The case demonstrated that a young male with epilepsy suffering from intermittently and mildly elevated bilirubin caused by GS. GS is characterized by mild, chronic, intermittent unconjugated hyperbilirubinemia without other hepatic diseases or overt hemolysis. Fasting, physical exercise, stress, along with some liver toxic drugs would make it clinically apparent, but treatment is typically not necessary [10]. Its pathogenesis involves the reduced activity of UGT1A1 [2], a phaseⅡdrug metabolic enzyme, which is primarily capable of converting a series of insoluble drugs such as irinotecan and atazanavir [11, 12] to water-soluble substances which are easy for the renal or biliary elimination and excretion. In addition, it is also the isozyme that plays a significant role in bilirubin conjugation. The activity of UGT1A1 can be reduced by 70% of the normal level among these patients [13], which results in intermittently and mildly elevated unconjugated bilirubin, mostly ranging from 20 to 50μmol/L but rarely exceeds 70μmol/L [14, 15].
Currently, the diagnosis of GS is usually one of exclusion, based on mild elevation of serum indirect bilirubin in the absence of other reasons of unconjugated hyperbilirubinemia [15, 16]. Physical examination, biochemistry tests, imaging studies and liver histology (usually not necessary) are also found to be normal in GS. Notably, genetic detection is playing an increasingly decisive role in differentiating GS from other hereditary hyperbilirubinemia like Crigler-Najjar syndrome [2]. According to the patient’s clinical manifestation, biochemistry of liver function, results of diagnostic tests, abdominal ultrasound, liver biopsy and WES, other causative factors of elevated bilirubin were excluded.
GS is susceptible to cause accumulative toxicity of certain therapeutic drugs metabolized by the enzyme UGT1A1,such as irinotecan and atazanav [17-19]. VPA and LTG are the common drugs for the treatment of generalized epileptic seizures [9]. The metabolism of VPA has an extensive range, 30%-40% of the dose is via conjugation with UDP-glucuronyl transferases (UGT) such as UGT1A3 and UGT2B7 [20], and the pathway of mitochondrial beta oxidation accounts for 40%. Other oxidative pathways such as Omega and omega-1 also are implicated in it [21]. On the other hand, the enzyme UGT1A4 may be involved in the metabolism of LTG [22]. Therefore, GS would not lead to accumulative toxicity of VPA and LTG. Furthermore, both the drugs would not inhibit the activity of UGT1A1 [23], namely, GS would not be induced by them.
Clarkson et al [5, 6] once reported that VPA/LTG can cause liver damage to various degrees, and hepatic injuries associated with these drugs can be classified to two subtypes: common type and fulminant liver failure. The former manifests temporary and reversible elevation of bilirubin and liver enzyme values, which is usually dose-dependent and the abnormality can return to normal shortly after the drug is withdrawn [24]; the latter is life-threatening and infrequent, occurring generally within 2-8 weeks (LTG) or 3 months (VPA) after initiating the use of LTG/VPA [25, 26]. In general, VPA side-effects would not manifest the symptoms of hypersensitivity like LTG but rather more characterized by signs which are quite similar to GS: fatigue, nausea, and even continuous vomiting [27]. That may cause confusion when we diagnosed the patient as GS. Despite the fact that VPA and LTG can engender abnormalities of liver tests, there was no concensus about the concrete figure of bilirubin elevation by consulting literatures.
In this case, we did not withdraw LTG immediately, considering the fact that the harm caused by epileptic seizures was much more severe than the signs of mild abnormal liver tests possibly induced by LTG. Furthermore, the patient was not diagnosed with hypersensitivity to LTG in that there was no fever, rash, eosinophilia, and evidence of multiple organ dysfunction during the treatment period [28].
However, after administration of AEDs, the bilirubin still showed slightly abnormal. We substituted LTG with LEV given that LEV, as a newly broad-spectrum AED with relatively fewer side-effects and fewer drug interactions, is increasingly used as adjunctive therapy to treat generalized epilepsy [29]. Moreover, it doesn’t inhibit the activity of UGT1A1, and about 34% of its dose is metabolized via enzymatic hydrolysis of the acetamide group in blood rather than liver cytochrome P450 enzymes, and the remainder is excreted in urine [7, 8]. Then the patient was clinically suspected of GS based on the diagnostic tests and the clinical manifestation after discontinuation of LTG while taking LEV. Furthermore, his WES and liver biopsy substantiated our assumption. Even after discontinuing LEV, the indirect bilirubin were still high intermittently. Up to now, there were, to our knowledge, almost no reports of bilirubin abnormalities caused by LEV monotherapy. For a patient with epilepsy suffering from repeatedly elevated bilirubin, timely diagnosis, treatment and periodical liver tests are necessary for choosing appropriate AEDs, especially when it co-exists with GS.