Volatile biomarkers for analysis of hepatic disorders

• US 6,248,078 B1
• Filed: 08/27/1999
• Issued: 06/19/2001
• Est. Priority Date: 08/31/1998
• Status: Expired due to Term

• Current Assignee: Johns Hopkins University
• Original Assignee: Johns Hopkins University
• Inventors: Jiang, Long, Sehnert, Shelley, Risby, Terence H., Burdick, James F.
• Primary Examiner(s): O'Connor, Cary
• Assistant Examiner(s): Natnithithadha, Navin
• Application Number:
  US09/385,657
• Time in Patent Office: 662 Days
• Field of Search: 600/529, 600/531, 600/532, 600/533, 600/537, 600/538, 600/539, 600/540, 600/541, 600/542, 600/543, 73/233
• US Class Current: 600/529
• CPC Class Codes: A61B 5/097 Devices for facilitating collection of breath or for directing breath into or through measuring devices
• CPC Class Codes: G01N 33/497 of gaseous biological material, e.g. breath

Abstract

The present invention features test systems and methods for detecting a hepatic disorder in a mammal and especially a primate. Preferred use of the invention involves staging the hepatic disorder in a human patient.

Claims

1. A test system for detecting a hepatic disorder in a mammal, the test system comprising:

a) a chamber for receiving respiratory gas from the mammal; and

b) a monitor for detecting at least one volatile organic molecule in the respiratory gas and for outputting the concentration of at least one of the detected organic molecules, wherein the monitor comprises or is interfaced with at least one of;

i) a computational system adapted to correlate the concentration of at least one of the detected organic molecules (test value) to at least one of a pre-determined control or analytical value, or

ii) a carbon dioxide analyzer for correcting the concentration of at least one of the detected molecules to an alveolar concentration of carbon dioxide.

2. The test system of claim 1, wherein the test system is adapted to stage the hepatic disorder and the output is a display in real-time.

32. The test system of claim 1, wherein the monitor comprises a mass spectrometer.

33. The test system of claim 32, wherein the mass spectrometer is an infra-red (IR) sensitive spectrometer or a gas chromatography-mass spectrometer (GC-MS).

34. The test system of claim 33, wherein the infra-red (IR) sensitive spectrophotometer is a mid-IR laser absorption spectrophotometer equipped with a Harriott multi-pass cell, the laser being a lead-salt tunable diode laser (TDL).

35. The test system of claim 32, wherein the computational system is further adapted to receive output from the mass spectrometer and to provide output in real-time to a user of the test system.

36. The test system of claim 1 in which the computational system is further adapted to receive input from the monitor and to output data to a user of the test system, wherein the monitor receives respiratory gas provided by a human subject.

51. The test system of claim 1, wherein the monitor is adapted to detect chemiluminescence or Raman scattering.

52. The test system of claim 1, wherein the monitor can further detect at least one of NO, CO, CO₂, N₂O, NH₃, C₂H₆, or H₂O₂.

53. The test system of claim 1, wherein the volatile organic molecule is carbonyl sulfide, hydrogen sulfide, methyl sulfide, dimethyl sulfide, allyl methyl sulfide;

or a cogener thereof.

54. The test system of claim 33, wherein the chamber is adapted to include an infra-red (IR) source.

55. The test system of claim 1, wherein the mammal is a human.

3. A test system for detecting and staging a hepatic disorder in a mammal, the test system comprising:

a) a gas collection apparatus for receiving respiratory gas from the mammal and for outputting volatile organic molecules in the gas,

b) a chromatography system for receiving the volatile organic molecules from the apparatus and for detecting volatile organic molecules comprising at least one of hydrocarbon or organosulfur molecule; and

c) a computational system adapted to process output from the chromatography system, wherein the computational system performs the following steps;

i) determine the concentration of volatile organic molecules detected by the chromatography system,

ii) correlate the concentration of at least one of the detected organic molecules to at least one of a pre-determined analytical or control value for the molecule, and

iii) output results.

4. The test system of claim 3, wherein the gas collection apparatus has a sampling volume of from between about 0.01 liters to 20 liters.

5. The test system of claim 3, wherein the chromatography system comprises a pair of detectors for detecting the hydrocarbon or sulfur.

6. The test system of claim 3, wherein computational system is adapted to correct the concentration of the volatile organic molecules to an alveolar concentration of carbon dioxide.

7. The test system of claim 3, wherein the pre-determined analytical value is the mean concentration of the molecule in respiratory gas collected from mammals suffering from the presence and stage of the hepatic disorder.

8. The test system of claim 3, wherein the predetermined control value is the mean concentration of the molecule in respiratory gas collected from normal mammals.

9. The test system of claim 3, wherein the computation system is adapted to perform a parametric test between the concentration of the detected organic molecule and the pre-determined analytical or control value.

10. The test system of claim 6, wherein the computational system is adapted to output at least one of the following:

the alveolar concentration of carbon dioxide, the concentration of the volatile organic molecule, the pre-determined analytical or control value, or control and results of a parametric test.

11. The test system of claim 7, wherein the pre-determined analytical or control value is the mean concentration of ethane, carbonyl sulfide or dimethyl sulfide in the respiratory gas samples.

12. The test system of claim 3, wherein the hepatic disorder is hepatocellular injury or a biliary tract disorder.

17. The method of claim 12, wherein the detected organic molecule is ethane, carbonyl sulfide, or dimethyl sulfide.

18. The method of claim 12, wherein the hepatic disorder is hepatocellular injury or a biliary tract disorder.

13. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, the method further comprising correcting the concentration of the organic molecule to an alveolar concentration of carbon dioxide.

14. The method of claim 13, wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters.

15. The method of claim 13, wherein prior to determining the concentration, the volatile organic molecules are separated on a chromatography system capable of detecting at least one of hydrocarbon or sulfur.

16. The method of claim 15, wherein the chromatography system comprises a pair of detectors for detecting hydrocarbon or sulfur.

56. The method of claim 13, 19, 24, or 29, wherein the mammal is a human.

19. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal into a gas collection apparatus,

b) separating the respiratory gas on a first gas chromatograph comprising a first detector capable of detecting hydrocarbon,

c) detecting ethane in the released molecules,

d) separating the respiratory gas on a second gas chromatograph comprising a second detector capable of detecting organosulfur molecules,

e) detecting at least one of carbonyl sulfide or dimethyl sulfide in the released molecules; and

f) correlating the concentration of at least one of ethane, carbonyl sulfide or dimethyl sulfide to presence and stage of the hepatic system disorder in the mammal.

20. The method of claim 19, wherein the gas collection apparatus has a sampling volume of from between about 0.01 liters to 20 liters.

21. The method of claim 20, wherein the gas collection apparatus comprises a chamber comprising a polymeric adsorbent and the method further comprises cooling the chamber from between about −

100°

C. to −

150°

C. to concentrate the volatile organic molecules in the adsorbent.

22. The method of claim 21, wherein the method further comprises heating the chamber from between about 100°

C. to 200°

C. to release the concentrated volatile organic molecules therefrom.

23. The method of claim 19, wherein the hepatic disorder is hepatocellular injury or a biliary tract disorder.

24. A method for detecting a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining concentration of carbonyl sulfide in the respiratory gas; and

c) correlating the concentration of carbonyl sulfide to the presence of the hepatic disorder in the mammal, the method further comprising correcting the concentration of carbonyl sulfide to an alveolar concentration of carbon dioxide.

25. The method of claim 24, wherein prior to determining the concentration, the respiratory gas is separated on a chromatographic system capable of detecting hydrocarbon and organosulfur molecules.

26. The method of claim 25, wherein the chromatography system comprises a pair of detectors for detecting the hydrocarbon or organosulfur molecules.

27. The method of claim 25, wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters.

28. The method of claim 24, wherein the hepatic disorder is hepatocellular injury or a biliary tract disorder.

29. A method for detecting hepatocellular injury or a biliary tract disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining concentration of at least one of ethane, carbonyl sulfide, or dimethyl sulfide in the respiratory gas; and

e) correlating the concentration of at least one of the ethane, carbonyl sulfide or dimethyl sulfide to the presence of the hepatocellular injury or the biliary tract disorder in the mammal, the method further comprising correcting the concentration of the ethane, carbonyl sulfide or dimethyl sulfide to an alveolar concentration of carbon dioxide.

30. The method of claim 29, wherein prior to determining the concentration, the respiratory gas is separated on a chromatographic system capable of detecting hydrocarbon and organosulfur molecules.

31. The method of claim 30, wherein the chromatography system comprises a pair of detectors for detecting the hydrocarbon or organosulfur molecules.

37. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters, the gas collection apparatus comprising a chamber comprising a polymeric adsorbent, wherein the method further comprises cooling the chamber from between about −

100°

C. to −

150°

C. to concentrate the volatile organic molecules in the adsorbent.

38. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters, the gas collection apparatus comprising a chamber comprising a polymeric adsorbent, wherein the method further comprises cooling the chamber from between about −

100°

C. to −

150°

C. to concentrate the volatile organic molecules in the adsorbent and heating the chamber from between about 100°

C. to 200°

C. to release the concentrated volatile organic molecules therefrom.

39. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, wherein the correlation step further comprises correcting the concentration of the organic molecule to an alveolar concentration of carbon dioxide.

40. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, wherein the correlating step further comprises comparing the concentration to a pre-determined analytical value indicative of presence and stage of the hepatic disorder in the mammal.

41. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, wherein the correlating step further comprises comparing the concentration to a pre-determined analytical value indicative of presence and stage of the hepatic disorder in the mammal and the pre-determined analytical value is the mean concentration of the organic molecule in respiratory gas collected from mammals suffering from the presence and stage of the hepatic disorder.

42. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, wherein the correlating step further comprises comparing the concentration to a pre-determined control value indicative of normal hepatic function.

43. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, wherein the correlating step further comprises comparing the concentration to a pre-determined control value indicative of normal hepatic function and the control value is the mean concentration of the organic molecule in respiratory gas collected from normal mammals.

44. A method for detecting and staging a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining the concentration of at least one volatile organic molecule in the respiratory gas; and

c) correlating the concentration of the volatile organic molecule to presence and stage of the hepatic disorder in the mammal, wherein the correlating step further comprises comparing the concentration to a pre-determined analytical value indicative of presence and stage of the hepatic disorder in the mammal, the correlating step further comprising performing a parametric test between the concentration of the detected organic molecule and the pre-determined analytical or control value.

45. A method for detecting a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining concentration of carbonyl sulfide in the respiratory gas; and

c) correlating the concentration of carbonyl sulfide to the presence of the hepatic disorder in the mammal, wherein prior to determining the concentration, the respiratory gas is separated on a chromatographic system capable of detecting hydrocarbon and organosulfur molecules, the chromatography system comprising a pair of detectors for detecting the hydrocarbon or organosulfur molecules and further wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters, the gas collection apparatus comprising a chamber comprising a polymeric adsorbent, the method further comprising cooling the chamber from between about −

100°

C. to −

150°

C. to concentrate the volatile organic molecules in the adsorbent.

46. A method for detecting a hepatic disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining concentration of carbonyl sulfide in the respiratory gas; and

c) correlating the concentration of carbonyl sulfide to the presence of the hepatic disorder in the mammal, wherein prior to determining the concentration, the respiratory gas is separated on a chromatographic system capable of detecting hydrocarbon and organosulfur molecules, the chromatography system comprising a pair of detectors for detecting the hydrocarbon or organosulfur molecules and further wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters, the gas collection apparatus comprising a chamber comprising a polymeric adsorbent, the method further comprising cooling the chamber from between about −

100°

C. to −

150°

C. to concentrate the volatile organic molecules in the adsorbent and heating the chamber from between about 100°

C. to 200°

C. to release the concentrated volatile organic molecules therefrom.

47. A method for detecting hepatocellular injury or a biliary tract disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining concentration of at least one of ethane, carbonyl sulfide, or dimethyl sulfide in the respiratory gas; and

c) correlating the concentration of at least one of the ethane, carbonyl sulfide or dimethyl sulfide to the presence of the hepatocellular injury or the biliary tract disorder in the mammal, wherein prior to determining the concentration, the respiratory gas is separated on a chromatographic system capable of detecting hydrocarbon and organosulfur molecules, the chromatography system comprising a pair of detectors for detecting the hydrocarbon or organosulfur molecules and further wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters.

48. A method for detecting hepatocellular injury or a biliary tract disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining concentration of at least one of ethane, carbonyl sulfide, or dimethyl sulfide in the respiratory gas; and

c) correlating the concentration of at least one of the ethane, carbonyl sulfide or dimethyl sulfide to the presence of the hepatocellular injury or the biliary tract disorder in the mammal, wherein prior to determining the concentration, the respiratory gas is separated on a chromatographic system capable of detecting hydrocarbon and organosulfur molecules, the chromatography system comprising a pair of detectors for detecting the hydrocarbon or organosulfur molecules and further wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters, the gas collection apparatus comprising a chamber comprising a polymeric adsorbent and the method further comprises cooling the chamber from between about −

100°

C. to −

150°

C. to concentrate the volatile organic molecules in the adsorbent.

49. A method for detecting hepatocellular injury or a biliary tract disorder in a mammal, the method comprising:

a) collecting respiratory gas from the mammal,

b) determining concentration of at least one of ethane, carbonyl sulfide, or dimethyl sulfide in the respiratory gas; and

c) correlating the concentration of at least one of the ethane, carbonyl sulfide or dimethyl sulfide to the presence of the hepatocellular injury or the biliary tract disorder in the mammal, wherein prior to determining the concentration, the respiratory gas is separated on a chromatographic system capable of detecting hydrocarbon and organosulfur molecules, the chromatography system comprising a pair of detectors for detecting the hydrocarbon or organosulfur molecules and further wherein the respiratory gas is collected into a gas collection apparatus having a sampling volume of from between about 0.01 liters to 20 liters, the gas collection apparatus comprising a chamber comprising a polymeric adsorbent and the method further comprises cooling the chamber from between about −

100°

C. to −

150°

C. to concentrate the volatile organic molecules in the adsorbent, wherein the method further comprises heating the chamber from between about 100°

C. to 200°

C. to release the concentrated volatile organic molecules therefrom.

50. The method of claim 49, wherein the method further comprises staging the hepatocellular injury or biliary tract disorder in the mammal.