Abnormal liver function tests associated with severe rhabdomyolysis

Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular constituents such as potassium,phosphate,urate and intracellular proteins such as myoglobin into the circulation,which may cause complications including acute kidney injury,electrolyte disturbance and cardiac instability.Abnormal liver function tests are frequently observed in cases of severe rhabdomyolysis.Typically,there is an increase in serum aminotransferases,namely aspartate aminotransferase and alanine aminotransferase.This raises the question of liver injury and often triggers a pathway of investigation which may lead to a liver biopsy.However,muscle can also be a source of the increased aminotransferase activity.This review discusses the dilemma of finding abnormal liver function tests in the setting of muscle injury and the potential implications of such an association.It delves into some of the clinical and experimental evidence for correlating muscle injury to raised aminotransferases,and discusses pathophysiological mechanisms such as oxidative stress which may cause actual liver injury.Serum aminotransferases lack tissue specificity to allow clinicians to distinguish primary liver injury from muscle injury.This review also explores potential approaches to improve the accuracy of our diagnostic tools,so that excessive or unnecessary liver investigations can be avoided.     

Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity

BACKGROUND & AIMS: Studies that evaluate the risk of hepatotoxicity from statins in hyperlipidemic subjects with elevated baseline serum transaminases are lacking. We conducted a study to test the hypothesis that patients with elevated baseline liver enzymes have higher risk of statin hepatotoxicity. METHODS: Our study consisted of the following 3 cohorts of patients seen between January 1, 1998 and June 31, 2002: Cohort 1: 342 hyperlipidemic patients with elevated baseline enzymes (AST >40 IU/L or ALT >35 IU/L) who were prescribed a statin; cohort 2: 1437 hyperlipidemic patients with normal transaminases who were prescribed a statin; and cohort 3: 2245 patients with elevated liver enzymes but who were not prescribed a statin. The effect of statins on liver biochemistries was assessed over a 6-month period after statins were prescribed. Elevations in liver biochemistries during follow-up were categorized into mild-moderate or severe based on predefined criteria. RESULTS: The incidence of mild-moderate elevations and severe elevations in liver biochemistries in cohort 1 were 4.7% and 0.6%, respectively. Compared with cohort 1, individuals in cohort 2 had lower incidence of mild-moderate elevations (1.9%, P = 0.002) but not severe elevations (0.2%, P = 0.2). However, between cohorts 1 and 3, there were no differences in the incidence of mild-moderate elevations (4.7% vs. 6.4%, respectively, P = 0.2) or severe elevations (0.6% vs. 0.4%, respectively, P = 0.6). Statin discontinuation during the follow-up was similar between cohorts 1 and 2 (11.1% vs. 10.7%, respectively, P = 0.8). CONCLUSIONS: These data suggest that individuals with elevated baseline liver enzymes do not have higher risk for hepatotoxicity from statins.     

γ-Glutamyl Transpeptidase in Men and Alanine Aminotransferase in Women are the Most Suitable Parameters Among Liver Function Tests for the Prediction of Metabolic Syndrome in Nonviral Hepatitis and Nonfatty Liver in the Elderly

Background/Aims:

Nonalchoholic fatty liver disease (NAFLD) has been reported as a hepatic manifestation of metabolic syndrome (MetS); it is common and accounts for 80% of the cases with abnormal liver function tests (LFTs). In addition, several studies have proved that there is a correlation between abnormal LFTs and MetS. Therefore, LFTs may represent the abnormal metabolic status of livers in the patients with MetS. To identify the early state of metabolic dysfunction, we investigate the value of LFTs for the future MetS development in the relatively healthy (non-NAFLD) elderly.

Patients and Methods:

A total of 16,912 subjects met the criteria for analysis. In the first stage of this study, subjects were enrolled in the cross-sectional study in order to find out the optimal cutoff value in different LFTs with higher chances to have MetS. In the second stage of the present study, subjects with MetS at baseline were excluded from the same study group, and a median 5.6-year longitudinal study was conducted on the rest of the group.

Results:

Among all LFTs, only aspartate aminotransferase in both genders and the α-fetal protein in women failed to show the significance in distinguishing subjects with MetS by the receiver operating characteristic curve. In the Kaplan–Meier plot, only γ-glutamyl transpeptidase (γ-GT) in men and the alanine aminotransferase (ALT) in women could be used to successfully separate subjects with higher risk of developing the MetS from those with lower risk. Finally, in the multivariant Cox regression model, similar results were identified. Still, the hazard ratio (HR) to have future MetS, γ-GT in men, and ALT in women showed significance (HR = 1.511 in men and 1.504 in women).

Conclusion:

Among all the different LFTs, γ-GT (>16 U/L) in male and ALT (>21 U/L) in female were the best predictors for the development of MetS in healthy elderly. These two liver markers could be an ancillary test in predicting future MetS development/diagnosis. Elevation of the LFTs without underlying liver diseases should be treated as a warning sign of the possible MetS development in the elderly.     

Routine blood tests to predict liver fibrosis in chronic hepatitis C

AIM: To verify the usefulness of FibroQ for predicting fibrosis in patients with chronic hepatitis C, compared with other noninvasive tests.METHODS: This retrospective cohort study included 237 consecutive patients with chronic hepatitis C who had undergone percutaneous liver biopsy before treatment. FibroQ, aspartate aminotransferase (AST)/alanine aminotransferase ratio (AAR), AST to platelet ratio index, cirrhosis discriminant score, age-platelet index (API), Pohl score, FIB-4 index, and Lok’s model were calculated and compared.RESULTS: FibroQ, FIB-4, AAR, API and Lok’s model results increased significantly as fibrosis advanced (analysis of variance test: P < 0.001). FibroQ trended to be superior in predicting significant fibrosis score in chronic hepatitis C compared with other noninvasive tests.CONCLUSION: FibroQ is a simple and useful test for predicting significant fibrosis in patients with chronic hepatitis C.     

日本血吸虫一种新腺苷酸激酶全长cDNA的克隆与功能分析

目的：对用表达序列标签（Expression Sequence Tag,EST）策略从日本血吸虫尾蚴cDNA文库中筛选出的新基因进行功能预测。方法：用NCBI站点的BLASTx及BLASTn程序对所获得的新基因序列进行同源性搜索；用NCBI BLAST站点的blast two sequence程序对同源性高的基因进行核苷酸及氨基酸水平的同源性比较；利用Motif Scan in a Protein Sequence对cDNA序列所编码的蛋白质进行结构域搜索；利用CD－Search程序对目标蛋白进行保守区域搜索。结果：发现一个与曼氏血吸虫22kDa单核苷酸激酶mRNA高度同源的日本血吸虫新基因，基因与氨基酸水平的同一性均分别为86．0％和87．0％；蛋白结构域搜索及保守区域搜索结果显示，该cDNA序列所编码的蛋白质是一种腺苷酸激酶。结论：用EST策略筛选新基因是一个可行的方法，所筛到的日本血吸虫新基因编码一种腺苷酸激酶，全长编码序列与曼氏血吸虫腺苷酸激酶mRNA高度同源。     

Protein kinase C alpha, epsilon and AP-1 mediate prolactin regulation of mitochondrial aspartate aminotransferase expression in the rat lateral prostate

Citrate accumulation and secretion are physiological functions of the prostate gland that are regulated by testosterone and prolactin. The metabolic pathway for citrate production in the prostate involves the activity of mitochondrial aspartate aminotransferase (mAAT). The expression of mAAT in the prostate is regulated by prolactin through a signal transduction pathway mediated by protein kinase C (PKC). In this report we determined which PKC isoforms are expressed in rat lateral prostate epithelial cells and their activation by prolactin. Eight PKC isoforms are expressed in the ventral and lateral prostate lobes. Although all eight isoforms are expressed, only PKC and PKC were stimulated by prolactin and only in the lateral prostate lobe. Activator protein-1 (AP-1) appears to be the target of prolactin-PKC signaling because prolactin stimulated nuclear protein binding to an AP-1 consensus oligodeoxynucleotide. Moreover, the nuclear binding protein stimulated by prolactin also bound an mAAT oligodeoxynucleotide that contained an AP-1 consensus sequence and which competed for binding with the consensus AP-1 oligodeoxynucleotide. A PKC antisense oligodeoxynucleotide blocked expression of mAAT mRNA. Thus, we conclude that PKC is a specific PKC isoform that mediates via AP-1 the signal for prolactin regulation of mAAT gene expression in rat lateral prostate epithelial cells.     

血清CK、CDH、AST检测在骨筋膜室综合征早期诊治中的应用观察

目的动态检测骨筋膜室综合征患者血清磷酸肌酸激酶（CK）、乳酸脱氢酶（LDH）、天冬氨酸氨基转移酶（AST）水平,探讨其在骨筋膜室综合征早期诊断及病情评估中的作用。方法选择四肢骨筋膜室综合征的患者40例,在伤后2、24h及1、2、3、4周动态检测血清CK、LDH、AST。在术中以及术后1、2、3周取患肢受累肌肉组织行病理检查。结果伤后2h时,患者血清CK、LDH、AST水平急剧升高,分别为正常值的20、2、4倍,24h时达峰值,CK、LDH和AST分别为正常值的42、4、10倍;1周时,LDH、AST依然高于正常值（P均〈0．05）。病理显示肌肉标本明显坏死,呈不可逆性变化。结论CK、LDH、AST的变化能客观反映骨筋膜室综合征的病情严重程度。当这些指标急剧升高时要高度警惕骨筋膜室综合征的发生。动态监测这些指标可为骨筋膜室综合征的早期诊断及病情评估提供帮助。     

Associations between γ-glutamyl transferase, metabolic abnormalities and inflammation in healthy subjects from a population-based cohort： A possible implication for oxidative stress

AIM: To examine the relationships between gamma-glutamyl-transferase (GGT), alanine-aminotransferase (ALT), aspartate-aminotransferase (AST) and various metabolic parameters, C-reactive protein (CRP) and an oxidative stress marker (nitrotyrosine, NT) in subjects without any metabolic abnormalities from a population-based sample. METHODS: Two hundred and five subjects with normal body mass index (BMI), glucose tolerance, and without any metabolic abnormality were studied out of 1 339 subjects, without known liver diseases, alcohol abuse or use of hepatotoxic drugs, who are representative of the 45-64 aged population of Asti (north-western Italy). RESULTS: In all patients metabolic parameters and hs-CRP levels linearly increase from the lowest to the highest ALT and GGT tertiles, while in subjects without metabolic abnormalities, there is a significant association between fasting glucose, uric acid, waist circumference, hs-CRP, triglyceride values, and GGT levels. In these subjects, male sex, higher hs-CRP and glucose levels are associated with GGT levels in a multiple regression model, after adjustments for multiple confounders. In the same model, median NT levels are significantly associated with the increasing GGT tertile (beta = 1.06; 95%CI 0.67-1.45), but not with the AST and ALT tertiles. In a multiple regression model, after adjusting for age, sex, BMI, waist, smoking, and alcohol consumption, both NT (beta = 0.05; 95%CI 0.02-0.08) and hs-CRP levels (beta = 0.09; 95%CI 0.03-0.15) are significantly associated with fasting glycemia. CONCLUSION: GGT, an easy, universally standardized and available measurement, could represent an early marker of sub-clinical inflammation and oxidative stress in otherwise healthy individuals. Prospective studies are needed to establish if GGT could predict future diabetes in these subjects.     

Decreased renal expressions of heat shock protein-72 and -25 are associated with renal dysfunction in biliary cirrhotic rats.

During the course of liver cirrhosis, severe renal complications frequently occur. However, the pathogenesis of renal dysfunction in liver cirrhosis has not been completely understood. In this study, we investigated the association between renal function and expressions of renal heat shock proteins (HSPs) in biliary cirrhotic rats. Following bile duct ligation (BDL), renal function and expressions of HSPs were compared in control and BDL cirrhotic rats. Serum BUN and creatinine levels were significantly higher in cirrhotic rats compared with control rats at 4 weeks post-BDL operation. Renal expressions of HSP72 and HSP25 were decreased with progression of liver cirrhosis in BDL rats by Western blotting. Immunohistochemistry revealed that expression of renal HSP72 was suppressed in tubular epithelial cells, and expression of renal HSP25 was suppressed not only in tubular epithelial cells but also in blood vessels in rats with liver cirrhosis. Renal expressions of HSP90 and HSP60 did not differ between control and BDL rats. Renal function was impaired in biliary cirrhotic rats with decreased expressions of renal HSP72 and HSP25. These findings suggest that decreased expressions of renal HSP72 and HSP25 may be a part of the pathogenesis of renal dysfunction in liver cirrhosis.     

丙氨酸氨基转移酶水平正常与轻度升高慢性HBV感染者的肝脏病理学特征比较

目的 探讨ALT/AST正常和ALT/AST轻度升高慢性HBV感染者的肝脏病理学特征,并进行比较. 方法 收集ALT/AST正常慢性HBV感染者134例,ALT/AST轻度升高慢性HBV感染者265例,采用肝脏穿刺术以进行肝活组织病理学检查;用荧光定量PCR法检测血清HBVDNA水平;用化学发光法定量检测血清HBV标志物(HBsAg、抗-HBs、HBeAg、抗-HBe、抗-HBc).计数资料采用x2检验分析,相关性采用Spearman等级相关分析. 结果 ALT/AST轻度升高组男性比例明显增加.ALT/AST正常组,50.0％ (67/134)的患者肝脏有中度以上的病理学改变,3.0％(4/134)的患者炎症或纤维化程度在3级(期)以上;ALT/AST轻度升高组,65.7％ (174/265)的患者肝脏有中度以上的病理学改变,16.2％ (43/265)的患者炎症或纤维化程度在3级(期)以上.ALT/AST轻度升高组肝脏炎症程度和纤维化程度均较ALT/AST正常组严重(x2=26.386,P＜0.01;x 2=15.299,P＜0.01).在ALT/AST正常组,炎症程度和纤维化程度均与年龄呈正相关(rs=0.620,P＜ 0.01;rs=0.347,P＜0.01);而在ALT/AST轻度升高组,炎症程度和纤维化程度均与年龄呈负相关(rs=-0.807,p＜0.01 ;rs=-0.557,P＜0.01).两组患者肝脏炎症程度和纤维化程度均与HBV DNA载量呈负相关(rs=-0.215,P＜0.01,rs=-0.527,P＜0.01;rs=-0.951,P＜ 0.01 ;rs=-0.715,P＜0.01),而与HBeAg阳性与否无明显相关性.结论 ALT/AST正常或轻度升高的慢性HBV感染者大部分肝脏均有中度以上的病理学改变;即使HBV DNA处于低水平,无论HBeAg阳性与否,也都是需要密切观察的群体.     

Bidirectional signals transduced by TOPK-ERK interaction increase tumorigenesis of HCT116 colorectal cancer cells

BACKGROUND & AIMS: Aberrant activation of Ras and Raf in mitogen-activated protein kinase (MAPK) signaling has been linked with cancer. However, the role of MAPK kinases (MAPKKs or MEKs) in cancer is unclear, although constitutively activated MEK1, which does not exist in nature, is "oncogenic." Herein, we found that T-cell-originated protein kinase (TOPK), a member of the MAPKK protein family, is highly expressed in human colorectal cancer tissues and cell lines and plays an important role in the transformation of colorectal cancer. METHODS: The biologic consequences of overexpression or knockdown of TOPK in JB6 Cl41 and HCT116 colorectal cancer cells were studied in vitro and in vivo, respectively. Kinase assay or transient transfection experiments were performed to study the bidirectional signaling pathway between TOPK and extracellular signal-regulated kinase (ERK). RESULTS: TOPK was shown to promote transformation in vitro and in vivo, and knockdown of TOPK in HCT116 colorectal cancer cells reduced this cell lines' tumorigenic properties in vitro and in vivo. Furthermore, a positive feedback loop between TOPK and ERK2 was identified. With epidermal growth factor treatment, knockdown of either TOPK or ERK2 in HCT116 cells resulted in a decreased phosphorylation of ERK2 or TOPK, respectively, and knockdown of TOPK in HCT116 colorectal cancer cells blocked the phosphorylation of downstream substrates of ERK2. CONCLUSIONS: The positive feedback loop between TOPK and ERK2 increases tumorigenesis properties of HCT116 colorectal cancer cells, and TOPK-regulated signaling may serve as a potential therapeutic target in colorectal cancer.     

Acid exposure activates the mitogen-activated protein kinase pathways in Barrett's esophagus

BACKGROUND & AIMS: To explore mechanisms whereby acid reflux might contribute to carcinogenesis in Barrett's esophagus (BE) we studied: (1) the effects of acid on the mitogen-activated protein kinase (MAPK) pathways, cell proliferation, and apoptosis in a Barrett's adenocarcinoma cell line (SEG-1); and (2) the ability of acid to activate the MAPK pathways in vivo in patients with BE. METHODS: SEG-1 cells were exposed to acidic media for 3 minutes, and the activities of 3 MAPKs (ERK, p38, and JNK) were determined. Proliferation was assessed using flow cytometry; cell growth and apoptosis were assessed using cell counts and an apoptosis ELISA assay. MAPK activation was studied in biopsy specimens taken from patients with BE before and after esophageal perfusion for 3 minutes with 0.1N HCl. RESULTS: Acid-exposed SEG-1 cells exhibited a significant increase in proliferation and total cell numbers, and a significant decrease in apoptosis. These effects were preceded by a rapid increase in the activities of ERK and p38, and a delayed increase in JNK activity. PD 98059 abolished the acid-induced increase in G0/G1 and decrease in subG0 phases of the cell cycle. Both SB 203580 and DN-JNK 1/2 inhibited the acid-induced progression from G0/G1 to G2/M. The acid-induced decrease in apoptosis was abolished by inhibition of either ERK or p38. In the patients, acid exposure significantly increased the activity of p38 in the metaplastic epithelium. CONCLUSIONS: Acid increases proliferation and survival, and decreases apoptosis in SEG-1 cells by activating the MAPK pathways. Acid also activates the MAPK pathways in BE in vivo. These findings suggest that acid might contribute to carcinogenesis in BE through activation of MAPK pathways.     

Severe immune-mediated drug-induced liver injury linked to ibandronate: A case report

Ibandronate is a widely used bisphosphonate with no previously well documented hepatotoxicity. We report the first case of ibandronate-related hepatotoxicity and, to our knowledge, the first case of immune-mediated drug-induced liver injury (DILI) related to bisphosphonates.