¹³C-Methacetin Breath Test (MBT) Methodology Study

Inclusion Criteria: Inclusion Criteria - General

• Adult subjects with 18 years of age or older

• Women of childbearing potential must have a negative serum or urinary hCG pregnancytest within 7 days prior to enrollment. During the study these women must use 2methods of contraception.

• Subject has given written informed consent, prior to any study related procedure notpart of the subject's normal medical care, with the understanding that consent may bewithdrawn at any time without prejudice to future medical care. Exclusion Criteria - General

• Severe heart, pulmonary or renal disease.

• Patient has previous surgical bypass surgery for morbid obesity

• Patient has extensive small bowel resection

• Any major surgery in the past 3 months.

• Patient is a recipient of any organ transplant

• Pregnant or breastfeeding women.

• Patient allergic to acetaminophen

• Patients who are taking hepatotoxic drugs

• Patient, based on the opinion of the investigator, should not be enrolled into thisstudy.

• Patients unable or unwilling to sign informed consent

• Patients that are participating in other clinical trials evaluating experimentaltreatments or procedures or have participated in a clinical trial in the past 3months. Exclusion Criteria (Day of MBT-general)

• Patient has not fasted for 8 hours.

• Patient has smoked on the day of the test.

• Patient that has taken drugs that can interfere with methacetin metabolism:fluvoxamine, amiodarone, ciprofloxacin, cimetidine, rifampin, carbamazepine within thelast 24 hours.

• Patient has taken Tylenol or any other acetaminophen related medications within thepast 24 hours.

• Patients that received any new medication in the last 48 hours.

• Patients that still suffer from any previous clinical intervention (e.g. biopsy)

• Have not consumed alcohol 24 hours prior the MBT and not consume on a regular basismore than 40gr for male and 20gr for female per day. Inclusion Criteria (Repeatability): Healthy Subjects:

• No known liver disease

• Non smokers

• BMI =20-25 kg/m2

• Normal liver enzymes (ALT < 40 U/L for men, < 30 U/L for women)

• Not taking any medications

• No known on-going chronic medical conditions (apart from allergy or orthopaedicconditions not requiring chronic therapy).

• Normal abdominal ultrasound (US) Cirrhotics:

• Diagnosis of cirrhosis by liver biopsy

• Or strong suspicion of cirrhosis by accepted criteria for the clinical diagnosis ofcirrhosis (e.g. peripheral edema or varices, palpable hard left lobe of the liver,small right lobe span or palpable splenomegaly), and/or radiological evidence ofcirrhosis (by abdominal sonography, computer assisted axial tomography, or magneticresonance imaging, showing a nodular liver and/or portosystemic collaterals withportal vein patency and/or ascites and/or splenomegaly, and/or colloid shift on acolloid-isotope liver-spleen scan), and/or laboratory variables (platelets <100,000/mm3, albumin< 3.5g/dL, or INR >1.3) Chronic Liver Patient (non cirrhotic): Patient who has been diagnosed with chronic liver disease for more than 6 months. Inclusion Criteria (COPD):

• No known liver disease

• BMI 20- 25 kg/m2

• Normal liver enzymes (ALT < 40 U/L for men, < 30 U/L for women)

• Patients with a COPD exacerbation with elevated PCO2 levels (> 50 mmHg)

• Without clinically overt right heart failure

• Ceased smoking for at least one month

• No other overt clinical dysfunction of major organ system Inclusion criteria (Smoker): Smokers:

• No known liver disease

• Active smoker of at least 10 cigarettes/day (stable number of cigarettes during pastmonth - not currently trying to quit).

• BMI 20- 25 kg/m2

• Normal liver enzymes (ALT < 40 U/L for men, < 30 U/L for women)

• Not taking any medications

• No known chronic medical conditions Inclusion criteria (CYP450 1A2 inhibitors): Healthy Subjects:

• No known liver disease

• Non smokers

• BMI 20- 25 kg/m2

• Normal liver enzymes (ALT < 40 U/L for men, < 30 U/L for women)

• Not taking any medications

• No known chronic medical conditions (allergy or orthopaedic condition not requiringchronic therapy allowed).

• Normal abdominal US Cirrhotic subjects:

• Diagnosis of cirrhosis by liver biopsy

• Or strong suspicion of cirrhosis by accepted criteria for the clinical diagnosis ofcirrhosis (e.g. peripheral edema or varices, palpable hard left lobe of the liver,small right lobe span or palpable splenomegaly), and/or radiological evidence ofcirrhosis (by abdominal sonography, computer assisted axial tomography, or magneticresonance imaging, showing a nodular liver and/or portosystemic collaterals withportal vein patency and/or ascites and/or splenomegaly, and/or colloid shift on acolloid-isotope liver-spleen scan), and/or laboratory variables (platelets <100,000/mm3, albumin< 3.5g/dL, or INR >1.3)

• Not receiving medication which is metabolized by CYP450 1A2 Inclusion criteria (Beta Blockers):

• Diagnosis of cirrhosis (by liver biopsy or clinical diagnosis): Strong suspicion of cirrhosis by accepted criteria for the clinical diagnosis of cirrhosis (e.g. peripheral edema or varices, palpable hard left lobe of the liver, small right lobespan or palpable splenomegaly), and/or radiological evidence of cirrhosis (by abdominalsonography, computer assisted axial tomography, or magnetic resonance imaging, showing anodular liver and/or portosystemic collaterals with portal vein patency and/or ascitesand/or splenomegaly, and/or colloid shift on a colloid-isotope liver-spleen scan), and/orlaboratory variables (platelets <100,000/mm3, albumin< 3.5g/dL, or INR >1.3)

• Naive to Beta Blockers - with a clinical indication for initiating therapy (eg.esophageal varices, portal hypertensive gastropathy)

• Resting pulse > 60 beats per minute

• Non smoker Inclusion criteria (Alcohol):

• No known liver disease

• Non smokers

• BMI 20- 25 kg/m2

• Normal liver enzymes (ALT < 40 U/L for men, < 30 U/L for women)

• Not taking any medications

• No known chronic medical conditions. (Allergy or orthopaedic condition not requiringchronic therapy allowed).

• Normal abdominal US

Exclusion Criteria: General

• Severe heart, pulmonary or renal disease.

• Patient has previous surgical bypass surgery for morbid obesity

• Patient has extensive small bowel resection

• Any major surgery in the past 3 months.

• Patient is a recipient of any organ transplant

• Pregnant or breastfeeding women.

• Patient allergic to acetaminophen

• Patients who are taking hepatotoxic drugs

• Patient, based on the opinion of the investigator, should not be enrolled into thisstudy.

• Patients unable or unwilling to sign informed consent

• Patients that are participating in other clinical trials evaluating experimentaltreatments or procedures or have participated in a clinical trial in the past 3months. Exclusion Criteria (Day of MBT-general)

• Patient has not fasted for 8 hours.

• Patient has smoked on the day of the test.

• Patient that has taken drugs that can interfere with methacetin metabolism:fluvoxamine, amiodarone, ciprofloxacin, cimetidine, rifampin, carbamazepine within thelast 24 hours.

• Patient has taken Tylenol or any other acetaminophen related medications within thepast 24 hours.

• Patients that received any new medication in the last 48 hours.

• Patients that still suffer from any previous clinical intervention (e.g. -

• Have not consumed alcohol 24 hours prior the MBT and not consume on a regular basismore than 40gr for male and 20gr for female per day.