatment approaches for hepatocellular carcinoma".)
肝細胞癌 (HCC) 病人 — 一些數據證明，mTOR 抑制劑 Sirolimus 可抑制腫瘤生長，可能對有肝細胞癌 (HCC) 病史的病人有幫助 [93-97]。有3篇試驗和14 項 Cohort study （包括有HCC 病史的病人）進行的統合分析中，與未使用mTOR 相比，mTOR 抑制劑與移植後五年總存活率增加有關（試驗：RR 1.13 ，95% CI 1.02 -1.26 和 Cohort study ：RR 1.17，95% 1.10-1.24）[97]。這些數據的臨床關聯性仍有待進一步的研究，因為統合分析中包含的多數研究都是觀察性的，並且存在選擇偏差。此外，多數移植中心的長期免疫抑制治療方式未使用 Sirolimus 單一療法，通常在停止 CNI 時添加第二種免疫抑制劑。 (參閱上文『 Rapamycin (mTOR)抑制劑機械標靶的使用』及「肝細胞癌治療方式簡要介紹」)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Liver transplantation".)
世界各地特定國家和地區的社會和政府資助指引的連結單獨提供。 (參閱「學會指引連結：肝臟移植」)

SUMMARY AND RECOMMENDATIONS

●Pathophysiology of acute rejection – Organ rejection is a multistep process that includes alloantigen recognition, lymphocyte activation, clonal expansion, and graft inflammation (figure 1 and figure 2). (See 'Pathophysiology of acute rejection' above.)
急性排斥的病理生理學－器官排斥是一個多步驟的過程，包括同種異體抗原辨識、淋巴球活化、克隆擴張和植體發炎（圖 1 和圖 2）。 (參閱上文『急性排斥反應的病理生理學』)

●General principles – All liver transplant recipients receive immunosuppression following transplantation (see 'General principles' above):
一般原則 – 所有肝臟移植病人在移植後均接受免疫抑制（參閱上文『一般原則』）：

•Goal of immunosuppression – The goal of immunosuppression is to lower the risk of rejection while minimizing the risk of adverse drug effects and recurrent liver disease.
免疫抑制的目標－免疫抑制的目標是降低排斥風險，同時盡量減少藥物不良反應和復發肝病的風險。

•Drug interactions – Some immunosuppressive drugs, such as calcineurin and mechanistic target of rapamycin (mTOR) inhibitors, are metabolized by the cytochrome P450 (eg, CYP3A4) enzyme system. Potential drug interactions affecting these agents, along with recommendations for alternatives, monitoring, and/or dose adjustments are listed in the tables (table 1 and table 2).
藥物交互作用 – 一些免疫抑制藥物，例如鈣調神經磷酸酶和 Rapamycin 機械標靶 (mTOR) 抑制劑，由細胞色素 P450（例如 CYP3A4）酶系統代謝。表中列出了影響這些藥物可能的藥物交互作用，以及替代方案、監測和/或劑量調整的建議（表 1 和表 2）。

●Initial immunosuppression – For most liver transplant recipients, the immunosuppressive regimen is center-specific and informed by the drug's mechanism of action, the available published evidence and clinical experience. We suggest an initial regimen consisting of triple immunosuppression with the following agents (Grade 2C):
起始免疫抑制－對於多數肝臟移植病人來說，免疫抑制治療方式是針對特定中心的，並根據藥物的作用機轉、現有已發表的證據和臨床經驗提供資訊。我們建議初始治療治療方式包括三重免疫抑制和以下藥物（2C 級）：

•A glucocorticoid (see 'Glucocorticoids' above)

•A calcineurin inhibitor (usually tacrolimus) (see 'Calcineurin inhibitors' above)
鈣調磷酸酶抑制劑(Calcineurin Inhibitor)（通常為 Tacrolimus ）(參閱上文『鈣調磷酸酶抑制劑(Calcineurin Inhibitor)’)

•An antimetabolite (usually mycophenolate) (see 'Antimetabolite agents' above)
抗代謝藥（通常為 Mycophenolate ）(參閱上文‘抗代謝藥’)

We maximize the level of immunosuppression in the early post-transplant period when the risk of rejection is greatest (ie, perioperative period until approximately three months post-transplant).
我們在移植後早期排斥風險最大（即手術全期直到移植後約三個月）時最大程度地提升免疫抑制程度。

●Maintenance therapy – We use long-term maintenance immunosuppression for liver transplant recipients because of the increased risk of graft rejection and graft loss without immunosuppression. Factors informing the specific maintenance regimen and dosing include the risk of graft rejection, risk of adverse drug effects, etiology of primary liver disease, recipient characteristics (eg, kidney function), and center-specific protocols. (See 'General approach' above.)
維持治療－我們對肝臟移植病人使用長期維持免疫抑制，因為如果未使用免疫抑制，植體排斥和植體減少的風險會增加。影響特定維持治療方式和劑量的因素包括植體排斥的風險、藥物不良反應的風險、原發性肝病的原因、受體特性（如腎功能）和中心特定治療方式。 (參閱上文『一般方法』)

Some liver transplant recipients develop complications or other conditions that are indications for modifying the maintenance regimen. A discussion of these special populations includes (see 'When and how to modify maintentance therapy' above):
有些肝臟移植病人會出現併發症或其他病症，這些病症需要調整維持治療方式。這些特殊族群的討論包括（請參閱上文『何時以及如何調整維持治療』）：

•Pregnancy and lactation. (See 'Pregnancy and lactation' above.)

•Recipients with CNI-related toxicity. (See 'Calcineurin inhibitor (CNI)-related toxicity' above.)
有 CNI 相關毒性的接受者。 (參閱上文『鈣調神經磷酸酶抑制劑(CNI)相關毒性’)

•Recipients who develop infection. (See 'Patients who develop infection' above.)
發生感染的接受者。 (參閱上文『出現感染的病人』)

•Recipients undergoing nontransplant surgery. (See 'Patients undergoing non-transplant surgery' above.)
接受非移植手術的接受者。 (參閱上文『接受非移植手術的病人』)

•Recipients with a new cancer. (See 'Patients with a new cancer' above.)

Adjustments to the immunosuppressive regimen should be done in consultation with the liver transplant team.
應與肝臟移植團隊協商對免疫抑制治療方式進行調整。

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Norman Sussman, MD, who contributed to an earlier version of this topic review.
UpToDate 編輯人員向 Norman Sussman 醫學博士表示感謝，他為本主題評論的早期版本做出貢獻。