BREATHID Octanoate Breath Test With or Without Methacetin Breath Test for Correlation With Biopsy in NASH

Clinical Study of the BreathID® System to Train the Algorithm for the ¹³C-Octanoate Breath Test With or Without the ¹³C-Methacetin Breath Test (OBT and MBT Respectively) for Correlation With Histological Findings Associated With Non-Alcoholic Steatohepatitis (NASH) and Other Liver Diseases

This study's aim is to develop an algorithm for the ¹³C-Octanoate Breath Test with or without the ¹³C-Methacetin Breath Test (OBT and MBT respectively) for correlation with histological findings associated with of Non-Alcoholic Steatohepatitis (NASH) and other liver diseases using the BreathID® System

Non-Alcoholic Steatohepatitis (NASH) is a growing epidemic in the western world due to the contemporary eating habits and life styles.NASH can lead to cirrhosis, hepatic carcinoma and other liver complications. There are currently some treatments available. The only definitive way of detecting NASH in patients with advanced liver disease is by liver biopsy. However, liver biopsy has disadvantages, such as sampling errors, chance of complications and does not lend itself to following up after treatment.

A non-invasive test that could potentially replace biopsy and aid in NASH detection and treatment monitoring, would improve management of suspected NASH patients without the need for biopsy. This protocol will obtain the results of one or two different breath tests to provide an accurate evaluation of the liver status in patients at high risk for NASH.

Inclusion Criteria:

1. Adult men or women (≥18 years of age)
2. Liver biopsy, indicating NAFLD/NASH, performed within 6 months prior to both breath tests OR undergoing liver biopsy to rule-out or confrim NAFLD/NASH. NOTE:The samples obtained meet defined quality criteria. (In Appendix II of protocol)
3. Any elevation of liver enzymes above the upper limit of normal (any or all of the following: AST, ALT, GGT, Alkaline phosphatase) for at least 3 months
4. No other known co-existent liver disease, excluded by appropriate serologic / other testing
5. Imaging - US / CT / MRI (if available) with the typical image of Fatty Liver or suggestive of NASH.
6. Patient (or legal guardian) able and willing to sign an Informed Consent Form
7. Can tolerate an overnight (8-hour) fast

Exclusion Criteria:

1. Positive studies for any of the following within three years prior to biopsy:

   1. Anti HCV positive
   2. Anti HB core antibody positive
   3. Iron saturation > 60% + gene test for hereditary hemochromatosis or iron overload as defined by presence of 3+ or 4+ stainable iron on liver biopsy
   4. Antinuclear antibody at a titer > 1: 160 along with hypergammaglobulinemia and 5 times ALT normal levels
   5. Alpha-1-antitrypsin level below lower limit of normal (< 150 mg/dl) or no PAS diastase resistant globules on biopsy.
   6. Primary biliary cirrhosis as defined by elevation of alkaline phosphatase greater than upper limit of normal and anti-mitochondrial antibody (AMA) of greater than 1:80 and consistent liver histology
   7. Low level of ceruloplasmin
   8. Drug-induced liver disease as defined on the basis of typical exposure and history

2. Patients known to have chronic liver disease other than NAFLD as routinely diagnosed by the investigator

3. Concurrent acute hepatic condition other than NAFLD

4. Alcohol consumption > 20 gm/day (0.71 oz/day) for women and > 30 gm/day (1.06 oz/day) for men

5. Drugs that may interfere with octanoate metabolism or can also cause NAFLD independent of the metabolic syndrome, including: corticosteroids, amiodarone, tetracycline, valproic acid, methotrexate, stavudine, zidovudine

6. When MBT is performed subject should not have taken any of the following at least 48 hours prior to the breath test: Acyclovir , allopurinol, carbamazepine, cimetidine, ciprofloxacin, daidzein, (herbal) disulfiram, echinacea, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, montelukast, norfloxacin, phenylpropanolamine, phenytoin, propafenone, rifampin, terbinafine, ticlopidine, thiabendazole, verapamil, zileuton or any medication that might interfere with Methacetin metabolism or might affect CYP 1A2

7. Patients that have had more than 10% weight change between biopsy and enrollment.

8. Hypersensitivity to any of the study substrates; i.e. Octanoate or Methacetin respectively

9. Known extra-hepatic diseases including but not limited to: severe congestive heart failure (NIHA>2), known severe pulmonary hypertension (>35 mmHg), history of chronic obstructive pulmonary disease or uncontrolled symptomatic bronchial asthma or uncontrolled diabetes mellitus (HA1c>9.5%)

10. Previous surgical GI bypass surgery

11. Extensive small bowel resection (>100 cm)

12. Known uncontrolled malabsorption or diarrhea

13. Concurrent total parenteral nutrition

14. Any organ transplant

15. Patients receiving any anti-viral treatment or any other liver directed therapy, procedure or surgery between the time of the biopsy and the breath test

16. Pregnant or breast feeding

17. Patients and/or legal guardian unable or refusing to sign informed consent

18. Patients that, based on the opinion of the investigator, should not be enrolled into this study due to safety / adherence reasons.

19. Patients participating in other clinical trials and already receiving experimental treatments or procedures

20. Patients with suspected or documented hepatocellular carcinoma by ultra-sound or other imaging modality

21. Patients diagnosed with partial / complete portal venous occlusion, hepatic venous occlusion, previous PHT surgery, or placement of a transjugular intrahepatic portosystemic shunt (TIPS) according to initial imaging studies.