毒理性
在使用第一代青霉素的人群中，偶有报告特发性肝损伤的罕见病例。许多病例报告出现在病毒性肝炎血清学检测可用之前，并且许多描述的患者有多种原因导致肝病（如败血症），并且还在接受其他可能对肝脏有毒性的药物。第一代青霉素可能会导致三种不同的肝损伤形式：（1）长期高剂量静脉注射青霉素时，血清转氨酶水平短暂、无症状升高，（2）与严重超敏反应相关的小幅肝损伤，以及（3）特发性、迟发性胆汁淤积性肝炎。这三种损伤形式可能发生在所有四代青霉素中，其中一些在某种青霉素形式中比另一种更常见。
静脉注射和肌肉注射高剂量青霉素可能与血清转氨酶升高有关，这通常是无需症状的，并且在停止治疗或改用其他抗生素后会迅速解决（案例1）。黄疸和碱性磷酸酶升高通常是缺席或轻微的。这种肝毒性在苯唑西林和羧苄西林中最常见，但也可能发生在第一代青霉素的注射形式中。这种损伤形式似乎直接对肝脏有毒。
对青霉素有严重超敏反应的患者，如史蒂文斯-约翰逊综合征或过敏性休克，可能会有伴随的肝损伤和黄疸，但目前尚不清楚这是否代表真正的青霉素肝毒性，或者是由高热、休克和全身免疫反应的并发症。青霉素的全身性过敏反应可能会伴随肝脏、脾脏和肾脏的肉芽肿，但通常没有特定肝炎损伤的证据。几乎所有青霉素都与超敏反应有关，但肝损伤通常被过敏并发症（皮疹、发热、过敏性休克）所掩盖。
最后，孤立的病例报告显示，第一代青霉素可以引起迟发性胆汁淤积性肝炎，这可能是特发性肝毒性。恶心、腹部不适、黄疸和瘙痒的症状通常在开始治疗后的1到4周出现，并且通常在完成疗程后的几天或几周后出现。血清酶模式通常是胆汁淤积性的，但如果在发作后不久进行检测，可能是混合性或肝细胞性的。免疫过敏特征很常见，但自身抗体形成是罕见的。大多数病例的严重程度为轻到中度，并且会迅速解决（案例2）。这种迟发的特发性胆汁淤积性肝炎是许多青霉素和头孢菌素的典型表现，其发生率因特定形式而异。特发性胆汁淤积性肝炎在使用天然青霉素时相当罕见，在使用某些广谱青霉素（如氯唑西林、氟氯西林）时更常见，在使用阿莫西林和克拉维酸时最常见。
可能性评分：C（可能是临床上明显肝损伤的罕见原因）。
Rare instances of idiosyncratic liver injury have been reported in persons receiving the first generation penicillins. Many case reports predated availability of serologic testing for viral hepatitis and many described patients with multiple reasons for having liver disease (such as sepsis) and who were receiving other potentially hepatotoxic agents. Three distinct forms of liver injury can occur with the first generation penicillins: (1) transient, asymptomatic elevations in serum aminotransferase levels with prolonged high doses of parenteral penicillin, (2) minor liver injury associated with severe hypersensitivity reactions, and (3) idiosyncratic, delayed cholestatic hepatitis. These three forms of injury probably occur with all four generations of penicillin, some being more common with one form of penicillin than another.
High doses of intravenous and intramuscular penicillin can be associated with serum aminotransferase elevations that are usually asymptomatic and resolve rapidly with stopping therapy or switching to another antibiotic (Case 1). Jaundice and elevations in alkaline phosphatase are usually absent or mild. This type of hepatotoxicity is most common with oxacillin and carbenicillin, but can occur with parenteral forms of the first generation penicillins as well. This form of injury appears to be direct hepatotoxicity.
Patients with severe hypersensitivity reactions to penicillin, such as Stevens-Johnson syndrome or anaphylaxis, may have an accompanying liver injury and jaundice, but it is not clear whether this represents true penicillin hepatotoxicity or a complication of hyperthermia, shock and generalized immune reactivity. Generalized allergic reactions to penicillin may be accompanied by granulomas in the liver, spleen and kidney, but are usually without evidence of specific hepatitis injury. Virtually all of the penicillins are associated with hypersensitivity reactions, but liver injury is usually overshadowed by the allergic complications (rash, fever, anaphylaxis).
Finally, isolated case reports have shown that the first generation penicillins can cause a delayed cholestatic hepatitis that probably represents idiosyncratic hepatotoxicity. Symptoms of nausea, abdominal discomfort, jaundice and pruritus generally arise 1 to 4 weeks after starting therapy, and often a few days or weeks after completing a course. The serum enzyme pattern is usually cholestatic, but may be mixed or hepatocellular if tested soon after onset. Immunoallergic features are common, but autoantibody formation is rare. Most cases are mild-to-moderate in severity and resolve rapidly (Case 2). This delayed form of idiosyncratic cholestatic hepatitis is typical of many penicillins and cephalosporins, varying in frequency with the specific form. Idiosyncratic, cholestatic hepatitis is quite rare with the natural penicillins, more common with certain broad spectrum penicillins (cloxacillin, flucloxacillin) and is most common with amoxicillin with clavulanic acid.
Likelihood score: C (probable rare cause of clinically apparent liver injury).
来源:LiverTox
