Methods for diagnosis and intervention of hepatic disorders

Abstract

The disclosure provides a method for quantification of hepatic function in a subject comprising measuring the clearance of an orally administered isotopically labeled cholic acid in a subject with, or suspected of having or developing, a hepatic disorder, for example, chronic hepatitis C. The disclosure further provides methods and kits for assessment of hepatic function.

We claim: 
     
         1 .- 22 . (canceled) 
     
     
         23 . A method for assessment of hepatic function in a subject having, or suspected of having or developing, a hepatic disorder, the method comprising:
 (a) receiving a plurality of blood or serum samples collected from the subject following oral administration of a distinguishable compound to the subject, wherein no additional distinguishable compound is intravenously co-administered, and wherein the samples have been collected from the subject over a time period of no more than about 180 minutes after administration;   (b) measuring concentration of the distinguishable compound in each sample;   (c) generating an individualized oral clearance curve from the concentration of the distinguishable compound in each sample comprising using a computer algorithm curve fitting to a model oral distinguishable compound clearance curve;   (d) computing the area under the individualized oral clearance curve (AUC) and dividing the dose (in mg) by AUC of the orally administered distinguishable compound to obtain the oral distinguishable compound clearance in the subject; and   (e) comparing the oral distinguishable compound clearance in the subject to an oral distinguishable compound clearance cutoff value as an indicator of the relative hepatic function in the subject.   
     
     
         24 . The method of  claim 23 , wherein the distinguishable compound is a compound that is extracted from the portal blood in its first pass through the liver by at least about 60%, 80%, or 85% in healthy controls. 
     
     
         25 . The method of  claim 23 , wherein the distinguishable compound is a distinguishable bile acid or xenobiotic. 
     
     
         26 . The method of  claim 25 , wherein the distinguishable bile acid is a distinguishable cholate compound selected from the group consisting of distinguishable cholic acids, distinguishable glycine-conjugated cholic acids, distinguishable taurine-conjugated cholic acids, distinguishable chenodeoxycholic acids, distinguishable glycine-conjugated chenodeoxycholic acids, and distinguishable taurine-conjugated chenodeoxycholic acids. 
     
     
         27 . The method according to  claim 25 , wherein the distinguishable bile acid is a stable isotope labeled distinguishable cholate compound. 
     
     
         28 . The method of  claim 23 , wherein collecting samples over an interval period of time comprises collecting samples over a period of about 90 minutes or less. 
     
     
         29 . The method of  claim 28 , wherein the samples comprise blood samples collected from the subject at about 5, 20, 45, 60 and 90 minutes post-administration. 
     
     
         30 . The method of  claim 23 , wherein the measuring step comprises quantifying the distinguishable compound in the samples by gas chromatography-mass spectrometry (GC-MS) or high pressure liquid chromatography-mass spectrometry (HPLC-MS). 
     
     
         31 . The method of  claim 23 , further comprising at least one additional hepatic assessment test. 
     
     
         32 . The method of  claim 31 , wherein the at least one additional hepatic assessment test is selected from the group consisting of clearance or metabolism of aminopyrine, clearance or metabolism of antipyrine, clearance or metabolism of bile acids other than cholate, clearance or metabolism of caffeine, clearance of or metabolism erythromycin, clearance or metabolism of nitroglycerin, clearance of or metabolism galactose, clearance or metabolism of indocyanine green, clearance or metabolism of lidocaine, clearance or metabolism of midazolam, clearance or metabolism of omeprazole, clearance or metabolism of dextromethorphan, clearance or metabolism of phenacetin, clearance or metabolism of methacetin, clearance or metabolism of methionine, ultrasonography, elastography, magnetic resonance imaging (MRI) elastography, liver-spleen scan, serum bilirubin analysis, alanine aminotransferase analysis, aspartate aminotransferase analysis, alkaline phosphatase analysis, prothrombin analysis, creatinine analysis, platelet count, blood count analysis, serum albumin and MELD (model for end-stage liver disease) score. 
     
     
         33 . The method of  claim 23 , wherein the comparing of clearance of the distinguishable compound in the subject to the cutoff value is an indication of a need for at least one therapeutic treatment of the subject with a hepatic disorder. 
     
     
         34 . The method of  claim 33 , wherein the at least one therapeutic treatment comprises an antiviral therapy. 
     
     
         35 . The method of  claim 33 , wherein the hepatic disorder comprises chronic hepatitis C. 
     
     
         36 . The method of  claim 23 , wherein the comparing of the clearance of the distinguishable compound in the subject to the cutoff value is an indication of one or more of stage of fibrosis, presence of varices, presence of large varices at risk to bleed, inability to respond to peginterferon/ribavirin in chronic hepatitis C, hepatic improvement in response to antiviral therapy, future decompensation, hepatic functional impairment in cholestatic liver disease (primary sclerosing cholangitis, PSC) or prediction of clinical outcome in chronic hepatitis C in the subject. 
     
     
         37 . The method of  claim 23 , wherein the step of comparing the clearance in the subject to a clearance cutoff is an indicator of future clinical outcome of at least one hepatic disorder in the subject. 
     
     
         38 . The method of  claim 37 , wherein the cutoff value for oral distinguishable compound clearance for defining a hepatitis C patient at greatest risk for future hepatic decompensation is oral distinguishable compound clearance <11 mL/(min kg). 
     
     
         39 . The method of  claim 23 , wherein the clearance cutoff value is derived from normal healthy controls, within a given individual over time, patients who respond to therapy, patients with large varices, patients with sustained virological response to antiviral therapy, patients unable to respond to antiviral therapy, patients with significant fibrosis, or patients with cirrhosis. 
     
     
         40 . A method for assessment of hepatic function in a subject having, or suspected of having or developing, a hepatic disorder, the method comprising:
 (a) receiving a plurality of blood or serum samples collected from the subject following oral administration of a dose of a first distinguishable compound (dose oral ) to the subject and intravenous co-administration of a dose of a second distinguishable compound (dose iv ) to the subject, wherein the samples have been collected over intervals spanning a time period of no more than 180 minutes after administration;   (b) quantifying the concentration of the first and the second distinguishable compounds in each sample by HPLC-MS;   (c) generating an individualized oral clearance curve from the concentration of the first distinguishable compound in each sample comprising using a computer algorithm curve fitting to a model oral distinguishable compound clearance curve and computing the area under the individualized oral clearance curve (AUCoral);   (d) generating an individualized intravenous clearance curve from the concentration of the second distinguishable compound in each sample by use of a computer algorithm curve fitting to a model intravenous distinguishable compound clearance curve and computing the area under the individualized intravenous clearance curve (AUCiv); and   (e) calculating the liver shunt fraction in the subject using the formula:
   AUCoral/AUCiv×Doseiv/Doseoral×100%;
 
   and   (f) comparing the liver shunt fraction in the subject to a distinguishable compound liver shunt fraction cutoff value, wherein the liver shunt fraction in the subject compared to the cutoff value is an indicator of the hepatic function of the subject.   
     
     
         41 . The method of  claim 40 , wherein the first and second distinguishable compounds are compounds that are extracted from the portal blood in its first pass through the liver by at least about 60%, 80%, or 85% in healthy controls. 
     
     
         42 . The method of  claim 40 , wherein the first and second distinguishable compounds are distinguishable bile acids or xenobiotics. 
     
     
         43 . The method of  claim 42 , wherein the first and second distinguishable bile acids are distinguishable cholate compounds independently selected from the group consisting of distinguishable cholic acids, distinguishable glycine-conjugated cholic acids, distinguishable taurine-conjugated cholic acids, distinguishable chenodeoxycholic acids, distinguishable glycine-conjugated chenodeoxycholic acids, and distinguishable taurine-conjugated chenodeoxycholic acids. 
     
     
         44 . The method according to  claim 42 , wherein the first and second distinguishable bile acids are stable isotope labeled distinguishable cholate compounds. 
     
     
         45 . The method of  claim 40 , wherein the collecting step comprises collecting samples over a period of about 90 minutes or less. 
     
     
         46 . The method of  claim 45 , wherein the samples comprise blood or serum samples collected from the subject at about 5, 20, 45, 60, and 90 minutes post-dose. 
     
     
         47 . The method of  claim 40 , wherein the comparing of the liver shunt fraction in the subject to the cutoff value is an indicator of a need for at least one therapeutic treatment of the subject with a hepatic disorder. 
     
     
         48 . The method of  claim 47 , wherein the at least one therapeutic treatment comprises an antiviral therapy. 
     
     
         49 . The method of  claim 47 , wherein the hepatic disorder comprises chronic hepatitis C. 
     
     
         50 . The method of  claim 40 , further comprising at least one additional hepatic assessment test. 
     
     
         51 . The method of  claim 50 , wherein the at least one additional hepatic assessment test is selected from the group consisting of clearance or metabolism of aminopyrine, clearance or metabolism of antipyrine, clearance or metabolism of bile acids other than cholate, clearance or metabolism of caffeine, clearance of or metabolism erythromycin, clearance or metabolism of nitroglycerin, clearance of or metabolism galactose, clearance or metabolism of indocyanine green, clearance or metabolism of lidocaine, clearance or metabolism of midazolam, clearance or metabolism of omeprazole, clearance or metabolism of dextromethorphan, clearance or metabolism of phenacetin, clearance or metabolism of methacetin, clearance or metabolism of methionine, ultrasonography, elastography, magnetic resonance imaging (MRI) elastography, liver-spleen scan, serum bilirubin analysis, alanine aminotransferase analysis, aspartate aminotransferase analysis, alkaline phosphatase analysis, prothrombin analysis, creatinine analysis, platelet count, blood count analysis, serum albumin and MELD (model for end-stage liver disease) score. 
     
     
         52 . The method of  claim 40 , wherein the step of comparing the liver shunt fraction in the subject to the shunt cutoff is an indicator of future clinical outcome of at least one hepatic disorder in the subject. 
     
     
         53 . The method of  claim 52 , wherein the cutoff value for shunt for defining a hepatitis C patient at greatest risk for future hepatic decompensation is liver shunt fraction ≥39%. 
     
     
         54 . The method of  claim 40 , wherein the shunt cutoff value is derived from normal healthy controls, within a given individual over time, patients who respond to therapy, patients with large varices, patients with sustained virological response to antiviral therapy, patients unable to respond to antiviral therapy, patients with significant fibrosis, or patients with cirrhosis.