Liver Disturbance Research Articles

Nickel Nanoparticles Induced Hepatotoxicity in Mice via Lipid-Metabolism-Dysfunction-Regulated Inflammatory Injury.

Nickel nanoparticles (NiNPs) have wide applications in industry and biomedicine due to their unique characteristics. The liver is the major organ responsible for nutrient metabolism, exogenous substance detoxification and biotransformation of medicines containing nanoparticles. Hence, it is urgent to further understand the principles and potential mechanisms of hepatic effects on NiNPs administration. In this study, we explored the liver impacts in male C57/BL6 mice through intraperitoneal injection with NiNPs at doses of 10, 20 and 40 mg/kg/day for 7 and 28 days. The results showed that NiNPs treatment increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and induced pathological changes in liver tissues. Moreover, hepatic triglyceride (TG) content and lipid droplet deposition identified via de novo lipogenesis (DNL) progression were enhanced after NiNPs injection. Additionally, sustained NiNPs exposure induced a remarkable hepatic inflammatory response, significantly promoted endoplasmic reticulum stress (ER stress) sensors Ire1α, Perk and Atf6, and activated the occurrence of liver cell apoptosis. Overall, the research indicated that NiNPs exposure induced liver injury and disturbance of lipid metabolism. These findings revealed the public hazard from extreme exposure to NiNPs and provided new information on biological toxicity and biosafety evaluation.

Drug-Induced Liver Disturbance During the Treatment of COVID-19.

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in Wuhan, China, at the end of 2019. The World Health Organization named the resulting infectious disease as coronavirus disease-2019 (COVID-19). Many studies concluded that patients infected with SARS-CoV-2 have different degrees of liver disturbance. However, the relationship between the drugs used for COVID-19 treatment and liver disturbance remains controversial. It is essential to evaluate the potential liver damage caused by various drugs in order to help guide clinical practice. This review analyzed the effect of drugs on hepatic function during the treatment of COVID-19.

Carbon-ion radiotherapy subsequent to balloon-occluded retrograde transvenous obliteration for hepatocellular carcinoma with hepatic encephalopathy: a multidisciplinary approach

Radical treatments of hepatocellular carcinoma (HCC) with hepatic encephalopathy (HE) can be often difficult due to poor liver function or disturbance of consciousness. An effective treatment requires a combinatorial approach incorporating a treatment for HE and radical therapy for HCC that does not compromise liver function. Here, we report a case of a 78-year-old Japanese male with HCC and HE caused by splenorenal shunt. Serum ammonia levels were high. He was not suitable for surgery, percutaneous radiofrequency ablation, or transarterial chemoembolization due to the location of the tumor and poor liver function, which included HE. Thus, he underwent BRTO, with an immediate improvement in both HE and serum ammonia levels. After BRTO, he received C-ion RT as a radical treatment for HCC. After treatment, HCC was well controlled; however, at 35 months post-initiation of C-ion RT, he developed local recurrence without a further reduction in liver function status. Therefore, we repeated C-ion RT. The patient remains alive at 3 months post-treatment, with no evidence of local recurrence, distant metastasis, or toxicity. Although this is a single case report, it suggests that a combinatorial treatment consisting of BRTO and C-ion RT may increase survival rates of patients with HCC and HE.

Proteomics evaluation of enniatins acute toxicity in rat liver

Enniatins (ENs) are emerging mycotoxins produced by Fusarium fungi which are cytotoxic also at low concentrations due to its ionophoric properties. The aim of this study was to evaluate the hepatic toxicity of ENs exposure at different concentrations in Wistar rats through a proteomic approach. Animals were intoxicated by oral gavage with medium (EN A 256, ENA1 353, ENB 540, ENB1 296 μg/mL) and high concentrations (ENA 513, ENA1 706, ENB 1021, ENB1 593 μg/mL) of an ENs mixture and sacrificed after 8 h. Protein extraction was performed using powdered liver. Peptides were analyzed using a liquid chromatography coupled with a quadrupole time-of-flight mass spectrometer. Proteins were filtered by abundance using Mass Professional Profiler software (Agilent Technologies) and 57 were differentially expressed when compared to the control. In terms of abundance, the liver biomarker Carboamoyl-phosphate synthase showed the highest levels in all conditions employed while actin-1 had the lowest. Bioinformatic analysis using DAVID platform reported acetylation, nucleotide phosphate-binding region:NAD and catalytic activity as the most represented terms. Furthermore, metabolism was the most significant and enriched pathway in Reactome overrepresentation. In conclusion, ENs acute exposure caused protein expression changes related to major cellular processes in rats, hinting its involvement in liver disturbance.

Polysaccharides from Dicliptera chinensis ameliorate liver disturbance by regulating TLR-4/NF-κB and AMPK/Nrf2 signalling pathways.

The purpose of this study was to alleviate liver disturbance by applying polysaccharides from Dicliptera chinensis (DCP) to act on the adenosine monophosphate–activated protein kinase/ nuclear factor erythroid 2‐related factor 2 (AMPK/ Nrf2) oxidative stress pathway and the Toll‐like receptor 4 (TLR‐4)/ nuclear factor kappa‐B (NF‐κB) inflammatory pathway and to establish an in vivo liver disturbance model using male C57BL/6J and TLR‐4 knockout (−/−) mice. For this, we evaluated the expression levels of SREBP‐1 and Nrf2 after silencing the expression of AMPK using siRNA technology. Our results show that with regard to the TLR‐4/ NF‐κB inflammatory pathway, DCP inhibits TLR‐4, up‐regulates the expression of peroxisome proliferator‐activated receptor‐γ (PPAR‐γ), reduces the expression of phospho(p)‐NF‐κB and leads to the reduction of downstream inflammatory factors, such as tumour necrosis factor‐α (TNF‐α), interleukin (IL)‐6 and IL‐1β, thereby inhibiting the inflammatory response. Regarding the AMPK/ Nrf2 oxidative stress pathway, DCP up‐regulates the expression of p‐AMPK and Nrf2, in addition to regulating glucose and lipid metabolism, oxidative stress and ameliorating liver disturbance symptoms. In summary, our study shows that DCP alleviates liver disturbances by inhibiting mechanisms used during liver inflammation and oxidative stress depression, which provides a new strategy for the clinical treatment of liver disturbance.

Ceftriaxone allergy in a pediatric cohort

Ceftriaxone allergy in children is common and in this small cohort we aimed to characterize the demographic and clinical histories of 14 children with reported immediate drug hypersensitivity to ceftriaxone. Data was collected from children presenting to the Montreal Children’s Hospital with suspected ceftriaxone allergy. A standardized questionnaire was completed by the patient’s parents about the suspected allergic reaction. We had a total of 14 children who had history of allergic reaction after receiving ceftriaxone. Among the 14 patients with suspected ceftriaxone allergy,60% were males and median age was 7 (IQR: 2.90,13.13). Among all,12 (85%) underwent skin testing to ceftriaxone including prick tests and intradermal (ID 20mg/ml ).Three patients (25%) had a positive ID test and were instructed to avoid ceftriaxone and 9 patients (75%) had a negative skin test. Among the group with negative skin tests, three (33 %) had a negative challenge to ceftriaxone,4 patients (44%) had a negative oral challenge to cephalosporins but were not interested in ceftriaxone challenge and one patient was instructed to avoid all cephalosporins completely given a history of mild liver disturbance and eosinophilia which was suggestive of DRESS.There was one patient with negative skin testing and a pending IV ceftriaxone challenge. The majority of children in this cohort with a history of immediate hypersensitivity reactions to ceftriaxone had negative skin testing and one-third had a successful challenge to IV ceftriaxone. We aim to extend our cohort to determine factors associated with true ceftriaxone allergy.

Decreasing Carbon Tetrachloride Toxicity using Date-seed (Phoenix dactylifera L.) Steeping in Rats

Many toxic compounds in foods cause liver damage and disturbance of bodily function. Inflammation will precede liver damage as an initial response to poisoning. The inflammatory response depends heavily on the strength of the body’s immune system. Many foods, drugs, and other compounds can decrease the immune system, but few serve as immunostimulants. This study aims to prove the decreasing of carbon tetrachloride toxicity using date-seed (Phoenix dactylifera L.) steeping to improve rat immunity. This was an experiment with pre- and posttest with a control group design. Wistar white rats were grouped into 6 groups, healthy control (HC), negative control (NC), positive control (PC), treatment dose 1 g/ kg (T1), treatment dose 3 g/kg (T3), and treatment dose 5 g/kg (T5). All of the groups were induced by CCL4 before treatment except the HC group. The observed data were interleukin-6 (IL-6), lymphocyte count, and C-reactive protein (CRP). Data from the groups were compared with an ANOVA test and followed by a post hoc test if a significant result was found. The results showed that there were significant differences between IL-6, lymphocyte count, and CRP between HC and other groups that CCL4-induced. After the delivery of date-seed steeping, levels of IL-6 and CRP decreased, and the lymphocyte count increased significantly. The group with the 5 g/kg treatment dose was the most effective group for inhibiting the increase of IL-6 and CRP, but a dose of 3 g/kg was the most effective to increase lymphocyte count. Date-seed steeping suppresses pro-inflammation mediators; it has a potency which improves cytokine pro-inflammation by inhibiting the inflammation process. Thus, date seed can be used as a cheap source of anti-inflammation that can be considered as a health opportunity for developing countries.

Serum vaspin level as a predictive indicator in the amelioration of fatty liver and metabolic disturbance in patients with severe obesity after laparoscopic vertical banded gastroplasty.

Background:This study is all about predicting the value of serum vaspin level in the amelioration of fatty liver and metabolic disturbance in patients with severe obesity after laparoscopic vertical banded gastroplasty (LVBG).Methods:A total of 164 patients (from January 2012 to May 2015) with severe obesity were chosen and performed LVBG. Enzyme-linked immunosorbent assay was performed to detect the serum vaspin level. The patients were given a biochemical automatic analyzer to measure the biochemical indicators. Homeostasis model assessment (HOMA) helps in the calculation of fasting insulin level (FINS) and insulin resistance (IR). The changes in fatty liver were examined by computed tomography (CT). Receiver operating characteristic curve is used to increase the predictive value of serum vaspin level in the amelioration of liver function and disturbances in the metabolism.Results:Weight, BMI, waist circumference, serum vaspin level, and triglyceride (TG) decreased, but CT value of liver increased at 4th, 7th, and 12th month after surgery. After the 7th and 12th month period of surgery, the alanine aminotransferase, aspartate aminotransferase, FINS, and HOMA-IR reduced in the patients (P <.005). The area under ROC curve (AUC) is about 0.871 ± 0.031 with 95%CI of 0.810–0.931 (P <.001). The sensitivity, specificity, and accuracy of serum vaspin level ≤0.9 were 87.80%, 78.05%, and 83.28%, respectively. BMI, FINS, and serum vaspin level ≤0.9 were the influencing factors of the amelioration of fatty liver and metabolic disturbance.Conclusion:This study proves that the serum vaspin level serves as a predictive indicator in the amelioration of fatty liver and metabolic disturbance in patients with severe obesity after LVBG.

Untargeted Metabolomics Analysis of ABCC6-Deficient Mice Discloses an Altered Metabolic Liver Profile.

Loss-of-function mutations in the transmembrane ABCC6 transport protein cause pseudoxanthoma elasticum (PXE), an ectopic, metabolic mineralization disorder that affects the skin, eye, and vessels. ABCC6 is assumed to mediate efflux of one or several small molecule compounds from the liver cytosol to the circulation. Untargeted metabolomics using liquid chromatography-mass spectrometry was employed to inspect liver cytosolic extracts from mice with targeted disruption of the Abcc6 gene. Absence of the ABCC6 protein induced an altered profile of metabolites in the liver causing accumulation of compounds as more features were upregulated than downregulated in ABCC6-deficient mice. However, no differences of the identified metabolites in liver could be detected in plasma, whereas urine reflected some of the changes. Of note, N-acetylated amino acids and pantothenic acid (vitamin B5), which is involved in acetylation reactions, were accumulated in the liver. None of the identified metabolites seems to explain mineralization in extrahepatic tissues, but the present study now shows that abrogated ABCC6 function does cause alterations in the metabolic profile of the liver in accordance with PXE being a metabolic disease originating from liver disturbance. Further studies of these changes and the further identification of yet unknown metabolites may help to clarify the liver-related pathomechanism of PXE.

Liver transplantation for a patient with Turner syndrome presenting severe portal hypertension: a case report and literature review.

BackgroundLiver involvement in Turner syndrome (TS) patients has been more clearly clarified in recent years. Most of the clinical manifestations in TS are asymptomatic and can be detected as liver test abnormalities; however, a few cases may present with end-stage liver disease and thus require liver transplantation (LT). To the best of our knowledge, only three cases undergoing LT for liver involvements in TS have been previously reported.Case presentationA 30-year-old female successfully underwent living donor LT for liver dysfunction related to TS syndrome. The diagnosis of TS was established by a cytogenetic analysis at 16 years of age. She received several sessions of endoscopic therapy for recurrent esophageal varices, which was complicated by ascites and spontaneous bacterial peritonitis since 27 years of age. Radiological findings of her liver before LT chronologically showed the progression of atrophy with disturbance of the major portal inflow. And then, she was finally indicated for LT. Pathologic findings of the explanted liver showed vascular abnormalities, obliterative portal venopathy, which may have induced liver dysfunction with severe portal hypertension. The patient’s postoperative course was uneventful.ConclusionsThe clinicopathologic information obtained by the current case can provide an insight into understanding pathophysiological mechanisms of liver involvement in TS patients. TS patients presenting with severe liver atrophy and disturbance of the major portal inflow should be indicated for LT.

Idiosyncratic nature of voriconazole photosensitivity in children undergoing cancer therapy

A paucity of paediatric data exists. The authors describe a rela-tionship between dose, plasma levels and toxicity in childrenwith invasive fungal disease treated with voriconazole. Not sur-prisingly, given the adult data, it confirms a large variability invoriconazole trough levels and toxicity at trough serum levels.5.5 mg/L. Toxicities included neurological side effects, gastro-intestinal or liver disturbance, phototoxicity and other skin reac-tions. Additionally, Soler-Palaci´n et al.

Esplenomegalia induzida por drogas.

The diagnosis of splenomegaly due to drugs is based on a recent history of exposure to a drug before the spleen enlargement. The purpose of this paper is to review studies of the literature on drugs that may induce to splenomegaly. Drugs may provoke the enlargement of spleen by direct effect in splenic cells or as a side effect of disturbances in other organs, mainly liver and haematoimmunologic system. Some drugs provoke severe haemolysis associated with splenomegaly. Another cause of spleen increasing in size is the venous congestion due to liver disturbance with portal vein occlusion. All these drug side effects are usually transitory and splenomegaly disappears when the medication is discontinued. This is a complex problem that must be better studied to be understood in order to prevent its occurrence and to find the best treatment.

Early Incidence of Fatty Liver and Metabolic Disturbance in an Ovine Intrauterine Model of Increased Androgen Exposure.

Early Incidence of Fatty Liver and Metabolic Disturbance in an Ovine Intrauterine Model of Increased Androgen Exposure.

The Incidence of Veno-Occlusive Disease Following Allogeneic Hematopoietic Stem Cell Transplantation Has Diminished and the Outcome Improved over the Last Decade

The evolution of the incidence, morbidity, and mortality of veno-occlusive disease (VOD) was analyzed in 845 allogeneic hematopoietic stem cell transplantations (allo-HSCTs) performed over 24 years. A total of 117 patients and 73 patients developed VOD following the Seattle and the Baltimore diagnostic criteria, respectively (cumulative incidence 13.8% and 8.8%). The cumulative incidence was significantly higher in the period 1985 to 1996 than in 1997 to 2008 (11.5% vs 6.5%; P= .01). This decline was because of the low incidence of VOD among reduced-intensity conditioning-HSCT (RIC-HSCT) (2.1%) and the reduction among those receiving myeloablative-HSCT from unrelated donors (32.7% vs 10.5%, P = .001). A total of 35 patients had severe VOD (26 with multiorgan failure [MOF]), and 20 died by VOD (cumulative mortality rate 17.3%, Seattle, or 22.5%, Baltimore). The mortality declined since 1997 (from 22% to 9%; P = .06, Seattle, and from 36% to 14%; P= .04, Baltimore), with the introduction of defibrotide being the only relevant change in the management of patients. This occurred even though the severity of VOD was similar in both periods. Among those with MOF, only 2 of 8 (25%) receiving defibrotide died versus 14 of 18 (78%) receiving other treatments (P = .007). Myeloablative conditioning, previous liver disease, poor performance status, and alternative donors were the variables with higher impact on VOD development. In summary, although VOD remains a dreaded early complication of HSCT, technical and therapeutic progress in recent decades have notably reduced its incidence and improved the outcome.

A case of dermatomyositis with “liver disease associated with rheumatoid diseases” positive for anti-liver–kidney microsome-1 antibody

We reported a case of dermatomyositis (DM) with liver disturbance in a 50-year-old Japanese female. She presented with fever, muscle weakness, and typical DM rashes. On clinical and serological examinations, the liver impairment was initially diagnosed as probable autoimmune hepatitis, which was denied by a histological study despite positive anti-liver-kidney microsome-1 antibody. Finally, she was diagnosed as having DM with "liver disease associated with rheumatoid diseases", and treatment with oral prednisone (40 mg/day) achieved normalization of liver and muscle enzyme levels as well as improvement of symptoms associated with DM. Liver involvement in patients with polymyositis (PM)/DM has not been well described and is considered to be uncommon. Full clarification of the etiology of liver impairment with a histological examination in collagen diseases including PM/DM is useful to determine the proper dose of corticosteroids for the treatment of collagen diseases and their liver complications.

First European Chemotherapy Schedule for Elderly Patients with Acute Lymphoblastic Leukemia: Promising Remission Rate and Feasible Moderate Dose Intensity Consolidation

Only few elderly ALL patients are entered to prospective trials and the data on patient characteristics and outcome are scarce. The European Working Group for Adult ALL (EWALL), which was funded in 2001 by all major national European study groups for adult ALL, therefore focused on the development of rational treatment approaches for elderly ALL as an unmet medical need. The group agreed on a chemotherapy backbone mainly based on elements derived from previous French and German protocols for elderly ALL. After a pre-phase with dexamethasone +/− cyclophosphamide the 4-week-induction comprised dexamethasone (10 mg/m2, d1–2,8–11), vincristine (1 mg, d 1,8), idarubicine (10 mg, d 1–2,8–9) in phase I and cyclophosphamide (500 mg/m2, d15–17) and cytarabine (60 mg/m2, d16–19, 23–26) in phase II. Consolidation consisted of 6 alternating cycles with 3 times methotrexate (1000 mg/m2, d1) and E.coli asparaginase (10000 U/m², d2) and 3 times high-dose cytarabine (1000 mg/m2/q12 hrs, d1,3,5) followed by maintenance with mercaptopurine, methotrexate and vincristine/dexamethasone pulses for a total treatment duration of 2 yrs. Dose reductions were recommended for pts older than 70 yrs, and slight modifications were made in the three participating countries. In a separate protocol the backbone chemotherapy is used in combination with Dasatinib for pts with Ph/BCR-ABL+ ALL. Between 1/07 and 8/08 54 pts with Ph-negative ALL from 33 centers were treated, and 40 pts were evaluable for response after induction (France 20, Germany 13 and Spain 7). The median age was 66 (56–73) yrs with 22% older than 70 yrs. General condition (ECOG) was 2–3 in 23%. 65% had c/pre-B-ALL, 15% pro-B, 17% T-lineage and 1 pt biphenotypic ALL. Cytogenetics (N=30) were normal in 40%, t(4;11) in 7%, complex in 7% and with other aberrations in 47%. 23% had WBC above 30000/μl at diagnosis. 34 (85%) pts achieved CR after induction. PR or failure was observed in 7% resp. No pt died during induction. 85% of the pts were alive at a median follow-up of 8 mo. The probability of survival after 1 year is 61%. 4/34 CR pts were withdrawn in CR from further treatment (12%). Of the remaining 30 CR pts 23 are in CCR (77%), 1 died in CR due to fungal septicaemia (3%), 6 relapsed (20%). The probability of continuous CR after 1 year is 49% with a median remission duration of 9 mo. During induction I and II the majority of pts experienced grade III–IV adverse events (AE), most frequently cytopenias (>90%) and infections (16% phase I, 25% phase II). Treatment with HDMTX/ASP (Cons I or III) was evaluable in 44 cycles. 45% were associated with grade III–IV AE, most frequently cytopenias, infections, liver disturbance and allergy to asparaginase in 2 pts. HDAC (Cons II or IV) was evaluable in 34 cycles with 47% grade III–IV AEs, again mostly cytopenias. With this age adapted induction regimen for elderly pts (median age: 66 yrs) a high CR rate (85%) was achieved. The moderate intensity consolidation treatment was tolerable, and the low rate of treatment related death elucidates the fact that intensive supportive treatment e.g prophylaxis/treatment of infections can be successful in elderly pts. It is noteworthy that treatment with asparaginase as a major drug for ALL, which was so far rarely used in elderly pts, was feasible as well. Although follow-up is short, the survival probability of 61% after 1 year is promising. In future trials new investigational drugs will be added to the backbone in order to evaluate their efficacy and feasibility in randomised studies. Partly supported by the European Union (European Leukemia Net)

Drug-induced splenic enlargement

Splenomegaly results from different abnormal conditions susceptible to drugs. Their diagnosis is based on a history of exposure to a drug before the spleen enlargement. This paper reviews studies on drugs that may induce to splenomegaly. Drugs may provoke the enlargement of the spleen by direct effect on splenic cells or as a side effect of disturbances in other organs, such as the liver, or systems, such as the haematoimmunological system. Some drugs provoke severe haemolysis associated with splenomegaly. Another cause of spleen increasing in size is the venous congestion due to liver disturbance with portal vein occlusion as side complications of drugs. All these drug side effects are usually transitory and splenomegaly disappears when the medication is discontinued. This is a complex problem that must be better studied to be understood in order to prevent its occurrence and to find the best treatment.

A [meso‐Tetrakis(4‐sulfonatophenyl)porphyrinato]zinc(II) Complex As an Oral Therapeutic for the Treatment of Type 2 Diabetic KKAy Mice

We prepared and characterized [meso-tetrakis(4-sulfonatophenyl)porphyrinato]zinc(II) ([Zn(tpps)]), and investigated its in vitro insulin-mimetic activity and in vivo hypoglycemic effect in type 2 diabetic KKA(y) mice. The results were compared with those of previously proposed insulin-mimetic zinc(II) complexes and zinc sulfate (ZnSO(4)). The in vitro insulin-mimetic activity of [Zn(tpps)] was considerably better than that of bis(allixinato)zinc(II) ([Zn(alx)(2)]), bis(maltolato)zinc(II) ([Zn(mal)(2)]), bis(2-aminomethylpyridinato)zinc(II) ([Zn(2-ampy)(2)](2+)), and ZnSO(4). In particular, the order of in vitro insulin-mimetic activity of the complexes was determined to be: [Zn(tpps)]>[Zn(alx)(2)]>[Zn(mal)(2)]>[Zn(2-ampy)](2+)>ZnSO(4). [Zn(tpps)] normalized the hyperglycemia of KKA(y) mice within 21 days when administered orally at doses of 10-20 mg (0.15-0.31 mmol) Zn per kg body mass for 28 days. In addition, metabolic syndromes such as insulin resistance, the degree of renal disturbance, and the degree of liver disturbance were significantly improved in [Zn(tpps)]-treated KKA(y) mice relative to those administered with saline and ZnSO(4). The improvement in diabetes was validated by the results of oral glucose-tolerance tests and the decrease in the HbA(1c) level observed. In contrast, ZnSO(4) and the ligand H(2)tpps did not lower the elevated blood glucose level under the same experimental conditions. Based on these observations, [Zn(tpps)] is proposed to be the first orally active zinc(II)-porphyrin complex for the efficacious treatment of not only type 2 diabetes but also metabolic syndromes in animals.

Increased von Willebrand Factor Over Decreased ADAMTS13 Activity May Contribute to the Development of Liver Disturbance and Multiorgan Failure in Patients With Alcoholic Hepatitis

Severe alcoholic hepatitis (SAH) in addition to alcoholic hepatitis (AH) is a life-threatening complication of alcohol abuse, and its pathogenesis remains unclear. The deficiency of ADAMTS13 results in an increase of the plasma unusually large von Willebrand factor multimer (UL-VWFM) and finally causes microcirculatory disturbance and multiorgan failure. We investigated the relationship of ADAMTS13 and von Willebrand factor antigen (VWF:Ag) with the clinical features of AH and SAH. The plasma levels of ADAMTS13 activity, VWF:Ag, and UL-VWFM were determined in 24 patients with AH, 5 with SAH, and 10 with alcoholic liver cirrhosis (LC). The ADAMTS13 activity was significantly lower in SAH (mean 24%), AH (62%), and LC (76%) than in the healthy subjects (102%, n=62). The VWF:Ag levels were higher in SAH (806%), AH (405%), and LC (514%) than in the healthy subjects (100%), resulting in a higher ratio of VWF:Ag to ADAMTS13 activity in SAH (102.2), AH (8.9), and LC (8.6) compared with the healthy subjects (1.0). In 3 nonsurvivors with SAH and multiorgan failure, the protease activity markedly decreased (from 4.5 to 16%), and VWF:Ag remarkably increased (from 560 to 1,202%), resulting in an extremely high ratio of VWF:Ag to the activity (from 35.0 to 240.4). At the recovery stage in the survivors with SAH and AH, the protease activity increased and the VWF:Ag decreased, whereas in a nonsurvivor with SAH, the activity remained extremely low and the VWF:Ag was still high. Unusually large von Willebrand factor multimer was detected in 80.0% of SAH and 55.6% of AH. Multivariate analysis showed that the serum albumin and platelet count independently correlated with VWF:Ag. The enhanced production of UL-VWFM over deficient activity of ADAMTS13 may, in part, contribute to not only the progression of liver injury but also the development of multiorgan failure through microcirculatory disturbance in SAH in addition to AH. The imbalance between the plasma ADAMTS13 activity and VWF:Ag could be a useful prognostic marker in AH.

Increased Plasma VWF Antigen over Decreased ADAMTS13 Activity in Patients with Liver Cirrhosis: Relationship to Degree of Liver Disturbance and Clinical Features.

Background/aims: Deficiency of plasma ADAMTS13 activity (:act) accumulates unusually large von Willebrand factor multimer (UL-VWFM) in circulation that might induce platelet thrombi formation. We demonstrated that hepatic stellate cells are major ADAMTS13-producing cells in human liver using in situ hybridization and immunohistochemistry (Blood , 2005, 106:922), and a decreased plasma ADAMTS13:act in patients with cirrhotic biliary atresia can be fully restored after living-related liver transplantation (Blood 2000, 96:636a). Taken these findings together, ADAMTS13 may play a role on the regulation of sinusoidal microcirculation in the liver. We, therefore, investigated the relationship of ADAMTS13 and its substrate (UL-VWFM) to clinical features in patients with chronic liver diseases.Methods: Plasma levels of ADAMTS13:act, ADAMTS13 antigen (:ag) and VWF antigen (VWF:ag) were determined in 33 patients with chronic hepatitis (CH) and 109 liver cirrhosis (LC). ADAMTS13:act was measured by both the classic VWFM assay and the novel monoclonal antibody-based ELISA (Transfusion 2006, 46:1444). The ADAMTS13:ag was quantified by a sandwich ELISA using two anti-ADAMTS13 murine monoclonal Abs (A10 and C7), and the UL-VWFM was analyzed by a SDS−0.9% agarose gel electrophoresis.Results: ADAMTS13:act in LC progressively decreased from the highest in Child A (mean 79%), to Child B (63%), to the lowest in Child C (30%), compared with CH (87%) and normal healthy subjects (N, 102%). The activity measured by VWFM assay highly correlated with that assayed by ELISA (r=0.75, p<0.001), which was also correlated with ADAMTS13:ag (r=0.79, p<0.001). Markedly decreased ADAMTS13 :act was noted in cirrhotics with hepatic encephalopathy (28%), refractory ascites (25%), and hepatorenal syndrome (13%). The multivariate analysis showed Child-Pugh score and spleen volume as independent factors contributing to the activity (r=0.69, p<0.001). VWF:ag was remarkably high with the progression of liver disturbance (N 100%, CH 245%, Child A LC 320%, Child B LC 436%, Child C LC 486%, respectively), resulting in extremely increased ratio of VWF:ag to ADAMTS13 activity in advanced cirrhotics (N 1.0, CH 2.9, Child A LC 4.3, Child B LC 13.3, Child C LC 43.2, respectively). The cirrhotics with UL-VWFM showed higher Child-Pugh score (10.8 vs. 7.7, p<0.001), lower hemoglobin levels (9.6 g/dl vs. 11.3 g/dl, p<0.005), severe thrombocytopenia (6.2 x104/mm3 vs. 9.2 x104/mm3, p<0.05), higher C-reactive protein (3.8 mg/dl vs. 0.9 mg/dl, p<0.001), and higher serum creatinine (1.5 mg/dl vs. 0,9 mg/dl, p<0.005) than those without.Conclusions: Both the activity and antigen of plasma ADAMTS13 decrease with increasing severity of cirrhotics. The imbalance of a larger amount of UL-VWFM over the decreased plasma level of ADAMTS13 may reflect the predisposing state for the development of microcirculatory disturbance in advanced cirrhotics.