药物性肝损害临床特点的研究
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摘要
肝脏是机体处理体内代谢产物的重要器官,也是多数药物的解毒器官,药物和肝脏的关系非常密切。而药物性肝损害(drug induced liver injury,DILI)则是指药物和/或化学物质经呼吸道、消化道和静脉等途径进入人体而导致的肝脏损害。随着药物的广泛应用、新药的不断涌现和联合用药的增多,DILl已成为国内外常见且较严重的药源性疾病。
国内外有关发生DILI药物报道较多,常见的药物种类差别较大,对临床的提示作用非常有限;发生DILI的机制比较复杂,临床工作中如何快速判定肝损伤是否为药物所致,以及损伤的类型和程度,是临床工作者急需解决的问题;DILI与酒精性肝病(ALD)有时在临床上(包括实验室)有许多相似之处,并且容易混淆,但两者在治疗和预后方面存在很大的差异。
系统地研究DILl的临床特点,对DILI的预防、治疗和预后的判断具有重要的意义。
研究材料与方法
1、登录CNKI网,选择中国期刊全文数据库,以“药物性肝损害”为关键词,时间限定为2003-2008年,下载与引起肝损害药物相关的全部文献及文献详细题录。阅读原文将文献分为病例分析和个案报道,将每篇文献报道的致肝损害药物及例数分别统计并汇总。
2、收集2004年7月~2009年1月在中国医科大学附属第一医院消化内科收治住院的DILI患者共145例,对所有病例进行复习,剔除不符合诊断标准的病例后,共得到符合DILI诊断标准的病例105例。其中男性38例,女性67例。年龄19~79(平均年龄49.16±15.92)岁。记录用药史、临床症状、体征、临床项目及治疗情况等。
3、收集2000年1月~2004年12月的住院患者中,符合DILI诊断标准患者152例,年龄波动在18~85岁,平均年龄45.84±15.73岁;符合ALD诊断标准的ALD患者181例,年龄波动在25~78岁,平均年龄47.88±10.98岁。记录年龄、性别、身高、体重、发病年龄、入院日期、基础疾病、饮酒史和服药史,治疗前主要症状和主要实验室指标等。
4、统计学处理使用SPSSll.5统计软件对对各相关数据进行统计分析,设定P<0.05为统计学的显著性差异。
结果
1、引起药物性肝损害常见药物分析
(1)共收集文献197篇,涉及的病例数为11643人次,其中病例分析96篇,个案报道101篇。中药致肝损害报道共22篇。抗甲状腺药物致肝损害报道12篇,个案报道中,抗结核药致肝损害报道最多(28篇)。
(2)导致DILI常见的药物中,抗结核药比例最高,其次是中药和抗生素,三者累计之和达69.75%。解热镇痛药、抗甲状腺药和抗肿瘤药物均在5%以上。三者之和达16.75%。病例分析中,抗结核药、中药和抗生素三者累计之和达63.33%;而在个案报道中,单纯抗结核药引起者即达67.8%。无论是个案报道,还是病例分析,中药和保健品引起的DILI均稳定在20%左右。
(3)8篇70例重症肝损害的文献报道中,病例分析、个案报道各4篇。导致重症DILI常见的药物众,近2/3病例是由中草药、抗结核药物和抗生素类,其中中草药就占据了近1/3,药物包括雷公藤及治疗病毒性肝病、类风湿关节炎、银屑病、肥胖等疾病的中草药和偏方;抗肿瘤药、免疫抑制剂和抗甲状腺药物也是引起重症DILI不可忽视的因素。
2、DILI的临床特点
(1)在临床上DILI的首发症状依次为:乏力(18.10%)、腹痛(18.10%)、黄疸(10.48%)、腹胀(10.48%)、发热(9.57%)、肝酶升高(9.52%)、尿黄(8.57%)、纳差(5.71%)、恶心(5.71%)、瘙痒(2.86%)、腹泻(1.90%)等。除黄疸外,大多数患者出现的临床症状往往认为是原发病所致,黄疸出来后才促使患者就诊。本组病例就诊时总胆红素超过正常者为71.43%(75/105),仅有略超过一半的患者(56/105)就诊时出现明显的黄疸,仍然有28.57%的患者是以肝脏酶学增高而就诊,所以DILI比其他原因所致肝病的病程较长。
(2)根据肝功能实验结果,参照国际DILl分型标准,可将DILl分为3型。肝细胞型、肝内胆汁淤积型和混合型的比例分别为34.29%、25.71%和40%,中草药导致的胆汁淤积型肝损伤的发病率明显高于肝细胞型的发病率(x 2=54.11,P<0.001)。
(3)实验室检查中,DILI的生化检查明显不同于其他肝病,主要表现在酶学改变和胆红素排泄障碍,而且肝脏酶学与胆红素呈正相关,与肾功呈负相关。DILI早期对蛋白合成功能几乎无影响,但药物量大(如大剂量扑热息痛类或大量单味中草药)毒性大、晚期或严重肝坏死时蛋白变化就比较明显。
(4)各酶学间相互之比≥1,诊断DILI患者的阳性率无论是胞浆酶还是胆道酶均较高,尤其是AST,与其他酶(ALT、GGT和ALP)之比≥1,诊断DILI阳性率均超过60%。进一步进行卡方检验,可见反映肝细胞损伤的酶类(AST、ALT)与反应胆道酶类(GGT、ALP)之比对诊断DILI的阳性率大部分均有显著性的差异,而肝细胞酶之间、胆道酶之间的比值对诊断无意义。
3、DILI与ALD的临床差异
(1)两组患者常见临床症状发生率临床上,恶心、纳差、乏力、腹痛、腹泻、腹胀、出血、黄疸、瘙痒出现的百分比都比较高,腹痛、腹泻、腹胀及出血等症状在DILI中的发生率高于ALD,其中腹胀在两者间具有显著性差异(p<0.05);而恶心、纳差、乏力、黄疸及瘙痒等症状在ALD中的发生率高于DILI,尤其乏力和黄疸在ALD患者中更突出(p<0.01)。
(2)实验室检查在两组病例中的差别DILI组中ALT、ALP、TBIL、ALB、PLT等均高于ALD;而WBC在ALD组明显高于DILI组。AST、GGT、RBC和MCV两者之间无明显差异。
(3)治疗结果的差别治疗2周后,ALD组经过戒酒、充分的营养支持和改善肝脏代谢药物后,大部分临床症状即有明显的恢复,生化学指标在4~6周基本恢复正常;DILI组的症状和体征恢复较慢,尤其是黄疸比较顽固,个别病例黄疸持续增高(尽管在治疗中)4周后才逐渐下降,ALP、GGT的复常时间一般为4~8周,TBIL的复常可延之3~6个月。
讨论
所有的抗结核药对肝脏均有一定损害,加之抗结核药多需要联合使用,增加了肝损害的危险性;多重耐药性肺结核增多,使用药的剂量增大、种类增多;免疫力低下的人群增多,这些人群常合并使用其他药物,更容易出现肝损害。本研究统计中抗结核药物致肝损害在我国药物性肝损害中所占比例最高,且结核发病呈全球上升的趋势,因此抗结核药致肝损害应引起重视。
欧美国家DILI最常见药物为对乙酰氨基酚等解热镇痛药及抗生素,而我国等亚洲国家则因广泛应用中药而与之不同。日本的调查研究发现以保健品、民间偏方及传统草药引起的DILI比例在不断增高。本研究中,中药引起的严重肝损害占30%之多,远远高于其他药物,可见在弘扬传统医学同时亦应对其可能出现的危害引起足够重视。
随着抗生素种类的日益繁多及风湿免疫等系统疾病发病机制的日益明晰,肿瘤等疾病发病率的增高等,其相关药物可能致肝损害的风险亦应得到足够的重视。
DILI之所以发生,除某些疾病(肿瘤、皮肤病、风湿热等)必须应用特殊药物外,还与临床症状无特异性有关。大多数患者出现的临床症状往往认为是原发病所致,黄疸出来后才促使患者就诊。本组病例就诊时总胆红素超过正常者为71.43%(75/105),仅有略超过一半的患者(56/105)就诊时出现明显的黄疸,仍然有28.57%的患者是以肝脏酶学增高而就诊,所以DILI比其他原因所致肝病的病程较长。
通用的DILI分型主要依据于临床指标的主次和高低。一般来说,反映肝细胞线粒体损伤及肝腺泡病变的敏感指标ALT和AST,反映肝细胞水平的胆汁流生成和排泄障碍的主要是GGT、ALP和胆红素;混合型可能涵盖了所有生化学指标的异常。无论何型,疾病的早期对蛋白合成功能几乎没有影响。本组病例在入院时,无论是总蛋白,还是白蛋白均无异常,此点也是鉴别其他肝病的重要依据。
目前有关诊断DILI的生化学指标间关系的研究较少,本次在这一方面进行了尝试。从肝脏酶学、胆红素排泄功能和肾功能之间相关性研究可见,入院时肝脏酶学与胆红素呈正相关,与肾功呈负相关。说明早期药物代谢过程中仅造成肝脏的损伤,没有影响到其它系统(泌尿、血液等)的功能障碍。及时发现、早期的停药和及时治疗对预防暴发性肝衰竭(继发多发性脏器功能不全)具有重要的意义。
为了简化诊断程序,在本次研究中,探讨了各生化指标在DILI发生中的相互关系。主要是取各酶学间相互之比≥1,求得诊断DILI患者的阳性率(%),寻找各变量间的内在联系。结果可见,反映肝细胞损伤的酶类(AST、ALT)与反应胆道酶类(GGT、ALP)之比对诊断DILI的阳性率大部分均有显著性的差异,尤其是AST与其它酶类之间的比值意义更大,进一步证明DILI的发生与线粒体的损伤有关,而肝细胞酶之间、胆道酶之间的比值对诊断无参考价值。但此结果还需要大样本进一步临床探讨。
正因为酒精也是一种特殊的药物,所以与药物引起的肝损害在临床上的表现就有许多相似之处。在本研究中,恶心、纳差、乏力、腹痛、腹泻、腹胀、出血、黄疸、瘙痒出现的百分比都比较高,腹痛、腹泻、腹胀及出血等症状在DILI中的发生率高于ALD,其中腹胀在两者间具有显著性差异(p<0.05);而恶心、纳差、乏力、黄疸及瘙痒等症状在ALD中的发生率高于DILI,尤其乏力和黄疸在ALD患者中更突出(p<0.01)。这种差异的机制并不十分清楚,可能与药物直接或间接造成胃肠黏膜损伤有关,出血常常是药物对凝血系统的影响而引起;恶心、纳差、乏力、黄疸及瘙痒等症状在ALD中常见,是因为酒精及其代谢产物影响了肝脏的蛋白质合成、胆汁酸的生成与排泄,以及氧化应激而生成的炎性细胞因子造成各种代谢紊乱所致。如果两种因素同时存在,就会出现临床症状的叠加。
GGT和平均红细胞容积(MCV)的增高被认为是反映饮酒的重要实验室指标,在本次研究中,GGT的增高比较明显,有一半的患者MCV呈现增大的趋势,符合ALD的临床特征。一般认为血清转氨酶一般在正常上限5倍以内,并且以AST升高占优势(AST/ALT>2),因为酒精具有线粒体毒性和酒精抑制吡哆醛活性的作用,所以ALT几乎正常。尽管AST、ALT也有不同程度的增高,但本组病例未发现以AST升高占优势。由于ALD时常发生无菌性炎症反应(主要是TNF-alpha产生增加),血白细胞常有明显增加。以上表现在本研究中均得到证实。
结论
1、导致我国药物性肝损害常见的药物依次为抗结核药、中药和抗生素,三者累计之和达69.75%。
2、导致重症DILI常见的药物中,中草药就占据了近1/3,其次为抗结核药物和抗生素类,抗肿瘤药、免疫抑制剂和抗甲状腺药物也是引起重症DILI不可忽视的因素。
3、DILI早期的症状可能是以乏力、腹痛为主,皮肤黏膜黄染(或胆红素升高)可能是促使就诊的主要原因。
4、单纯生化学检查可粗略估计DILI的细胞损伤类型,即ALT增高反映肝细胞型,ALP、GOT增高反映胆道系统的损伤。
5、反映肝细胞损伤的酶类(AST、ALT)与反应胆道酶类(GGT、ALP)相互之比≥1,诊断DILI阳性率均超过60%,而肝细胞酶之间、胆道酶之间的比值对诊断无参考价值。
6、尽管临床症状在DILI和ALD中有重叠,但腹痛、腹泻、腹胀及出血等症状在DILI中的发生率高于ALD;其中腹胀在两者间具有显著性差异(p<0.05);而恶心、纳差、乏力、黄疸及瘙痒等症状在ALD中的发生率高于DILI,尤其乏力和黄疸在ALD患者中更突出(p<0.01)。
7、DILI在临床上呈急性经过,所以反映细胞浆酶(ALT、AST)及反映胆汁分泌和排泄功能的指标(ALP、TBIL)均较ALD升高;ALD为慢性酒精中毒所致,除GGT(反映酒精损伤特异性酶)外,常导致蛋白合成功能下降,以及对血象各组分(WBC、MCV、PLT)的影响远高于DILI。
8、经过戒酒、充分的营养支持和改善肝脏代谢药物后,ALD组临床症状和实验室指标恢复比较快,而DILI组大部分症状和体征比ALD组恢复较慢,尤其是黄疸的复常可延之3-6个月。
Study of Clinical characteristics of drug-induced liver injury
The liver is an important organ not only in the vivo processing of metabolites but also in detoxificating of most drugs.Drug induced liver injury(DILI) refers to the liver damage caused by the intake of drugs and/Or chemicals through respiratory tract, digestive tract and vein approach etc.With the wide application of drugs,the emergence of new drugs and the increase in drug combination,DILI has become a common and more serious medicine source liver disease.
Many drugs have been reported to be DILI related at home and abroad,but the overall clinical significance is so limited since the spectrum is so diverse.Thus it is becoming a problem needing to be solved that how to make a fast judgment for the diagnosis of DILI as well as its type and degree.It is noteworthy that there is significant difference between DILI and alcoholic liver disease(ALD) in therapeutic and prognostic aspects though confusions can always be found for their resemblance in clinical manifestations as well as laboratory findings.
System research of the clinical characteristics of DILI has great guiding significance for its prevention,therapy and prognosis.
Materials and Methods
1、Login National Knowledge Infrastructure(CNKI),select Chinese Journal Full-text Database(CJFD),choose "drug-induced liver injury" as keywords and time limited from 2003 to 2008,download all the literature and titles in detail related to liver damage caused by drug.Then the original texts will be divided into case analysis and case reports,for each of which the reported drug and the number of cases will be analyzed statistically.
2、We collect 145 DILI patients hospitalized in the department of Gastroenterology of the First Affiliated Hospital of China Medical University from July 2004 to January 2009.Except the cases not fitting the diagnostic criteria,a total of 105 cases aging from 19 to 79 years(average age 49.16±15.92) were obtained,including 38 cases of male,67 cases of female.For all of them,the medication history,clinical symptoms and signs,blood biochemistry and therapy were recorded.
3、Among the hospitalized patients we collected from January 2000 to December 2004,152 cases were in line with the diagnostic criteria for DILI with age from 18 to 85 years old(the average age of 45.84±15.73 years);181 cases meet the diagnostic criteria for ALD aging from 25 to 78 years old(the average age of 47.88±10.98 years old).For each of them,age,gender,body height and weight,onset age,admission date, underlying disease,medication history and history of drinking,pre-treatment symptoms and main laboratory indicators were recorded respectively.
4、Statistical analysis All the data were analyzed statistically with SPSS 11.5 software,setting P＜0.05 as statistically significant difference.
Results
1、Analysis of common drugs causing drug-induced liver injury
(1)A total of 197 literatures were collected,including 96 case analysis and 101 case reports,involving 11,643 patients.Reports related to traditional Chinese medicine-induced liver injury were 22 cases and those for antithyroid drug-induced liver injury were 12.The anti-tuberculosis drug-induced liver injury was the most frequent according to the case reports(28 cases).
(2)Among the common drugs related to DILI,anti-tuberculosis drugs occupied the highest proportion,followed by traditional Chinese medicine and antibiotics.All the three elements amount to 69.75%totally.The proportions of antipyretic analgesics, anti-thyroid drugs and anti-cancer drugs are more than 5%respectively,up to 16.75% in sum.According to case analysis,the anti-tuberculosis drugs,traditional Chinese medicine and antibiotics account for 63.33%totally.However,DILI simply caused by anti-Tuberculosis(TB) drugs amounts to 67.8%as to case reports.In both case reports and case analysis,traditional Chinese medicine and health products take a stable proportion around 20%respectively.
(3)For the 8 literatures involving 70 cases of severe liver injury,there are 4 case analysis and 4 cases reports.In the common drugs which cause severe DILI,nearly 2/ 3 are Chinese herbal medicine,anti-TB drugs and antibiotics,with Chinese herbal medicine holding for almost 1/3.These herbal medicine include Tripterygium wilfordii and those for the treatment virus hepatitis,rheumatoid arthritis,psoriasis, obesity and prescriptions;antineoplastic agents,immunosuppressants and anti-thyroid drug are also unneglectable causes of severe DILI.
2、Blood biochemical characteristics of DILI
(1) The first onset clinical symptoms of DILI include fatigue(18.10%), abdominal pain(18.10%),jaundice(10.48%),abdominal distension(10.48%),fever (9.57%),elevated liver enzymes(9.52%),yellow urine(8.57%),anorexia(5.71%), nausea(5.71%),pruritus(2.86%),diarrhea(1.90%) and so on.Except for jaundice, most of the clinical symptoms were thought to be caused by primary disease and the patients didn't seek treatment until the jaundice turned out.When administrated,more than 71.43%(75/105) of patients in this group have abnormal level of total bilirubin; only slightly more than half of the patients(56/105) have obvious jaundice while there are still 28.57%of patients administrated for the elevated liver enzyme.Therefore, DILI has a longer course than the liver diseases caused by other factors.
(2) According to the experimental results of liver function with reference to the international standard classification,DILI can be divided into 3 types:Liver cell type, intrahepatic cholestasis and mixed type,with ratio of 34.29%,25.71%and 40% respectively.The incidence of cholestasis type liver injury was significantly higher than that of liver cell type(x~2=54.11,P＜0.001).
(3) The result of biochemical examination in DILI is significantly different from other liver diseases,mainly manifested in the enzymatic changes and disorder of bilirubin excretion.Further,DILI and liver enzymes and bilirubin are positively correlated,while negatively correlated with the renal function.The synthesis of protein was mostly not affected in the early stage of DILI,but obvious changes in protein synthesis can be observed when a large quantity of drugs(such as high-dose paracetamol or a large number of single herbs) with more toxicity were took,and late or severe hepatic necrosis happened.
(4) When the ratio of enzymes≥1,the positive rate of diagnosis for DILI is high either in the cytosolic enzyme or enzymes of biliary tract,especially Aspartate Transaminase(AST) followed by Alkaline phosphatase(ALP),for both of which the positive rate are more than 60%.Further chi-square test reflected that the ratio between the liver cell injury enzymes AST and Alanine aminotransferase(ALT) and responsive enzymes of biliary tractγ-glutamyltranspeptidase enzyme(GGT) and ALP is helpful for the diagnosis of DILI while the ratio simply between liver cell enzymes or the biliary tract enzymes was meaningless.
3、Clinical differences between DILI and ALD
(1)The incidence of ordinary clinical symptoms Clinically,the incidence of nausea,anorexia,fatigue,abdominal pain,diarrhea,abdominal distension,bleeding, jaundice,itching appears high.In addition,the incidence of abdominal pain,diarrhea, abdominal distension and bleeding is higher in DILI than in ALD,with significant difference of abdominal distension between the two groups(p＜0.05) while nausea, anorexia,fatigue,jaundice and itching are more frequent in alcoholic liver diseases, weakness and jaundice are more prominent in patients with alcoholic liver disease especially(p＜0.01).
(2) The differences in laboratory tests between the two groups The levels of ALT,ALP,Total bilirubin(TBIL),Albumin(ALB),Platelet(PLT),etc are higher in DILI group compared with ALD while White blood cell(WBC) are significantly higher in ALD.There was no significant difference in AST,GGT,Red blood cells (RBC) or mean corpuscular volume(MCV) between the two groups.
(3) The differences in treatment results After two weeks' treatment,the majority of the clinical symptoms of ALD group showed apparent recovery after abstinence,adequate nutritional support and application of drugs improving liver metabolism,besides that chemical indicators returned to normal in 4 to 6 weeks. Compared to that,a slow resumption of the symptoms and signs was observed in DILI group,especially obstinate jaundice;jaundice in some cases continued to increase (although in the treatment) until 4 weeks later;the time of ALP,GGT normalization is 4 to 8 weeks while that of TBIL can prolong to 3 to 6 months.
Discussion
All the anti-tuberculosis drugs can cause liver damage and the risk was further increased by the combination of many anti-TB drugs.With the increase of multi-drug resistant tuberculosis,the drug dose and type increased;liver damage is more likely to happen to the population with low immunity who often use a combination of other drugs.According to our study,anti-tuberculosis drugs induced liver injury had the highest proportion in our country,which should be paid great attention to since the incidence of tuberculosis has an upward trend in the whole world.
In Europe and the United States,the most common drugs related to DILI are antipyretic analgesics such as acetaminophen and antibiotics,which are different from our country and other Asian countries due to the wider use of Chinese medicine.A Japanese study found a rising proportion of DILI due to the use of health care products,civil remedies and traditional herbal medicine.As to our study,traditional Chinese medicine-induced severe liver damage accounts for30%,which is much higher than the other drugs.As a result,enough attention should be paid to its potential to cause damage at the same time of promoting traditional medicine.
Their drug-related risk of liver damage should also be emphasized with an increasing type of antibiotics and the deeper understanding of the mechanism of rheumatic diseases as well as the increasing incidence of cancer and other diseases
The occurrence of DILI is not only due to the application of special drugs for certain diseases(tumor,skin diseases,rheumatic fever,etc) but also to the non-specificity of its clinical symptoms.
Except for jaundice,most of the clinical symptoms were thought to be caused by primary disease and the patients didn't seek treatment until the jaundice turned out. When administrated,more than 71.43%(75/105) of patients in this group have abnormal level of total bilirubin;only slightly more than half of the patients(56/105) have obvious jaundice while there are still 28.57%of patients administrated for the elevated liver enzyme.Therefore,DILI has a longer course than the liver diseases caused by other factors.
The general standard for classification of DILI mainly depends on blood biochemistry.Generally,ALT and AST are sensitive to reflecting liver mitochondria injury and acinar lesions,while GGT,ALP and bilirubin are sensitive to disturbance of formation and excretion of bile;the mixed type may cover all possible abnormalities.In our study,both the total protein and albumin were within normal range when admitted, which is important basis for the differential diagnosis for other liver diseases.
Our study had an attempt to find relationship of the various index of DILI which has rarely been investigated.From the research about the relevance of liver enzyme, bilirubin excretion and renal function,it can be seen that the level of liver enzymes was positively correlated with bilirubin,while negatively correlated with renal function when the patients were admitted.It is suggested that only the liver was impacted instead of other systems(urinary,blood,etc) in the early stage of drug metabolism. Timely detection and early withdraw of drug are of great significance for the prevention of fulminant hepatic failure(secondary to multiple organ dysfunction).
In order to simplify the diagnostic procedures,our study explored the inter-relationship of various biochemical indexes.We compared positive rate(%) of the ratio between enzymes≥1 obtained in patients diagnosed as DILI and looked for their inner contact.The results reflect that the ratio between enzymes in response of liver cell injury(AST,ALT) and enzymes in response of biliary tract injury(GGT,ALP) shows significant differences for the majority of the positive rate of DILI,particularly the ratio between AST and other enzymes.This provides further evidence for the relationship between the occurrence of DILI and mitochondrial damage.Meanwhile,the ratio simply between the liver cell enzymes or the biliary tract enzymes is not valuable for the diagnosis of DILI which also requires further clinical study with larger sample.
Lots of clinical similarities can be found in the ALD and DILI,since alcohol is also a special kind of drug.In this study,nausea,anorexia,fatigue,abdominal pain, diarrhea,abdominal distension,bleeding,jaundice and itching all have high incidence, while the incidence of abdominal pain,diarrhea,abdominal distension and bleeding are higher in DILI than ALD,with significant difference in distention between the two groups(p＜0.05);However,the incidence of nausea,anorexia,fatigue,jaundice and pruritus is higher in ALD than DILI,with fatigue and jaundice more prominent(p＜0.01)in patients with ALD in particular.Mechanism for this difference is still not very clear,which may be related to the directly or indirectly gastrointestinal mucosal injury caused by drugs,while bleeding is usually due to the impact on coagulation system; The occurrence of nausea,anorexia,fatigue,jaundice and itching in ALD may be explained by the impact of protein synthesis,bile acid formation and excretion in the liver as well as the metabolic disorders of inflammatory cytokines generated by oxidative stress.If the two factors exist simultaneously,there will be superposition of clinical symptoms.
The increases of GGT and MCV have been viewed as the indicators of drinking. In this study,GGT increased obviously and half of the patients showed increasing trend of MCV,which is in line with the clinical features of ALD.In ALD,serum transaminase is usually less than 5 times the upper limit with AST increased dominantly(AST/ALT＞2) and ALT within normal range,as a result of the mitochondrial toxicity and inhibition of pyridoxal activity ~[9]caused by alcohol. Although the AST and ALT have also increased to varying degrees,but found no predominance of the AST increase has been found in this group.In ALD,there is frequently a marked increase in blood leukocyte due to the aseptic inflammatory response(mainly arising from increased TNF-α),which has been confirmed in this study.
Conclusion
(1) Common causes of drug-induced liver injury in China are consequently anti-tuberculosis drug,traditional Chinese medicine and antibiotics,with a total of the three and up to 69.75%.
(2) As to the common causes of severe DILI,Chinese herbal medicine hold for almost 1/3,followed by anti-TB drugs and antibiotics,while antineoplastic agents, immunosuppressants and anti-thyroid drugs are also unneglectable.
(3) Fatigue,abdominal pain are frequently the early symptoms of DILI,while mucocutaneous stained yellow(or elevated bilirubin)is probably the main reason for visit.
(4) Simple biochemical examinations DILI can be used to roughly estimate the type of cell injury:increased ALT indicates the type of liver cell injury while increased ALP and GGT reflect the damage of biliary system.
(5) The ratio between enzymes in response of liver cell injury(AST,ALT) and enzymes in response of biliary tract injury(GGT,ALP) shows significant differences for the majority of the positive rate of DILI.Meanwhile,the ratio simply between the liver cell enzymes or the biliary tract enzymes is not valuable for the diagnosis of DILI.
(6) Although many symptoms are overlapping in DILI and ALD,the incidence of abdominal pain,abdominal distension and diarrhea are higher in DILI than ALD with significant difference in distention between the two groups(p＜0.05);However, the incidence of nausea,anorexia,fatigue,jaundice and pruritus is higher in ALD than DILI,with fatigue and jaundice more prominent(p＜0.01) in patients with ALD in particular.
(7) As a clinically acute process,DILI showed higher level of hepatocytoplasmic enzymes(ALT,AST) and enzymes(ALP,TBIL) reflecting the function of bile secretion and excretion than those of ALD.Except for the changes in GGT(specific enzyme for alcoholic damage),the function of protein synthesis is often decreased,as well as much higher impact on the components of the blood(WBC,MCV,PLT) than DILI since ALD is caused by chronic alcoholism.
(8) The restoration of clinical symptoms and laboratory indicators is relatively fast in ALD group,after abstinence,adequate nutritional support and application of drugs improving liver metabolism;while most of symptoms and signs in DILI group recovered more slowly than ALD group,especially the resumption of jaundice which can extend to 3 to 6 months.
国内外有关发生DILI药物报道较多,常见的药物种类差别较大,对临床的提示作用非常有限;发生DILI的机制比较复杂,临床工作中如何快速判定肝损伤是否为药物所致,以及损伤的类型和程度,是临床工作者急需解决的问题;DILI与酒精性肝病(ALD)有时在临床上(包括实验室)有许多相似之处,并且容易混淆,但两者在治疗和预后方面存在很大的差异。
系统地研究DILl的临床特点,对DILI的预防、治疗和预后的判断具有重要的意义。
研究材料与方法
1、登录CNKI网,选择中国期刊全文数据库,以“药物性肝损害”为关键词,时间限定为2003-2008年,下载与引起肝损害药物相关的全部文献及文献详细题录。阅读原文将文献分为病例分析和个案报道,将每篇文献报道的致肝损害药物及例数分别统计并汇总。
2、收集2004年7月~2009年1月在中国医科大学附属第一医院消化内科收治住院的DILI患者共145例,对所有病例进行复习,剔除不符合诊断标准的病例后,共得到符合DILI诊断标准的病例105例。其中男性38例,女性67例。年龄19~79(平均年龄49.16±15.92)岁。记录用药史、临床症状、体征、临床项目及治疗情况等。
3、收集2000年1月~2004年12月的住院患者中,符合DILI诊断标准患者152例,年龄波动在18~85岁,平均年龄45.84±15.73岁;符合ALD诊断标准的ALD患者181例,年龄波动在25~78岁,平均年龄47.88±10.98岁。记录年龄、性别、身高、体重、发病年龄、入院日期、基础疾病、饮酒史和服药史,治疗前主要症状和主要实验室指标等。
4、统计学处理使用SPSSll.5统计软件对对各相关数据进行统计分析,设定P<0.05为统计学的显著性差异。
结果
1、引起药物性肝损害常见药物分析
(1)共收集文献197篇,涉及的病例数为11643人次,其中病例分析96篇,个案报道101篇。中药致肝损害报道共22篇。抗甲状腺药物致肝损害报道12篇,个案报道中,抗结核药致肝损害报道最多(28篇)。
(2)导致DILI常见的药物中,抗结核药比例最高,其次是中药和抗生素,三者累计之和达69.75%。解热镇痛药、抗甲状腺药和抗肿瘤药物均在5%以上。三者之和达16.75%。病例分析中,抗结核药、中药和抗生素三者累计之和达63.33%;而在个案报道中,单纯抗结核药引起者即达67.8%。无论是个案报道,还是病例分析,中药和保健品引起的DILI均稳定在20%左右。
(3)8篇70例重症肝损害的文献报道中,病例分析、个案报道各4篇。导致重症DILI常见的药物众,近2/3病例是由中草药、抗结核药物和抗生素类,其中中草药就占据了近1/3,药物包括雷公藤及治疗病毒性肝病、类风湿关节炎、银屑病、肥胖等疾病的中草药和偏方;抗肿瘤药、免疫抑制剂和抗甲状腺药物也是引起重症DILI不可忽视的因素。
2、DILI的临床特点
(1)在临床上DILI的首发症状依次为:乏力(18.10%)、腹痛(18.10%)、黄疸(10.48%)、腹胀(10.48%)、发热(9.57%)、肝酶升高(9.52%)、尿黄(8.57%)、纳差(5.71%)、恶心(5.71%)、瘙痒(2.86%)、腹泻(1.90%)等。除黄疸外,大多数患者出现的临床症状往往认为是原发病所致,黄疸出来后才促使患者就诊。本组病例就诊时总胆红素超过正常者为71.43%(75/105),仅有略超过一半的患者(56/105)就诊时出现明显的黄疸,仍然有28.57%的患者是以肝脏酶学增高而就诊,所以DILI比其他原因所致肝病的病程较长。
(2)根据肝功能实验结果,参照国际DILl分型标准,可将DILl分为3型。肝细胞型、肝内胆汁淤积型和混合型的比例分别为34.29%、25.71%和40%,中草药导致的胆汁淤积型肝损伤的发病率明显高于肝细胞型的发病率(x 2=54.11,P<0.001)。
(3)实验室检查中,DILI的生化检查明显不同于其他肝病,主要表现在酶学改变和胆红素排泄障碍,而且肝脏酶学与胆红素呈正相关,与肾功呈负相关。DILI早期对蛋白合成功能几乎无影响,但药物量大(如大剂量扑热息痛类或大量单味中草药)毒性大、晚期或严重肝坏死时蛋白变化就比较明显。
(4)各酶学间相互之比≥1,诊断DILI患者的阳性率无论是胞浆酶还是胆道酶均较高,尤其是AST,与其他酶(ALT、GGT和ALP)之比≥1,诊断DILI阳性率均超过60%。进一步进行卡方检验,可见反映肝细胞损伤的酶类(AST、ALT)与反应胆道酶类(GGT、ALP)之比对诊断DILI的阳性率大部分均有显著性的差异,而肝细胞酶之间、胆道酶之间的比值对诊断无意义。
3、DILI与ALD的临床差异
(1)两组患者常见临床症状发生率临床上,恶心、纳差、乏力、腹痛、腹泻、腹胀、出血、黄疸、瘙痒出现的百分比都比较高,腹痛、腹泻、腹胀及出血等症状在DILI中的发生率高于ALD,其中腹胀在两者间具有显著性差异(p<0.05);而恶心、纳差、乏力、黄疸及瘙痒等症状在ALD中的发生率高于DILI,尤其乏力和黄疸在ALD患者中更突出(p<0.01)。
(2)实验室检查在两组病例中的差别DILI组中ALT、ALP、TBIL、ALB、PLT等均高于ALD;而WBC在ALD组明显高于DILI组。AST、GGT、RBC和MCV两者之间无明显差异。
(3)治疗结果的差别治疗2周后,ALD组经过戒酒、充分的营养支持和改善肝脏代谢药物后,大部分临床症状即有明显的恢复,生化学指标在4~6周基本恢复正常;DILI组的症状和体征恢复较慢,尤其是黄疸比较顽固,个别病例黄疸持续增高(尽管在治疗中)4周后才逐渐下降,ALP、GGT的复常时间一般为4~8周,TBIL的复常可延之3~6个月。
讨论
所有的抗结核药对肝脏均有一定损害,加之抗结核药多需要联合使用,增加了肝损害的危险性;多重耐药性肺结核增多,使用药的剂量增大、种类增多;免疫力低下的人群增多,这些人群常合并使用其他药物,更容易出现肝损害。本研究统计中抗结核药物致肝损害在我国药物性肝损害中所占比例最高,且结核发病呈全球上升的趋势,因此抗结核药致肝损害应引起重视。
欧美国家DILI最常见药物为对乙酰氨基酚等解热镇痛药及抗生素,而我国等亚洲国家则因广泛应用中药而与之不同。日本的调查研究发现以保健品、民间偏方及传统草药引起的DILI比例在不断增高。本研究中,中药引起的严重肝损害占30%之多,远远高于其他药物,可见在弘扬传统医学同时亦应对其可能出现的危害引起足够重视。
随着抗生素种类的日益繁多及风湿免疫等系统疾病发病机制的日益明晰,肿瘤等疾病发病率的增高等,其相关药物可能致肝损害的风险亦应得到足够的重视。
DILI之所以发生,除某些疾病(肿瘤、皮肤病、风湿热等)必须应用特殊药物外,还与临床症状无特异性有关。大多数患者出现的临床症状往往认为是原发病所致,黄疸出来后才促使患者就诊。本组病例就诊时总胆红素超过正常者为71.43%(75/105),仅有略超过一半的患者(56/105)就诊时出现明显的黄疸,仍然有28.57%的患者是以肝脏酶学增高而就诊,所以DILI比其他原因所致肝病的病程较长。
通用的DILI分型主要依据于临床指标的主次和高低。一般来说,反映肝细胞线粒体损伤及肝腺泡病变的敏感指标ALT和AST,反映肝细胞水平的胆汁流生成和排泄障碍的主要是GGT、ALP和胆红素;混合型可能涵盖了所有生化学指标的异常。无论何型,疾病的早期对蛋白合成功能几乎没有影响。本组病例在入院时,无论是总蛋白,还是白蛋白均无异常,此点也是鉴别其他肝病的重要依据。
目前有关诊断DILI的生化学指标间关系的研究较少,本次在这一方面进行了尝试。从肝脏酶学、胆红素排泄功能和肾功能之间相关性研究可见,入院时肝脏酶学与胆红素呈正相关,与肾功呈负相关。说明早期药物代谢过程中仅造成肝脏的损伤,没有影响到其它系统(泌尿、血液等)的功能障碍。及时发现、早期的停药和及时治疗对预防暴发性肝衰竭(继发多发性脏器功能不全)具有重要的意义。
为了简化诊断程序,在本次研究中,探讨了各生化指标在DILI发生中的相互关系。主要是取各酶学间相互之比≥1,求得诊断DILI患者的阳性率(%),寻找各变量间的内在联系。结果可见,反映肝细胞损伤的酶类(AST、ALT)与反应胆道酶类(GGT、ALP)之比对诊断DILI的阳性率大部分均有显著性的差异,尤其是AST与其它酶类之间的比值意义更大,进一步证明DILI的发生与线粒体的损伤有关,而肝细胞酶之间、胆道酶之间的比值对诊断无参考价值。但此结果还需要大样本进一步临床探讨。
正因为酒精也是一种特殊的药物,所以与药物引起的肝损害在临床上的表现就有许多相似之处。在本研究中,恶心、纳差、乏力、腹痛、腹泻、腹胀、出血、黄疸、瘙痒出现的百分比都比较高,腹痛、腹泻、腹胀及出血等症状在DILI中的发生率高于ALD,其中腹胀在两者间具有显著性差异(p<0.05);而恶心、纳差、乏力、黄疸及瘙痒等症状在ALD中的发生率高于DILI,尤其乏力和黄疸在ALD患者中更突出(p<0.01)。这种差异的机制并不十分清楚,可能与药物直接或间接造成胃肠黏膜损伤有关,出血常常是药物对凝血系统的影响而引起;恶心、纳差、乏力、黄疸及瘙痒等症状在ALD中常见,是因为酒精及其代谢产物影响了肝脏的蛋白质合成、胆汁酸的生成与排泄,以及氧化应激而生成的炎性细胞因子造成各种代谢紊乱所致。如果两种因素同时存在,就会出现临床症状的叠加。
GGT和平均红细胞容积(MCV)的增高被认为是反映饮酒的重要实验室指标,在本次研究中,GGT的增高比较明显,有一半的患者MCV呈现增大的趋势,符合ALD的临床特征。一般认为血清转氨酶一般在正常上限5倍以内,并且以AST升高占优势(AST/ALT>2),因为酒精具有线粒体毒性和酒精抑制吡哆醛活性的作用,所以ALT几乎正常。尽管AST、ALT也有不同程度的增高,但本组病例未发现以AST升高占优势。由于ALD时常发生无菌性炎症反应(主要是TNF-alpha产生增加),血白细胞常有明显增加。以上表现在本研究中均得到证实。
结论
1、导致我国药物性肝损害常见的药物依次为抗结核药、中药和抗生素,三者累计之和达69.75%。
2、导致重症DILI常见的药物中,中草药就占据了近1/3,其次为抗结核药物和抗生素类,抗肿瘤药、免疫抑制剂和抗甲状腺药物也是引起重症DILI不可忽视的因素。
3、DILI早期的症状可能是以乏力、腹痛为主,皮肤黏膜黄染(或胆红素升高)可能是促使就诊的主要原因。
4、单纯生化学检查可粗略估计DILI的细胞损伤类型,即ALT增高反映肝细胞型,ALP、GOT增高反映胆道系统的损伤。
5、反映肝细胞损伤的酶类(AST、ALT)与反应胆道酶类(GGT、ALP)相互之比≥1,诊断DILI阳性率均超过60%,而肝细胞酶之间、胆道酶之间的比值对诊断无参考价值。
6、尽管临床症状在DILI和ALD中有重叠,但腹痛、腹泻、腹胀及出血等症状在DILI中的发生率高于ALD;其中腹胀在两者间具有显著性差异(p<0.05);而恶心、纳差、乏力、黄疸及瘙痒等症状在ALD中的发生率高于DILI,尤其乏力和黄疸在ALD患者中更突出(p<0.01)。
7、DILI在临床上呈急性经过,所以反映细胞浆酶(ALT、AST)及反映胆汁分泌和排泄功能的指标(ALP、TBIL)均较ALD升高;ALD为慢性酒精中毒所致,除GGT(反映酒精损伤特异性酶)外,常导致蛋白合成功能下降,以及对血象各组分(WBC、MCV、PLT)的影响远高于DILI。
8、经过戒酒、充分的营养支持和改善肝脏代谢药物后,ALD组临床症状和实验室指标恢复比较快,而DILI组大部分症状和体征比ALD组恢复较慢,尤其是黄疸的复常可延之3-6个月。
Study of Clinical characteristics of drug-induced liver injury
The liver is an important organ not only in the vivo processing of metabolites but also in detoxificating of most drugs.Drug induced liver injury(DILI) refers to the liver damage caused by the intake of drugs and/Or chemicals through respiratory tract, digestive tract and vein approach etc.With the wide application of drugs,the emergence of new drugs and the increase in drug combination,DILI has become a common and more serious medicine source liver disease.
Many drugs have been reported to be DILI related at home and abroad,but the overall clinical significance is so limited since the spectrum is so diverse.Thus it is becoming a problem needing to be solved that how to make a fast judgment for the diagnosis of DILI as well as its type and degree.It is noteworthy that there is significant difference between DILI and alcoholic liver disease(ALD) in therapeutic and prognostic aspects though confusions can always be found for their resemblance in clinical manifestations as well as laboratory findings.
System research of the clinical characteristics of DILI has great guiding significance for its prevention,therapy and prognosis.
Materials and Methods
1、Login National Knowledge Infrastructure(CNKI),select Chinese Journal Full-text Database(CJFD),choose "drug-induced liver injury" as keywords and time limited from 2003 to 2008,download all the literature and titles in detail related to liver damage caused by drug.Then the original texts will be divided into case analysis and case reports,for each of which the reported drug and the number of cases will be analyzed statistically.
2、We collect 145 DILI patients hospitalized in the department of Gastroenterology of the First Affiliated Hospital of China Medical University from July 2004 to January 2009.Except the cases not fitting the diagnostic criteria,a total of 105 cases aging from 19 to 79 years(average age 49.16±15.92) were obtained,including 38 cases of male,67 cases of female.For all of them,the medication history,clinical symptoms and signs,blood biochemistry and therapy were recorded.
3、Among the hospitalized patients we collected from January 2000 to December 2004,152 cases were in line with the diagnostic criteria for DILI with age from 18 to 85 years old(the average age of 45.84±15.73 years);181 cases meet the diagnostic criteria for ALD aging from 25 to 78 years old(the average age of 47.88±10.98 years old).For each of them,age,gender,body height and weight,onset age,admission date, underlying disease,medication history and history of drinking,pre-treatment symptoms and main laboratory indicators were recorded respectively.
4、Statistical analysis All the data were analyzed statistically with SPSS 11.5 software,setting P＜0.05 as statistically significant difference.
Results
1、Analysis of common drugs causing drug-induced liver injury
(1)A total of 197 literatures were collected,including 96 case analysis and 101 case reports,involving 11,643 patients.Reports related to traditional Chinese medicine-induced liver injury were 22 cases and those for antithyroid drug-induced liver injury were 12.The anti-tuberculosis drug-induced liver injury was the most frequent according to the case reports(28 cases).
(2)Among the common drugs related to DILI,anti-tuberculosis drugs occupied the highest proportion,followed by traditional Chinese medicine and antibiotics.All the three elements amount to 69.75%totally.The proportions of antipyretic analgesics, anti-thyroid drugs and anti-cancer drugs are more than 5%respectively,up to 16.75% in sum.According to case analysis,the anti-tuberculosis drugs,traditional Chinese medicine and antibiotics account for 63.33%totally.However,DILI simply caused by anti-Tuberculosis(TB) drugs amounts to 67.8%as to case reports.In both case reports and case analysis,traditional Chinese medicine and health products take a stable proportion around 20%respectively.
(3)For the 8 literatures involving 70 cases of severe liver injury,there are 4 case analysis and 4 cases reports.In the common drugs which cause severe DILI,nearly 2/ 3 are Chinese herbal medicine,anti-TB drugs and antibiotics,with Chinese herbal medicine holding for almost 1/3.These herbal medicine include Tripterygium wilfordii and those for the treatment virus hepatitis,rheumatoid arthritis,psoriasis, obesity and prescriptions;antineoplastic agents,immunosuppressants and anti-thyroid drug are also unneglectable causes of severe DILI.
2、Blood biochemical characteristics of DILI
(1) The first onset clinical symptoms of DILI include fatigue(18.10%), abdominal pain(18.10%),jaundice(10.48%),abdominal distension(10.48%),fever (9.57%),elevated liver enzymes(9.52%),yellow urine(8.57%),anorexia(5.71%), nausea(5.71%),pruritus(2.86%),diarrhea(1.90%) and so on.Except for jaundice, most of the clinical symptoms were thought to be caused by primary disease and the patients didn't seek treatment until the jaundice turned out.When administrated,more than 71.43%(75/105) of patients in this group have abnormal level of total bilirubin; only slightly more than half of the patients(56/105) have obvious jaundice while there are still 28.57%of patients administrated for the elevated liver enzyme.Therefore, DILI has a longer course than the liver diseases caused by other factors.
(2) According to the experimental results of liver function with reference to the international standard classification,DILI can be divided into 3 types:Liver cell type, intrahepatic cholestasis and mixed type,with ratio of 34.29%,25.71%and 40% respectively.The incidence of cholestasis type liver injury was significantly higher than that of liver cell type(x~2=54.11,P＜0.001).
(3) The result of biochemical examination in DILI is significantly different from other liver diseases,mainly manifested in the enzymatic changes and disorder of bilirubin excretion.Further,DILI and liver enzymes and bilirubin are positively correlated,while negatively correlated with the renal function.The synthesis of protein was mostly not affected in the early stage of DILI,but obvious changes in protein synthesis can be observed when a large quantity of drugs(such as high-dose paracetamol or a large number of single herbs) with more toxicity were took,and late or severe hepatic necrosis happened.
(4) When the ratio of enzymes≥1,the positive rate of diagnosis for DILI is high either in the cytosolic enzyme or enzymes of biliary tract,especially Aspartate Transaminase(AST) followed by Alkaline phosphatase(ALP),for both of which the positive rate are more than 60%.Further chi-square test reflected that the ratio between the liver cell injury enzymes AST and Alanine aminotransferase(ALT) and responsive enzymes of biliary tractγ-glutamyltranspeptidase enzyme(GGT) and ALP is helpful for the diagnosis of DILI while the ratio simply between liver cell enzymes or the biliary tract enzymes was meaningless.
3、Clinical differences between DILI and ALD
(1)The incidence of ordinary clinical symptoms Clinically,the incidence of nausea,anorexia,fatigue,abdominal pain,diarrhea,abdominal distension,bleeding, jaundice,itching appears high.In addition,the incidence of abdominal pain,diarrhea, abdominal distension and bleeding is higher in DILI than in ALD,with significant difference of abdominal distension between the two groups(p＜0.05) while nausea, anorexia,fatigue,jaundice and itching are more frequent in alcoholic liver diseases, weakness and jaundice are more prominent in patients with alcoholic liver disease especially(p＜0.01).
(2) The differences in laboratory tests between the two groups The levels of ALT,ALP,Total bilirubin(TBIL),Albumin(ALB),Platelet(PLT),etc are higher in DILI group compared with ALD while White blood cell(WBC) are significantly higher in ALD.There was no significant difference in AST,GGT,Red blood cells (RBC) or mean corpuscular volume(MCV) between the two groups.
(3) The differences in treatment results After two weeks' treatment,the majority of the clinical symptoms of ALD group showed apparent recovery after abstinence,adequate nutritional support and application of drugs improving liver metabolism,besides that chemical indicators returned to normal in 4 to 6 weeks. Compared to that,a slow resumption of the symptoms and signs was observed in DILI group,especially obstinate jaundice;jaundice in some cases continued to increase (although in the treatment) until 4 weeks later;the time of ALP,GGT normalization is 4 to 8 weeks while that of TBIL can prolong to 3 to 6 months.
Discussion
All the anti-tuberculosis drugs can cause liver damage and the risk was further increased by the combination of many anti-TB drugs.With the increase of multi-drug resistant tuberculosis,the drug dose and type increased;liver damage is more likely to happen to the population with low immunity who often use a combination of other drugs.According to our study,anti-tuberculosis drugs induced liver injury had the highest proportion in our country,which should be paid great attention to since the incidence of tuberculosis has an upward trend in the whole world.
In Europe and the United States,the most common drugs related to DILI are antipyretic analgesics such as acetaminophen and antibiotics,which are different from our country and other Asian countries due to the wider use of Chinese medicine.A Japanese study found a rising proportion of DILI due to the use of health care products,civil remedies and traditional herbal medicine.As to our study,traditional Chinese medicine-induced severe liver damage accounts for30%,which is much higher than the other drugs.As a result,enough attention should be paid to its potential to cause damage at the same time of promoting traditional medicine.
Their drug-related risk of liver damage should also be emphasized with an increasing type of antibiotics and the deeper understanding of the mechanism of rheumatic diseases as well as the increasing incidence of cancer and other diseases
The occurrence of DILI is not only due to the application of special drugs for certain diseases(tumor,skin diseases,rheumatic fever,etc) but also to the non-specificity of its clinical symptoms.
Except for jaundice,most of the clinical symptoms were thought to be caused by primary disease and the patients didn't seek treatment until the jaundice turned out. When administrated,more than 71.43%(75/105) of patients in this group have abnormal level of total bilirubin;only slightly more than half of the patients(56/105) have obvious jaundice while there are still 28.57%of patients administrated for the elevated liver enzyme.Therefore,DILI has a longer course than the liver diseases caused by other factors.
The general standard for classification of DILI mainly depends on blood biochemistry.Generally,ALT and AST are sensitive to reflecting liver mitochondria injury and acinar lesions,while GGT,ALP and bilirubin are sensitive to disturbance of formation and excretion of bile;the mixed type may cover all possible abnormalities.In our study,both the total protein and albumin were within normal range when admitted, which is important basis for the differential diagnosis for other liver diseases.
Our study had an attempt to find relationship of the various index of DILI which has rarely been investigated.From the research about the relevance of liver enzyme, bilirubin excretion and renal function,it can be seen that the level of liver enzymes was positively correlated with bilirubin,while negatively correlated with renal function when the patients were admitted.It is suggested that only the liver was impacted instead of other systems(urinary,blood,etc) in the early stage of drug metabolism. Timely detection and early withdraw of drug are of great significance for the prevention of fulminant hepatic failure(secondary to multiple organ dysfunction).
In order to simplify the diagnostic procedures,our study explored the inter-relationship of various biochemical indexes.We compared positive rate(%) of the ratio between enzymes≥1 obtained in patients diagnosed as DILI and looked for their inner contact.The results reflect that the ratio between enzymes in response of liver cell injury(AST,ALT) and enzymes in response of biliary tract injury(GGT,ALP) shows significant differences for the majority of the positive rate of DILI,particularly the ratio between AST and other enzymes.This provides further evidence for the relationship between the occurrence of DILI and mitochondrial damage.Meanwhile,the ratio simply between the liver cell enzymes or the biliary tract enzymes is not valuable for the diagnosis of DILI which also requires further clinical study with larger sample.
Lots of clinical similarities can be found in the ALD and DILI,since alcohol is also a special kind of drug.In this study,nausea,anorexia,fatigue,abdominal pain, diarrhea,abdominal distension,bleeding,jaundice and itching all have high incidence, while the incidence of abdominal pain,diarrhea,abdominal distension and bleeding are higher in DILI than ALD,with significant difference in distention between the two groups(p＜0.05);However,the incidence of nausea,anorexia,fatigue,jaundice and pruritus is higher in ALD than DILI,with fatigue and jaundice more prominent(p＜0.01)in patients with ALD in particular.Mechanism for this difference is still not very clear,which may be related to the directly or indirectly gastrointestinal mucosal injury caused by drugs,while bleeding is usually due to the impact on coagulation system; The occurrence of nausea,anorexia,fatigue,jaundice and itching in ALD may be explained by the impact of protein synthesis,bile acid formation and excretion in the liver as well as the metabolic disorders of inflammatory cytokines generated by oxidative stress.If the two factors exist simultaneously,there will be superposition of clinical symptoms.
The increases of GGT and MCV have been viewed as the indicators of drinking. In this study,GGT increased obviously and half of the patients showed increasing trend of MCV,which is in line with the clinical features of ALD.In ALD,serum transaminase is usually less than 5 times the upper limit with AST increased dominantly(AST/ALT＞2) and ALT within normal range,as a result of the mitochondrial toxicity and inhibition of pyridoxal activity ~[9]caused by alcohol. Although the AST and ALT have also increased to varying degrees,but found no predominance of the AST increase has been found in this group.In ALD,there is frequently a marked increase in blood leukocyte due to the aseptic inflammatory response(mainly arising from increased TNF-α),which has been confirmed in this study.
Conclusion
(1) Common causes of drug-induced liver injury in China are consequently anti-tuberculosis drug,traditional Chinese medicine and antibiotics,with a total of the three and up to 69.75%.
(2) As to the common causes of severe DILI,Chinese herbal medicine hold for almost 1/3,followed by anti-TB drugs and antibiotics,while antineoplastic agents, immunosuppressants and anti-thyroid drugs are also unneglectable.
(3) Fatigue,abdominal pain are frequently the early symptoms of DILI,while mucocutaneous stained yellow(or elevated bilirubin)is probably the main reason for visit.
(4) Simple biochemical examinations DILI can be used to roughly estimate the type of cell injury:increased ALT indicates the type of liver cell injury while increased ALP and GGT reflect the damage of biliary system.
(5) The ratio between enzymes in response of liver cell injury(AST,ALT) and enzymes in response of biliary tract injury(GGT,ALP) shows significant differences for the majority of the positive rate of DILI.Meanwhile,the ratio simply between the liver cell enzymes or the biliary tract enzymes is not valuable for the diagnosis of DILI.
(6) Although many symptoms are overlapping in DILI and ALD,the incidence of abdominal pain,abdominal distension and diarrhea are higher in DILI than ALD with significant difference in distention between the two groups(p＜0.05);However, the incidence of nausea,anorexia,fatigue,jaundice and pruritus is higher in ALD than DILI,with fatigue and jaundice more prominent(p＜0.01) in patients with ALD in particular.
(7) As a clinically acute process,DILI showed higher level of hepatocytoplasmic enzymes(ALT,AST) and enzymes(ALP,TBIL) reflecting the function of bile secretion and excretion than those of ALD.Except for the changes in GGT(specific enzyme for alcoholic damage),the function of protein synthesis is often decreased,as well as much higher impact on the components of the blood(WBC,MCV,PLT) than DILI since ALD is caused by chronic alcoholism.
(8) The restoration of clinical symptoms and laboratory indicators is relatively fast in ALD group,after abstinence,adequate nutritional support and application of drugs improving liver metabolism;while most of symptoms and signs in DILI group recovered more slowly than ALD group,especially the resumption of jaundice which can extend to 3 to 6 months.
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