Hageman factor, high molecular weight kininogen, and prekallikrein in chronic liver disease.

Cordova, C; Violi, Francesco; Alessandri, C.; Ferro, Domenico; Saliola, Mirella; Balsano, F

doi:10.1136/jcp.39.9.1003

Cited by 6 publications

(3 citation statements)

References 10 publications

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“…Initially synthesized in the liver, prekallikrein is converted to kallikrein by factor 12 and eventually cleaves HMWK to release bradykinin. In a study by Cordova and colleagues [ 37 ] the activities of the Hagemann factor, HMWK and prekallikrein were reduced and dependent on the degree of liver failure. Equally, plasma kallikrein clearance was markedly reduced in APAP intoxicated rat livers [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury

et al. 2013

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BackgroundAcetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP-induced liver injury (AILI).MethodsHealthy volunteers (n = 36) received either placebo or acetaminophen at the maximum daily dose of 4 g for 7 days. Blood samples were taken prior to and after APAP treatment. Serum proteomic profiling was done by 2D SDS-PAGE and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Additionally, the proteins C-reactive protein, haptoglobin and hemopexin were studied by quantitative immunoassays.ResultsOne-third of study subjects presented more than four-fold increased alanine transaminase activity to evidence liver injury, while serum proteomics informed on 20 proteins as significantly regulated. These function primarily in acute phase and immune response. Pre-treatment associations included C-reactive protein, haptoglobin isoforms and retinol binding protein being up to six-fold higher in AILI susceptible individuals, whereas alpha1-antitrypsin, serum amyloid A, kininogen and transtyretin were regulated by nearly five-fold in AILI responders. When compared with published findings for steatohepatitis and cases of hepatocellular, cholestatic and mixed DILI, 10 proteins were identified as uniquely associated with risk for AILI, including plasminogen. Notably, this zymogen facilitates macrophage chemotactic migration and inflammatory response as reported for plasminogen-deficient mice shown to be resistant to APAP hepatotoxicity. Finally, analysis of a publicly available database of gene expression profiles of cultures of human hepatocytes treated with drugs labeled as no- (n = 8), low- (n = 45) or most-DILI-concern (n = 39) confirmed regulation of the identified biomarkers to demonstrate utility in predicting risk for liver injury.ConclusionsThe significant regulation of acute phase reactants points to an important link between AILI and the immune system. Monitoring of serum acute phase reactants prior to drug treatment may contribute to prevention and management of AILI, and may also be of utility for other drugs with known liver liabilities.

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Section: Discussionmentioning

confidence: 99%

Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury

et al. 2013

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“…A P value of less than 0.05 was considered to indicate a statistically significant difference or correlation. plasma-concentrations of HK have been described (14,15), but the cause of this reduction or the effect on the molecule or on its catabolic products is unknown. To date, LK has never been assessed in cirrhotic plasma.…”

Section: Introductionmentioning

confidence: 99%

Parallel Reduction of Plasma Levels of High and Low Molecular Weight Kininogen in Patients with Cirrhosis

et al. 1999

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SummaryLittle is known about the regulation of high-molecular-weight-kininogen (HK) and low-molecular-weight-kininogen (LK) or the relationship of each to the degree of liver function impairment in patients with cirrhosis. In this study, we evaluated HK and LK quantitatively by a recently described particle concentration fluorescence immunoassay (PCFIA) and qualitatively by SDS PAGE and immunoblotting analyses in plasma from 33 patients with cirrhosis presenting various degrees of impairment of liver function. Thirty-three healthy subjects served as normal controls. Patients with cirrhosis had significantly lower plasma levels of HK (median 49 μg/ml [range 22-99 μg/ml]) and LK (58 μg/ml [15-100 μg/ml]) than normal subjects (HK 83 μg/ml [65-115 μg/ml]; LK 80 μg/ml [45-120 μg/ml]) (p < 0.0001). The plasma concentrations of HK and LK were directly related to plasma levels of cholinesterase (P < 0.0001) and albumin (P < 0.0001 and P < 0.001) and inversely to the Child-Pugh score (P < 0.0001) and to prothrombin time ratio (P < 0.0001) (reflecting the clinical and laboratory abnormalities in liver disease). Similar to normal individuals, in patients with cirrhosis, plasma HK and LK levels paralleled one another, suggesting that a coordinate regulation of those proteins persists in liver disease. SDS PAGE and immunoblotting analyses of kininogens in cirrhotic plasma showed a pattern similar to that observed in normal controls for LK (a single band at 66 kDa) with some lower molecular weight forms noted in cirrhotic plasma. A slight increase of cleavage of HK (a major band at 130 kDa and a faint but increased band at 107 kDa) was evident. The increased cleavage of HK was confirmed by the lower cleaved kininogen index (CKI), as compared to normal controls. These data suggest a defect in hepatic synthesis as well as increased destructive cleavage of both kininogens in plasma from patients with cirrhosis. The decrease of important regulatory proteins like kininogens may contribute to the imbalance in coagulation and fibrinolytic systems, which frequently occurs in cirrhotic patients.

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“…PK levels observed by us in cirrhotic patients demonstrate the pattern reported previously. [5][6][7][8]10 In this disease PK remains a good index of the elimination of protein synthesis in the liver.…”

Section: Plasma Prekallikrein Levels In Liver Disease 447mentioning

confidence: 99%

Plasma Prekallikrein Levels in Patients with Hepatocellular Carcinoma and Liver Cirrhosis: A Pilot Study

et al. 1993

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SUMMARY. The concentration of plasma prekallikrein (PK) in five patients with hepatocellular carcinoma (HCC) has been measured and related to levels in 18 patients with liver cirrhosis (LC) and 30 healthy subjects. It was found that the mean PK level was significantly increased in patients with HCC, while patients with LC demonstrated lower concentrations, as compared with healthy subjects. The results indicate that PK might be useful in screening cirrhotic patients for HCC. Longitudinal studies of PK in a larger group of patients at risk of developing HCC are therefore recommended.

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Hageman factor, high molecular weight kininogen, and prekallikrein in chronic liver disease.

Cited by 6 publications

References 10 publications

Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury

Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury

Parallel Reduction of Plasma Levels of High and Low Molecular Weight Kininogen in Patients with Cirrhosis

Plasma Prekallikrein Levels in Patients with Hepatocellular Carcinoma and Liver Cirrhosis: A Pilot Study

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