# US 2018/0024153 A1 · Disease severity index for assessment of chronic liver disease > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2018/0024153 A1 - Document ID: US20180024153A1 - Status: Published application - Kind: A1 - Application number: 15/673,191 - Filed: 2017-08-09 - Published: 2018-01-25 - Earliest claimed: 2012-11-12 - Assignees: The Regents of the University of Colorado, a body corporate - Applicants: The Regents of the University of Colorado, a Body Corporate - Inventors: Gregory Thomas Everson; Steve Mark Helmke - Web page: https://patentgrep.com/patent/US20180024153A1 ## CPC - G01N 33/92: involving lipids, e.g. cholesterol {, lipoproteins, or their receptors (steroid hormones G01N33/743)} - A61K 31/575: substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol - G16H 50/20: for computer-aided diagnosis, e.g. based on medical expert systems - G16H 50/30: for calculating health indices; for individual health risk assessment - G01N 2800/085: Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin - G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - G16H: HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA ## Abstract 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. ## Claims ### Claim 1 A method of displaying likelihood or risk of future clinical outcome, disease severity, and/or disease status in a patient having a chronic liver disease, the method comprising a. obtaining cholate test results in the patient comprising a portal hepatic filtration rate (portal HFR) value and a systemic hepatic filtration rate (systemic HFR) value from the patient at one or more test days; b. deriving one or more disease severity index (DSI) value(s) or mathematically transformed DSI value(s) of the patient from the portal and systemic HFR values or mathematically transformed portal and mathematically transformed systemic HFR values at the one or more test days; c. plotting the DSI value(s) or mathematically transformed DSI value(s) of the patient on a two-dimensional graphical plot, wherein the graphical plot is divided into a multiplicity of disease severity index (DSI) value zones predetermined by DSI values or mathematically transformed DSI values obtained from one or more groups of known subjects having a known clinical outcome, disease severity and/or disease status; and d. determining the location of each DSI value or mathematically transformed DSI value of the patient within the DSI value zones, wherein the location is indicative of likelihood or risk of experiencing a future clinical outcome, disease severity and/or disease status in the patient. ### Claim 2 (depends on 1) The method of claim 1, wherein the one or more portal and systemic HFR values or mathematically transformed portal and systemic HFR values are obtained on the same test day. ### Claim 3 (depends on 1) The method of claim 1, wherein the clinical outcome is selected from the group consisting of Child-Turcotte-Pugh (CTP) progression, variceal hemorrhage, ascites, splenomegaly, varices, portal hypertension (PHTN), hepatic encephalopathy, decompensation, or liver-related death. ### Claim 4 (depends on 1) The method of claim 1, wherein the chronic liver disease is selected from chronic hepatitis C (CHC), chronic hepatitis B, alcoholic liver disease, Alcoholic SteatoHepatitis (ASH), Non-Alcoholic Fatty Liver Disease (NAFLD), steatosis, Non-Alcoholic SteatoHepatitis (NASH), autoimmune liver disease, cryptogenic cirrhosis, hemochromatosis, Wilson's disease, alpha-1-antitrypsin deficiency, primary sclerosing cholangitis (PSC), cholestatic liver disease, and hepatocellular carcinoma (HCC). ### Claim 5 (depends on 4) The method of claim 4, wherein the chronic liver disease is selected from the group consisting of CHC, PSC, and NASH. ### Claim 6 (depends on 1) The method of claim 1, wherein the DSI value zones on the plot define cutoffs delineating one or more of healthy liver function, mild disease, moderate disease, and severe disease. ### Claim 7 (depends on 1) The method of claim 1, wherein changes in DSI values within the patient over time are plotted on the graph and used to inform the patient of status of likelihood or risk for future clinical outcomes, disease severity, and/or disease status. ### Claim 8 (depends on 1) The method of claim 1, wherein the disease status is selected from disease progression, disease improvement, need for treatment, effectiveness of treatment, disease prognosis, sustained virological response, risk of hepatic decompensation in patients with hepatocellular carcinoma (HCC) being evaluated for hepatic resection, and/or prioritizing liver transplant in the patient. ### Claim 9 (depends on 8) The method of claim 8, 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, obesity treatment, diabetes mellitus treatment, insulin, insulin sensitizing agents, interventional treatment, liver transplant, lifestyle changes, dietary restrictions, low glycemic index diet, antioxidants, vitamin supplements, transjugular intrahepatic portosystemic shunt (TIPS), hepatic resection, catheter-directed thrombolysis, balloon dilation and stent placement, balloon-dilation and drainage, weight loss, exercise, and avoidance of alcohol. ### Claim 10 (depends on 1) The method of claim 1, wherein the DSI value zones are predetermined by calculating a disease severity index (DSI) value in each subject in a group of known subjects having a known clinical outcome, disease severity and/or disease status, by a method comprising (a) obtaining one or more liver function test values in each known subject in the group, wherein the one or more liver function test values are obtained from one or more liver function tests selected from the group consisting of SHUNT, portal hepatic filtration rate (portal HFR), and systemic hepatic filtration rate (systemic HFR); (b) employing a disease severity index equation (DSI equation) to obtain a DSI value for each known subject in the group, 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 known subject from step (a) or a mathematically transformed liver function test value in the known subject from step (a); and the at least one term of the DSI equation is multiplied by a coefficient specific to the liver function test; and (c) performing statistical comparison of the DSI values from each known subject in the group to provide one or more DSI cut-off values, and plotting the DSI cut-off values on the graphical plot to form the DSI value zone for the group of known subjects having a known clinical outcome, disease severity and/or disease status. ### Claim 11 (depends on 10) The method of claim 10, wherein the group of known subjects is selected from a group of healthy subjects, or a group of subjects with chronic liver disease having Ishak fibrosis score (liver biopsy) F2 (mild portal fibrosis), F3, F4 (moderate bridging fibrosis), F5 (nodular formation and incomplete cirrhosis), or F6 (cirrhosis); portal hypertension; Childs-Turcotte-Pugh (CTP) score A; CTP score B, CTP score C; primary sclerosing cholangitis (PSC) not listed for transplant; PSC listed for liver transplant; PSC listed for liver transplant without varices; PSC listed for liver transplant with varices; ascites; stomal bleeding; splemomegaly; varices; variceal hemorrhage; hepatic encephalopathy, decompensation; or liver related death. ### Claim 12 A method of monitoring likelihood or risk of future clinical outcome, disease severity, and/or disease status in a patient having a chronic liver disease, the method comprising a. obtaining cholate test results in the patient comprising a portal hepatic filtration rate (portal HFR) value and a systemic hepatic filtration rate (systemic HFR) value from the patient at one or more test days; b. deriving one or more a disease severity index (DSI) values or mathematically transformed DSI values from the portal and systemic HFR values or mathematically transformed portal and mathematically transformed systemic HFR values at the one or more test days; and c. comparing the one or more DSI values or mathematically transformed DSI values in the patient to one or more DSI values or mathematically transformed DSI cut-off values, one or more normal healthy subjects, known subjects, or one or more DSI values or mathematically transformed DSI values within the patient over time, wherein the comparing is indicative of likelihood or risk of experiencing a future clinical outcome, disease severity and/or disease status in the patient. ### Claim 13 (depends on 12) The method of claim 12, wherein the clinical outcome is selected from the group consisting of Child-Turcotte-Pugh (CTP) progression, variceal hemorrhage, ascites, splenomegaly, varices, portal hypertension (PHTN), hepatic encephalopathy, decompensation, or liver-related death. ### Claim 14 (depends on 12) The method of claim 12, wherein the chronic liver disease is selected from chronic hepatitis C (CHC), chronic hepatitis B, alcoholic liver disease, Alcoholic SteatoHepatitis (ASH), Non-Alcoholic Fatty Liver Disease (NAFLD), steatosis, Non-Alcoholic SteatoHepatitis (NASH), autoimmune liver disease, cryptogenic cirrhosis, hemochromatosis, Wilson's disease, alpha-1-antitrypsin deficiency, primary sclerosing cholangitis (PSC), cholestatic liver disease, and hepatocellular carcinoma (HCC). ### Claim 15 (depends on 14) The method of claim 14, wherein the chronic liver disease is selected from the group consisting of CHC, PSC, and NASH. ### Claim 16 (depends on 15) The method of claim 15, wherein the monitoring of disease status is selected from monitoring disease progression, disease improvement, need for treatment, effectiveness of treatment, disease prognosis, sustained virological response, risk of hepatic decompensation in patients with hepatocellular carcinoma (HCC) being evaluated for hepatic resection, and/or prioritizing liver transplant in the patient. ### Claim 17 (depends on 16) The method of claim 16, 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. ### Claim 18 (depends on 17) The method of claim 17, 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, obesity treatment, diabetes mellitus treatment, insulin, insulin sensitizing agents, interventional treatment, liver transplant, lifestyle changes, and dietary restrictions, low glycemic index diet, antioxidants, vitamin supplements, transjugular intrahepatic portosystemic shunt (TIPS), hepatic resection, catheter-directed thrombolysis, balloon dilation and stent placement, balloon-dilation and drainage, weight loss, exercise, and avoidance of alcohol. ### Claim 19 (depends on 12) The method of claim 12, 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. ### Claim 20 (depends on 12) The method of claim 12, wherein the portal HFR 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 a chronic liver disease, following oral administration of a dose of a stable isotope labeled distinguishable cholate (doseoral) 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). ### Claim 21 (depends on 12) The method of claim 12, 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 (doseiv) 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). ### Claim 22 (depends on 12) The method of claim 12, wherein the deriving DSI value comprises employing a disease severity index equation (DSI equation) to obtain a DSI value or mathematically transformed DSI value in the patient, wherein the DSI equation comprises one or more portal HFR or mathematically transformed portal HFR terms, one or more systemic HFR or mathematically derived systemic HFR terms, and a constant to obtain the DSI value. ### Claim 23 (depends on 22) The method of claim 22, wherein the disease severity index (DSI) equation comprises DSI=A(SHUNT)+B(loge portal HFR)+C(loge 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. ### Claim 24 (depends on 23) The method of claim 23, wherein the SHUNT, the portal HFR, and/or the systemic HFR test values in the patient were obtained on the same day. ### Claim 25 (depends on 23) The method of claim 23, 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. ### Claim 26 (depends on 23) The method of claim 23, wherein the constant is a positive number between 5 and 125. ### Claim 27 A method of displaying likelihood or risk of future clinical outcome, disease severity, and/or disease status in a patient having a chronic liver disease, the method comprising a. obtaining cholate test results in the patient comprising a portal hepatic filtration rate (portal HFR) value and/or a systemic hepatic filtration rate (systemic HFR) value from the patient at one or more test days; b. plotting the cholate test results comprising the portal HFR value or a mathematically transformed portal HFR value on one axis of a graphical plot, and the systemic HFR value or a mathematically transformed systemic HFR value on a second axis of the graphical plot to define one or more data points on the plot, wherein the plot is divided into a multiplicity of disease severity index (DSI) value zones predetermined by DSI values or mathematically transformed DSI values obtained from one or more groups of known subjects having a known clinical outcome, disease severity and/or disease status; and c. determining the location of each data point within a DSI value zone, wherein the location of each data point within a DSI value zone is indicative of likelihood or risk of experiencing a future clinical outcome, disease severity and/or disease status in the patient. ### Claim 28 (depends on 27) The method of claim 27, wherein the portal HFR value or mathematically transformed portal HFR value is plotted on the X axis of the plot and systemic HFR value or mathematically transformed systemic HFR is plotted on the Y axis of the plot. ### Claim 29 (depends on 27) The method of claim 27, further comprising determining a disease severity index (DSI) value for the patient at the one or more test days. ### Claim 30 (depends on 27) The method of claim 27, wherein the plotting the cholate test results further comprises plotting one or more cholate shunt test values from the patient on the graphical plot.