Disease severity index for assessment of chronic liver disease and method for diagnosis of three distinct subtypes of primary sclerosing cholangitis

9,759,731

14/729987

June 03, 2015

A Disease Severity Index (DSI) is provided for assessment of chronic liver disease in a patient using non-invasive liver function test results. A DSI was derived from non-invasive liver function test results based on hepatic blood flow. The DSI is used in methods for prediction of clinical outcomes, prediction of response to antiviral treatment, and assessment of progression of chronic liver diseases. Non-invasive methods to diagnose three distinct categories of patients with Primary Sclerosing Cholangitis (PSC) are provided. The methods can be used to diagnose PSC patients as Slow Progressors, Moderate Progressors and Rapid Progressors.

The Regents of the University of Colorado (Denver, CO, US)

The Regents of the University of Colorado, a Body Corporate (Denver, CO, US)

1. A method for determining a disease severity index (DSI) value in a patient, the method comprising (a) obtaining one or more liver function test values in a patient having or at risk of a chronic liver disease, wherein the one or more liver function test values are obtained from one or more liver function tests selected from the group consisting of cholate SHUNT test, portal hepatic filtration rate (portal HFR), and systemic hepatic filtration rate (systemic HFR); and (b) employing a disease severity index equation (DSI equation) to obtain a DSI value in the patient, wherein the DSI equation comprises one or more terms and a constant to obtain the DSI value, wherein at least one term of the DSI equation independently represents a liver function test value in the patient from step (a) or a mathematically transformed liver function test value in the patient from step (a); and the at least one term of the DSI equation is multiplied by a coefficient specific to the liver function test, wherein the one or more liver function test values comprises a portal HFR test value in the patient determined by a method comprising (a) receiving a plurality of blood or serum samples collected from a patient having or at risk of a chronic liver disease, following oral administration of a dose of a stable isotope labeled distinguishable cholate (dose oral) to the patient, wherein the samples have been collected from the patient over intervals of from two to seven time points spanning a period of time of no more than 180 minutes after administration; (b) measuring concentration of the distinguishable cholate in each sample; (c) generating an individualized oral clearance curve from the concentration of the distinguishable cholate in each sample comprising using a computer algorithm curve fitting to a model distinguishable cholate clearance curve; (d) computing the area under the individualized oral clearance curve (AUC)(mg/mL/min) and dividing the dose (in mg) by AUC of the orally administered distinguishable cholate to obtain the oral cholate clearance in the patient; and (e) dividing the oral cholate clearance by the weight of the patient in kg to obtain the portal HFR value in the patient (mL/min/kg).

2. The method of claim 1 , further comprising (c) comparing the DSI value in the patient to one or more DSI cut-off values, one or more normal healthy controls, or one or more DSI values within the patient over time.

3. The method of claim 2 , wherein the comparing the DSI value in the patient to one or more DSI cut-off values is indicative of at least one clinical outcome.

4. The method of claim 3 , wherein the clinical outcome is selected from the group consisting of Child-Turcotte-Pugh (CTP) increase, varices, encephalopathy, ascites, and liver related death.

5. The method of claim 2 , wherein the comparing the DSI value within the patient over time is used to monitor the effectiveness of a treatment of chronic liver disease in the patient, wherein a decrease in the DSI value within the patient over time is indicative of treatment effectiveness.

6. The method of claim 5 , wherein the treatment of chronic liver disease in the patient is selected from the group consisting of antiviral treatment, antifibrotic treatment, antibiotics, immunosuppressive treatments, anti-cancer treatments, ursodeoxycholic acid, insulin sensitizing agents, interventional treatment, liver transplant, lifestyle changes, and dietary restrictions, low glycemic index diet, antioxidants, vitamin supplements, transjugular intrahepatic portosystemic shunt (TIPS), catheter-directed thrombolysis, balloon dilation and stent placement, balloon-dilation and drainage, weight loss, exercise, and avoidance of alcohol.

7. The method of claim 2 , wherein the comparing the DSI value in the patient over time is used to monitor the need for treatment of chronic liver disease in the patient, wherein an increase in the DSI value within the patient over time is indicative of a need for treatment in the patient.

8. The method of claim 2 , wherein the comparing the DSI value within the patient over time is used to monitor status of chronic liver disease in the patient, wherein change in DSI value within the patient over time is used to inform the patient of status of the disease and risk for future clinical outcomes, wherein an increase in the DSI value within the patient over time is indicative of a worse prognosis, and a decrease in the DSI value within the patient over time is indicative of a better prognosis.

9. The method of claim 1 , wherein the mathematically transformed liver function test value in the patient is selected from a log, antilog, natural log, natural antilog, or inverse of the liver function test value in the patient.

10. The method of claim 1 , wherein each term of the DSI equation independently represents a liver function test value in the patient from step (a) or a mathematically transformed liver function test value in the patient from step (a).

11. The method of claim 1 , wherein the chronic liver disease in the patient is chronic hepatitis C (CHC), chronic hepatitis B, alcoholic liver disease, alcoholic steatohepatitis (ASH), hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), autoimmune liver disease, cryptogenic cirrhosis, hemochromatosis, Wilson's disease, alpha-1-antitrypsin deficiency, or primary sclerosing cholangitis (PSC).

12. The method of claim 1 , wherein the SHUNT test value in the patient is determined by a method comprising (a) receiving a plurality of blood or serum samples collected from the patient having PSC, following oral administration of a dose of a first stable isotope labeled distinguishable cholate (dose oral) to the patient and simultaneous intravenous co-administration of a dose of a second stable isotope labeled distinguishable cholate (dose iv) to the patient, wherein the samples have been collected over intervals spanning a period of time after administration; (b) quantifying the concentration of the first and the second distinguishable cholates in each sample; (c) generating an individualized oral clearance curve from the concentration of the first distinguishable cholate in each sample comprising using a computer algorithm curve fitting to a model oral distinguishable cholate 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 cholate in each sample by use of a computer algorithm curve fitting to a model intravenous second distinguishable cholate clearance curve and computing the area under the individualized intravenous clearance curve (AUCiv); and (e) calculating the shunt value in the patient using the formula: AUC oral /AUC iv ×Dose iv /Dose oral ×100%.

13. The method of claim 12 , wherein the first distinguishable cholate is a first stable isotope labeled cholic acid and the second distinguishable cholate is a second stable isotope labeled cholic acid.

14. The method of claim 13 , wherein the first and second stable isotope labeled cholic acids are selected from 2,2,4,4-d4 cholate and 24-13C-cholate.

15. The method of claim 12 , wherein the samples have been collected from the patient at 5, 20, 45, 60 and 90 minutes after administration.

16. The method of claim 12 , wherein the samples have been collected over intervals spanning a period of time from the time of administration to a time selected from about 45 minutes to about 180 minutes after administration.

17. The method of claim 16 , wherein the samples have been collected over intervals spanning a period of time of about 90 minutes or less after administration.

18. The method of claim 1 , wherein the systemic HFR value in the patient is determined by a method comprising (a) receiving a plurality of blood or serum samples collected from a patient having or at risk of a chronic liver disease, following intravenous administration of a dose of a stable isotope labeled distinguishable cholate (dose iv) to the patient, wherein the samples have been collected from the patient over intervals spanning a period of time after administration; (b) measuring concentration of the distinguishable cholate in each sample; (c) generating an individualized intravenous clearance curve from the concentration of the distinguishable cholate in each sample comprising using a computer algorithm curve fitting to a model distinguishable cholate clearance curve; (d) computing the area under the individualized intravenous clearance curve (AUC)(mg/mL/min) and dividing the dose (in mg) by AUC of the intravenously administered stable isotope labeled cholic acid to obtain the intravenous cholate clearance in the patient; and (e) dividing the intravenous cholate clearance by the weight of the patient in kg to obtain the systemic HFR value in the patient (mL/min/kg).

19. The method of claim 1 , wherein the DSI equation has one or more additional terms representing values from clinical biochemistry laboratory assays selected from the group consisting of serum albumin, alanine transaminase, aspartate transaminase, alkaline phosphatase, total bilirubin, direct bilirubin, gamma glutamyl transpeptidase, 5′ Nucleotidase, PT-INR (prothrombin time-international normalized ratio), caffeine elimination, antipyrine clearance, galactose elimination capacity, formation of MEGX from lidocaine, methacetin-C13, and methionine-C13; and/or one or more additional terms representing clinical features selected from varices, ascites, and hepatic encephalopathy.

20. The method of claim 1 , wherein the disease severity index (DSI) equation comprises DSI= A (SHUNT)+ B (log e portal HFR)+ C (log e systemic HFR)+ D wherein SHUNT is SHUNT test value in the patient (%); portal HFR is portal hepatic flow rate (HFR) test value in the patient as mL/min/kg, wherein kg is body weight of the patient; systemic HFR is systemic HFR value in the patient as mL/min/kg, wherein kg is body weight of the patient; A is a SHUNT coefficient; B is a Portal HFR coefficient; C is a Systemic HFR coefficient; and D is the constant.

21. The method of claim 20 , wherein the disease severity index equation is DSI=5.34(SHUNT)−6.65(Log e Portal HFR)−8.57(Log e Systemic HFR)+44.66.

22. The method of claim 20 , wherein the disease severity index equation is DSI=5.75(SHUNT)−7.22(Log e Portal HFR)−8.45(Log e Systemic HFR)+50.

23. The method of claim 22 , wherein the DSI value is used for identifying increased risk for portal hypertension or decompensation in the chronic liver disease patient wherein a DSI≧18 indicates increased risk for portal hypertension (PHTN), and a DSI≧36 indicates an increased risk for decompensation.

24. The method of claim 20 , wherein the chronic liver disease is chronic hepatitis C and the disease severity index equation is DSI=9.84(SHUNT)−12.36 LOG e (portal HFR)+50.5.

25. The method of claim 20 , wherein the SHUNT, the portal HFR, and/or the systemic HFR test values in the patient were obtained on the same day.

26. The method of claim 20 , wherein the SHUNT coefficient is a number from 0 to positive 25; the Portal HFR coefficient is a number from 0 to negative 25; and the Systemic HFR coefficient is a number from 0 to negative 25.

27. The method of claim 20 , wherein the constant is a positive number between 5 and 125.

28. The method of claim 27 , wherein the portal hypertension (PHTN) is defined as splemomegaly or varices, and decompensation is defined as ascites or variceal hemorrhage.

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