High end-of-treatment hepatitis B core-related antigen levels predict hepatitis flare after stopping nucleot(s)ide analogue therapy.

BACKGROUND AND AIMS: Accurate biomarkers to predict outcomes following discontinuation of nucleos(t)ide analogue (NA) therapy are needed. We evaluated serum hepatitis B core-related antigen (HBcrAg) level as a biomarker for predicting outcomes after NA discontinuation. METHODS: Patients with HBeAg-negative chronic hepatitis B (CHB) without cirrhosis were enrolled in a prospective trial evaluating clinical outcomes until 96 weeks after NA discontinuation. End of treatment (EOT) and off-treatment levels of serum HBcrAg, HBsAg, HBV RNA and HBV DNA were used to predict key clinical outcomes including hepatitis flare (ALT ≥5 × ULN and HBV DNA > 2000 IU/mL). The SCALE-B score was calculated for the purposes of model validation. RESULTS: HBcrAg was tested amongst 65 participants. The median age was 54 years, 54% were male and 83% were Asian. HBcrAg was detectable in 86% patients. HBcrAg level ≥4 log U/mL at EOT was predictive of hepatitis flare [8/10 (80%) vs. 17/55 (31%), p = .001]. The presence of either HBcrAg ≥4 log U/mL or detectable HBV RNA at EOT predicted for both biochemical relapse and hepatitis flare. The SCALE-B model at EOT predicted for virological relapse, biochemical relapse, hepatitis flare and HBsAg loss in this cohort. An increase in the serum HBcrAg level off-treatment was also associated with hepatitis flare. No participant with EOT HBcrAg level ≥4 log U/mL achieved HBsAg loss. CONCLUSIONS: High levels of serum HBcrAg predict for hepatitis flare after stopping NA therapy and low likelihood of HBsAg loss at week 96. People with high levels of serum HBcrAg are not suitable candidates for NA discontinuation.

Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia.

Injectable insulin is an extensively used medication with potential life-threatening hypoglycaemic events. Here we report on insulin-conjugated silver sulfide quantum dots coated with a chitosan/glucose polymer to produce a responsive oral insulin nanoformulation. This formulation is pH responsive, is insoluble in acidic environments and shows increased absorption in human duodenum explants and Caenorhabditis elegans at neutral pH. The formulation is sensitive to glucosidase enzymes to trigger insulin release. It is found that the formulation distributes to the liver in mice and rats after oral administration and promotes a dose-dependent reduction in blood glucose without promoting hypoglycaemia or weight gain in diabetic rodents. Non-diabetic baboons also show a dose-dependent reduction in blood glucose. No biochemical or haematological toxicity or adverse events were observed in mice, rats and non-human primates. The formulation demonstrates the potential to orally control blood glucose without hypoglycaemic episodes.

Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants.

BACKGROUND AND AIMS: HBV RNA in peripheral blood reflects HBV cccDNA transcriptional activity and may predict clinical outcomes. The prospective Melbourne HBV-STOP trial studied nucleot(s)ide analog discontinuation in HBeAg-negative non-cirrhotic participants with long-term virological suppression. Ninety-six weeks after stopping treatment, the proportion of participants with virological relapse (HBV DNA > 2000 IU/mL), biochemical relapse (ALT > 2 × ULN and HBV DNA > 2000 IU/mL), or hepatitis flare (ALT > 5 × ULN and HBV DNA > 2000 IU/mL) was 89%, 58%, and 38%, respectively. We evaluated the ability of serum HBV RNA levels to predict these outcomes. APPROACH RESULTS: HBV RNA levels were measured using the Roche cobas 6800/8800 HBV RNA Investigational Assay. Sixty-five participants had baseline and longitudinal off-treatment specimens available for RNA testing. HBV RNA was detectable at baseline in 25% of participants and was associated with a higher risk of biochemical relapse (81% vs. 51%, p value 0.04) and hepatitis flare (63% vs. 31%, p value 0.04). Participants who had undetectable serum HBV RNA as well as HBsAg ≤ 100 IU/mL at baseline were less likely to experience virological relapse (4 of 9, 44%) than participants with detectable HBV RNA and HBsAg level > 100 IU/mL (15/15, 100%; p value 0.0009). Off-treatment levels of HBV RNA were correlated with HBV DNA and were associated with the risk of hepatitis flare. CONCLUSIONS: Serum HBV RNA may be a useful biomarker for guiding clinical decision-making before stopping nucleot(s)ide analog therapy. Baseline HBV RNA and HBsAg levels are associated with the risk of clinical relapse, hepatitis flare, and disease remission off-treatment.

Hepatitis B Virus Flares After Nucleot(s)ide Analogue Cessation Are Associated With Activation of Toll-Like Receptor Signaling Pathways.

BACKGROUND: We evaluated the patterns of peripheral Toll-like receptor (TLR) signaling activity and the expression of TLRs and natural killer (NK) cell activation in a cohort of patients experiencing severe hepatitis flares after stopping nucleot(s)ide analogues (NAs) therapy. METHODS: Samples were collected longitudinally from patients with chronic hepatitis B who were enrolled in a prospective study of NA discontinuation. Patients experiencing hepatitis flares were compared with patients with normal alanine aminotransferase. Peripheral blood mononuclear cells (PBMCs) were stimulated with TLR ligands and cytokine secretion in the cell culture supernatant measured. Expression of TLR2/4, NKG2D, NKp46, and triggering receptor expressed on myeloid cells 1 (TREM-1) on monocytes, NK, and NK-T cells was measured. RESULTS: Seventeen patients with severe reactivation hepatitis flares were compared to 12 nonflare patients. Hepatitis flares were associated with increased activity of TLR2-8 and TLR9 signaling in PBMCs at the time of peak flare compared to baseline. Hepatitis flares were also associated with (1) upregulation of TLR2 and (2) TREM-1 receptor expression on NK. There were no differences at baseline between flare patients and nonflare patients. CONCLUSIONS: Hepatitis flares off NA therapy have a significant innate inflammatory response with upregulation of TLR signaling on peripheral monocytes and TLR2 and TREM-1 expression on NK cells. This implicates the innate immune system in the immunopathogenesis of hepatitis B flares.

Stopping nucleot(s)ide analogues in non-cirrhotic HBeAg-negative chronic hepatitis B patients: HBsAg loss at 96 weeks is associated with low baseline HBsAg levels.

BACKGROUND AND AIMS: Current guidelines recommend long-term nucleot(s)ide analogue (NA) therapy for patients with HBeAg-negative chronic hepatitis B (CHB). However, disease remission has been described after stopping NA therapy, as well as HBsAg loss. METHODS: We performed a prospective multi-centre cohort study of stopping NA therapy. Inclusion criteria were HBeAg-negative CHB, the absence of cirrhosis and HBVDNA5× ULN occurred in 35 (32%); ALT flares were not associated with HBsAg loss. There were no unexpected safety issues. CONCLUSION: Virological reactivation was very common after stopping NA therapy and occurred earlier after stopping TDF versus ETV. The majority of patients had ALT <2× ULN at week 96, but only one-third achieved disease remission and HBsAg loss was rare. Very low HBsAg levels at baseline were uncommon but predicted for HBsAg loss and disease remission.

Reflux scintigraphy in gastro-esophageal reflux disease: a comparison study with 24 hour pH-impedance monitoring.

OBJECTIVE: Reflux scintigraphy is often used to diagnose gastro-esophageal reflux disease (GERD). However, the efficacy of this study remains controversial. Our aim was to determine the role of reflux scintigraphy in diagnosing GERD by comparing it to 24 h combined pH-impedance study as the gold standard. MATERIALS AND METHODS: Adult patients who presented for investigations of reflux symptoms were prospectively recruited into the study. All patients underwent high resolution esophageal manometry and those with major motor disorders of the esophagus were excluded. Eligible patients immediately underwent reflux scintigraphy following insertion of the pH-impedance catheter. RESULTS: Thirty patients were included in the study. Using a total acid exposure time (AET) of >4.2% as the reference for abnormal acid reflux, reflux scintigraphy had a sensitivity and specificity of 62.5 and 68.2%, respectively, in detecting acid reflux. When compared to AET >6%, reflux scintigraphy had a sensitivity and specificity of 66.7 and 62.5%, respectively, and a positive predictive value of 30.8% and a negative predictive value of 88.2%. There were no associations between outcomes of reflux scintigraphy and total AET (p = .46), total (acid or non-acid) reflux events (p = 0.11), proximal AET (p = .33) or the number of proximal reflux episodes (p = .75) on 24 h pH-impedance study. CONCLUSIONS: Reflux scintigraphy has limited role in diagnosing GERD when compared to 24 h combined pH-impedance monitoring.

Utility of minimal preparation computed tomography colonography in detecting colorectal cancer in elderly and frail patients.

BACKGROUND: Colorectal cancers result in substantial morbidity and mortality to the Australian society each year. The usual investigation for bowel malignancy is optical colonoscopy (OC), with computed tomography colonography (CTC) used as an alternative investigation. The catharsis and colon insufflation associated with these investigations pose a higher risk in the elderly and frail. Risks include perforation, serum electrolyte disturbance and anaesthesia/sedation risks. Minimal preparation computed tomography colonography (MPCTC) eliminates these risks. AIMS: To audit the accuracy of a MPCTC programme for the investigation of colonic masses in symptomatic elderly and frail patients. METHODS: This paper audits a 6-year period of MPCTC in an Australian tertiary referral hospital. A total of 145 patients underwent MPCTC during the study period. RESULTS: There were seven true positives, two false positives and two false negatives. Analysis of this population indicates a sensitivity of 0.78 (95% CI 0.51-1.05), specificity of 0.99 (95% CI 0.97-1.01), positive predictive value (PPV) of 0.78 (95% CI 0.51-1.05) and negative predictive value (NPV) of 0.99 (95% CI 0.97-1.01). These findings are concordant with other published studies. CONCLUSIONS: This audit confirms that minimal preparation CT colonography is a reasonable alternative to OC and CTC in detecting colorectal cancer in symptomatic elderly and frail patients, without the procedural risks inherent in more invasive investigations. For most patients, MPCTC ruled out significant colorectal carcinoma with a high NPV.

Full-Spectrum Endoscopy Improves Surveillance for Dysplasia in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) increase the risk of colorectal cancer. Surveillance colonoscopy with chromoendoscopy is recommended, but conventional forward-viewing colonoscopy (FVC) detects dysplasia with low levels of sensitivity. Full-spectrum endoscopy (FUSE) incorporates 2 additional lateral cameras to the forward camera of the colonoscope, allowing endoscopists to view behind folds and in blind spots, which might increase dysplasia detection. We compared FUSE vs FVC in the detection of dysplasia in patients with IBDs. METHODS: We performed a prospective, randomized, cross-over, tandem colonoscopy study comparing FVC vs FUSE in 52 subjects with IBD undergoing surveillance for neoplasia in Australia (23 with Crohn's colitis, 29 with ulcerative colitis; median age, 45.0 y; 60% male; mean IBD duration, 16.4 y). All subjects met national IBD surveillance inclusion criteria; 27 were assigned randomly to groups that underwent FVC followed by FUSE, and 25 were assigned to groups that underwent FUSE followed by FVC. All procedures were performed from February 2014 through December 2015. Random biopsy specimens were collected and visible lesions were collected; all were analyzed histologically. The primary end point was dysplasia missed by the first colonoscopy detected by the second colonoscopy. Dysplasia was diagnosed by an expert gastrointestinal pathologist blinded to the colonoscope allocation in consensus with a second expert pathologist. RESULTS: FVC missed 71.4% of dysplastic lesions per lesion whereas FUSE missed 25.0% per lesion (P = .0001); FVC missed 75.0% of dysplastic lesions per subject and FUSE missed 25.0% per subject (P = .046). FUSE identified a mean of 0.37 dysplastic lesions and FVC identified a mean of 0.13 dysplastic lesions (P = .044). The total colonoscopy times were similar (21.2 min for FUSE vs 19.1 min for FVC; P = .32), but withdrawal time was significantly longer for FUSE (15.8 min) than for FVC (12.0 min) (P = .03). Correcting for per-unit withdrawal time, the mean dysplasia miss rate per subject was significantly lower for FUSE (0.19) than for FVC (0.83; P < .0001). Targeted tissue acquisition identified significantly more dysplastic lesions than random biopsies (P < .0001). CONCLUSIONS: In a prospective cross-over study of IBD patients undergoing surveillance colonoscopy, we found panoramic views obtained by full-spectrum endoscopy increased the number of dysplastic lesions detected, compared with conventional forward-viewing colonoscopy. Trial no: ACTRN12616000047493.

Abdominal actinomycosis presenting as appendicitis: two case reports and review.

Abdominal actinomycosis (AA) is a rare infection caused by filamentous Gram-positive anaerobic bacteria Actinomyces. We report two cases of adults with AA who initially presented with clinical and radiological features of appendicitis. Both patients underwent appendicectomy with histopathology diagnostic for actinomycosis of the appendix and subsequently completed prolonged courses of oral penicillin. AA is a rare differential diagnosis for appendicitis and should be considered especially in patients with a chronic, indolent course and nonspecific abdominal symptoms. A high index of suspicion may avoid unnecessary surgery, as treatment with prolonged antibiotic therapy is very effective.

Managing HBV in pregnancy. Prevention, prophylaxis, treatment and follow-up: position paper produced by Australian, UK and New Zealand key opinion leaders.

Hepatitis B during pregnancy presents unique management issues for both the mother and fetus. These include the lack of a current cohesive strategy for treatment and follow-up of mothers and their babies; the uncertain risk of postpartum HBV flares; the lack of randomised trial data on the safety and efficacy of antiviral treatment in pregnancy; the lack of head-to-head studies comparing different antivirals in pregnancy; and the lack of epidemiologic information regarding infection across different populations globally. This position paper provides a comprehensive review of the management of women with HBV infection prior to conception, throughout each stage of pregnancy and postpartum, as well as recommendations and clinical approaches for the follow-up of children born to infected mothers, based on available evidence in the literature and recommendations from international experts. Prevention of perinatal transmission is an important component of global efforts to reduce the burden of chronic HBV since vertical transmission is responsible for most of the chronic infection worldwide.

Longer duration of transient elastography predicts unreliable liver stiffness measurements.

BACKGROUND: Transient elastography (TE) is a noninvasive, validated method to assess liver fibrosis by obtaining liver stiffness measurements (LSM). However, TE can be limited by unreliable measurement (UM). The relationship between the time taken to perform TE (duration) and UM has not been studied. OBJECTIVES: To determine whether the duration of TE correlates with UM. MATERIALS AND METHODS: We prospectively studied the frequency and predictors of UM over a 5-year period. UM was defined as follows: less than 10 successful measurements, success rate less than 60%, or interquartile range more than 30% of the median LSM value (IQR/LSM>30%). RESULTS: Among the 2834 patients with LSM analysed, UM occurred in 19.0%. Duration [odds ratio (OR) 4.2, 95% confidence interval (CI) 2.8-6.4; P<0.0001] was the strongest predictor of UM, followed by BMI more than 28 kg/m (OR 2.1, 95% CI 1.5-3.0; P<0.0001), age more than 52 (OR 1.6, 95% CI 1.1-2.3; P=0.007) and non-HBV aetiology (OR 1.6, 95% CI 1.1-2.3; P=0.02). An optimal cut-off of 3 min 47 s was calculated for predicting UM (sensitivity 70%, specificity 65%, OR 4.2, 95% CI 2.7-6.6, P<0.0001). Examinations that took longer than 8 min 10 s had a 90% chance of UM. CONCLUSION: In experienced hands, duration is a strong predictor of UM in patients undergoing TE. Examinations longer than 4 min are more likely to be unreliable. Examinations longer than 8 min are unlikely to yield a valid result and should be considered a futility endpoint. Older age and increased BMI and nonhepatitis B aetiology are independent, albeit weaker, predictors of UM.

Non-invasive estimation of liver fibrosis in non-alcoholic fatty liver disease using the 13 C-caffeine breath test.

BACKGROUND AND AIM: Fibrotic progression in non-alcoholic fatty liver disease (NAFLD) is associated with impaired hepatic function. The (13) C-caffeine breath test (CBT) is a non-invasive, quantitative test of liver function. We sought to determine the utility of the CBT in detecting hepatic fibrosis in NAFLD. METHODS: The CBT was applied to 48 patients with NAFLD. CBT results were compared to clinical, biochemical and histological data. Twenty-four healthy subjects served as controls. RESULTS: Patients with simple steatosis had similar CBT values (2.28 ± 0.71 Δ‰ per 100 mg caffeine) to controls (2.31 ± 0.85, P = 1.0). However, CBT was significantly reduced in patients with non-alcoholic steatohepatitis (1.59 ± 0.65, P = 0.005) and cirrhosis (1.00 ± 0.73, P < 0.001). CBT significantly correlated with Brunt's fibrosis score (r = -0.49, P < 0.001) but not with steatosis (P = 0.23) or inflammation (P = 0.08). CBT also correlated with international normalized ratio (r = -0.61, P < 0.001), albumin (r = 0.37, P = 0.009), aspartate aminotransferase/alanine aminotransferase (r = -0.34, P = 0.018) and platelets (r = 0.31, P = 0.03). On multivariate analysis, age (odds ratio 1.12, 95% confidence interval 1.042-1.203, P = 0.002) and CBT (OR 0.264, 95% CI 0.084-0.822, P = 0.02) were independent predictors of significant fibrosis (F ≥ 2). CBT yielded an area under the receiver operating characteristic curve of 0.86 for the diagnosis of cirrhosis. CONCLUSIONS: The CBT reflects the extent of hepatic fibrosis in NAFLD and represents a non-invasive predictor of fibrosis severity in this condition.

Hypophosphataemic osteomalacia in patients on adefovir dipivoxil.

Fanconi syndrome results from generalised renal tubular toxicity and, owing to phosphate wasting can cause hypophosphataemic osteomalacia. Large clinical trials advocated the safety of adefovir dipivoxil at a daily dose of 10 mg, the standard dose given to patients with hepatitis B. We diagnosed Fanconi syndrome in conjunction with severe osteomalacia in 2 hepatitis B-positive patients on standard-dose adefovir therapy. The first patient was a 40-year-old male with a 5 month history of bone pain involving his knees, ankles, and ribs. He had been receiving adefovir dipivoxil for 27 months before the development of hypophosphataemia, urinary phosphate wasting, and aminoaciduria. These abnormalities resolved within weeks of discontinuation of adefovir dipivoxil and supplementation with elemental phosphate, calcium carbonate, and cholecalciferol. The second patient was a 53-year-old female with a 6 month history of lethargy, cachexia, and generalized bone pain. She had been receiving adefovir for 64 months before the development of these symptoms. She had hypophosphataemia, hypocalcaemia, metabolic acidosis, and severe vitamin D deficiency, but initially no urinary phosphate wasting. Four months of high-dose cholecalciferol supplementation unmasked her Fanconi syndrome including significant urinary phosphate wasting. The patient improved within weeks of discontinuation of adefovir and supplementation with elemental phosphate, calcium carbonate, and calcitriol. Despite large clinical trials advocating the safety of adefovir dipivoxil at 10-mg daily, long-term use of this agent may be nephrotoxic and in rare cases, cause Fanconi syndrome and severe hypophosphataemic osteomalacia. Clinicians prescribing this drug should be aware of this potential complication.

The differential effect of gastroesophageal reflux disease on mechanostimulation and chemostimulation of the laryngopharynx.

OBJECTIVES: Laryngo-hypopharyngeal sensitivity (LPS) as measured by thresholds to mechanostimulation and chemostimulation is important in the prevention of pulmonary aspiration. The presence of gastroesophageal reflux disease (GERD) increases thresholds to mechanostimulation. However, the effect of GERD on thresholds to chemostimulation remains unknown. The aim of this study was to compare laryngo-hypopharyngeal thresholds to chemostimulation in subjects with GERD with those of healthy subjects and to determine the relationship between thresholds to mechanostimulation and chemostimulation. METHODS: Forty-eight patients with GERD and 18 control subjects without GERD underwent LPS testing using the Fiberoptic Endoscopic Evaluation of Swallowing with Sensory Testing technique. All 48 patients and 10 of the control subjects also underwent threshold testing for chemostimulation via hypopharyngeal infusions of normal saline and 0.1 N hydrochloric acid performed in a randomized, blinded manner. Thresholds to mechanical stimulation, as measured by the lowest air pressure level required to elicit the laryngeal adductor reflex (LAR), were determined before and after laryngo-hypopharyngeal infusions. Thresholds to chemical stimulation were measured by determining the infusion volume of acid or saline required to trigger an airway protection response. RESULTS: The mean LAR threshold of the patient group was significantly higher compared with that of control subjects (9.5 mm Hg vs 3.9 mm Hg, P < .01). Compared with control subjects, significantly less acid (0.13 mL vs 0.21 mL, P < .01) was required to trigger airway protective responses in GERD subjects. There is a strong negative correlation between the volume of acid infused and the LAR thresholds in the control subjects (r = -0.69, P < .05). CONCLUSIONS: Compared with the control subjects, subjects with GERD have significantly increased thresholds to mechanical stimulation, suggesting reduced mechanosensitivity, but significantly reduced thresholds to chemical stimulation, suggesting heightened chemosensitivity. There is an inverse relationship between mechanosensitivity and chemosensitivity. This relationship may be integral in maintaining airway protection.

Combination adefovir-lamivudine prevents emergence of adefovir resistance in lamivudine-resistant hepatitis B.

BACKGROUND AND AIM: The outcomes of lamivudine-resistant chronic hepatitis B patients treated with long-term adefovir dipivoxil have not been well described. This study aims to characterize the virological and biochemical response and to determine factors that may influence the development of resistance to adefovir. METHODS: A retrospective review was conducted on all patients with lamivudine-resistant chronic hepatitis B treated with adefovir for a minimum of 6 months at two tertiary referral centers. RESULTS: Data on 161 patients were analyzed. Seventy-two percent achieved an initial virological response with eventual normalization of alanine aminotransferase in only 67% of patients. Seventeen patients developed adefovir resistance with cumulative resistance rates of 3.2%, 8.8%, and 18% at 12, 24, and 36 months, respectively. Twelve (71%) of these patients had a biochemical breakthrough, with one death from fulminant hepatic failure. The median duration of lamivudine crossover was 1 month in adefovir-resistant patients, compared with 12 months for the remainder of the cohort (P < 0.01). Longer crossover therapy reduced the adefovir resistance rate, but did not eliminate it. No adefovir resistance is reported in those who were continued on long-term combination lamivudine-adefovir without a period of adefovir monotherapy. CONCLUSIONS: Combination lamivudine-adefovir therapy protected against the emergence of adefovir resistance.

Hepatic sinusoidal pseudocapillarization with aging in the non-human primate.

BACKGROUND/AIMS: Age-related changes in the hepatic sinusoid termed pseudocapillarization have been reported in the rat and human and have implications for disease susceptibility in old age. In this study, we investigated whether similar changes occur in the livers of old baboons and thus represent a widespread aging change. METHODS: Liver tissue from five young baboons (5.4+/-0.5yrs) and five old baboons (21.8+/-0.7yrs) was compared by transmission electron microscopy, scanning electron microscopy and immunohistochemistry. RESULTS: The thickness of the sinusoidal endothelium was increased in old baboons (130+/-8 nm versus 186+/-9 nm, P<0.001) and the frequency of endothelial fenestrae decreased, with the porosity declining from 4.2+/-0.5% to 2.4+/-0.4% (P=0.006). The expression of laminin and von Willebrands factor was more extensive in old baboons. Novel perisinusoidal ring-shaped cells, probably fat-engorged stellate cells, were prominent in the old baboons. CONCLUSIONS: Pseudocapillarization is a significant age-related change in the baboon liver. Aging in baboons is associated with a novel aging change in the stellate cell not reported in other species. Hepatic pseudocapillarization is a widespread aging liver change found in several species including humans and other non-human primates.

Validity of the 13C-caffeine breath test as a noninvasive, quantitative test of liver function.

The properties of caffeine render it an ideal substrate for a quantitative test of liver function. The aim of this study was to determine whether the caffeine breath test (CBT) using orally administered 13C-caffeine correlates reliably with plasma caffeine clearance and reflects varying degrees of liver dysfunction. The CBT was performed in 25 healthy controls; 20 subjects with noncirrhotic, chronic hepatitis B or C; and 20 subjects with cirrhosis. Plasma caffeine clearance was assayed simultaneously with the CBT in a cohort of these subjects. Over a broad range of caffeine clearances, the CBT exhibited a highly significant correlation with plasma clearance (r = 0.85, P <.001). Cirrhotic patients were characterized by significantly reduced CBT values (1.15 +/- 0.75 delta per thousand mg(-1)) compared with controls (2.23 +/- 0.76; P =.001) and hepatitic patients (1.83 +/- 1.05; P =.04). There was a significant inverse relationship between the CBT and Child-Pugh score (r = -.74, P =.002). The intraclass correlation coefficient between repeated CBTs in 20 subjects with normal and cirrhotic livers was 0.89. Although smoking was associated with an 86% to 141% increase in CBT in all groups, the CBT was able to distinguish control, hepatitic, and cirrhotic smokers (5.36 +/- 0.82, 3.63 +/- 1.21, and 2.14 +/- 1.14, respectively, P =.001). Multivariate analysis revealed that only smoking (P <.001) and disease state (P =.001) were significant predictors of the CBT. In conclusion, the 13C-CBT represents a valid indicator of plasma caffeine clearance and correlates reproducibly with hepatic dysfunction.