Transplantation for Alcoholic Hepatitis: Are We Achieving Justice and Utility?

Early liver transplantation for alcoholic hepatitis is a potentially life-saving treatment. As this practice becomes increasingly common, however, the liver transplant community is taking a fresh look at a familiar challenge: best stewardship of donor organs. Herein, we examine a few basic, necessary ethical and practical concerns relevant to this indication.

Prior Relapse, Ongoing Alcohol Consumption, and Failure to Engage in Treatment Predict Alcohol Relapse After Liver Transplantation.

BACKGROUND: Alcohol-related liver disease (ALD) is the leading indication for liver transplantation (LT) in the USA. Alcohol relapse post-LT can negatively impact long-term outcomes, and prognostic scoring systems are available for further study. AIMS: Our study aims were to: (1) evaluate the relationship between alcohol relapse and rejection and mortality, (2) investigate risk factors for relapse, and (3) assess predictive validity of the SIPAT (Stanford Integrated Psychosocial Assessment for Transplant) and SALT (Sustained Alcohol Use Post-Liver Transplant) scores on post-LT alcohol relapse. METHODS: We conducted a retrospective chart review of 155 patients transplanted for chronic ALD at a single transplant center. Cox proportional hazard models assessed the relationship between alcohol relapse and allograft rejection and psychosocial risk factors for relapse. RESULTS: 20% of patients met criteria for alcohol relapse. Alcohol relapse was associated with allograft rejection (HR 2.33, 95% CI 1.11-4.91, p = .03). Three variables most strongly associated with alcohol relapse: prior relapse, failure to engage in recommended alcohol treatment, and continued drinking with liver disease, which were combined into a psychosocial model. SIPAT score≥ 21 and SALT score ≥ 7 were associated with alcohol relapse (HR 6.40, 95% CI 1.36-30.18, p = .019 and HR 2.30, 95% CI 1.12-4.75, p = .024). Receiver operator characteristic analysis compared predictive ability of our psychosocial model to SIPAT (C-statistic .83 compared to .71) and SALT (C-statistic = .77 compared to .62). CONCLUSION: We identified important psychosocial predictors of post-LT alcohol relapse and validated SIPAT and SALT scores as pre-transplant risk factors for alcohol relapse.

Breath ammonia and ethanol increase in response to a high protein challenge.

Quantifying changes in ammonia and ethanol in blood and body fluid assays in response to food is cumbersome. We used breath analysis of ammonia, ethanol, hydrogen (an accepted standard of gut transit) and acetone to investigate gastrointestinal physiology. In 30 healthy participants, we measured each metabolite serially over 6 h in control and high protein trials. Two-way repeated measures ANOVA compared treatment (control versus intervention), change from baseline to maximum and interaction of treatment and time change. Interaction was significant for ammonia (p < 0.0001) and hydrogen (p < 0.0001). We describe the dynamic measurement of multiple metabolites in response to an oral challenge.

Hepatic fat and adenosine triphosphate measurement in overweight and obese adults using 1H and 31P magnetic resonance spectroscopy.

BACKGROUND/AIMS: Magnetic resonance spectroscopy (MRS) measures hepatic fat and adenosine triphosphate (ATP), but magnetic resonance studies are challenging in obese subjects. We aimed to evaluate the inter- and intrarater reliability and stability of hepatic fat and ATP measurements in a cohort of overweight and obese adults. METHODS: We measured hepatic fat and ATP using proton MRS ((1)H MRS) and phosphorus MRS ((31)P MRS) at baseline in adults enrolled in the Action for Health in Diabetes (Look AHEAD) clinical trial at one site. Using logistic regression, we determined factors associated with successful MRS data acquisition. We calculated the intra- and inter-rater reliability for hepatic fat and ATP based on 20 scans analysed twice by two readers. We also calculated the stability of these measures three times on five healthy volunteers. RESULTS: Of 244 participants recruited into our ancillary study, 185 agreed to MRS. We obtained usable hepatic fat data from 151 (82%) and ATP data from 105 (58%). Obesity was the strongest predictor of failed data acquisition; every unit increase in the body mass index reduced the likelihood of successful fat data by 11% and ATP data by 14%. The inter- and intrarater reliability were excellent for fat (intraclass correlation coefficient=0.99), but substantially more variable for ATP. Fat measures appeared relatively stable, but this was less true for ATP. CONCLUSIONS: Obesity can hinder (1)H and (31)P MRS data acquisition and subsequent analysis. This impact was greater for hepatic ATP than hepatic fat.

Repeated Measures of Blood and Breath Ammonia in Response to Control, Moderate and High Protein Dose in Healthy Men.

Ammonia physiology is important to numerous disease states including urea cycle disorders and hepatic encephalopathy. However, many unknowns persist regarding the ammonia response to common and potentially significant physiologic influences, such as food. Our aim was to evaluate the dynamic range of ammonia in response to an oral protein challenge in healthy participants. We measured blood and breath ammonia at baseline and every hour for 5.5 hours. Healthy men (N = 22, aged 18 to 24 years) consumed a 60 g protein shake (high dose); a subset of 10 consumed a 30 g protein shake (moderate dose) and 12 consumed an electrolyte drink containing 0 g protein (control). Change in blood ammonia over time varied by dose (p = 0.001). Difference in blood ammonia was significant for control versus high (p = 0.0004) and moderate versus high (p = 0.03). Change in breath ammonia over time varied by dose (p < 0.0001). Difference in breath ammonia was significant for control versus moderate (p = 0.03) and control versus high (p = 0.0003). Changes in blood and breath ammonia were detectable by fast, minimally-invasive (blood) or non-invasive (breath) point-of-care ammonia measurement methods. These pilot data may contribute to understanding normal ammonia metabolism. Novel measurement methods may aid research into genetic and metabolic ammonia disorders.

Trends in adult-to-adult living donor liver transplant organ donation: the Johns Hopkins experience.

Adult-to-adult living donor liver transplantation is an increasingly important option for 17000 patients awaiting liver transplantation in the United States. However, adult-to-adult living donor liver transplantation volumes peaked in 2001 (N = 518), and have gradually fallen in 2002 (N = 362), 2003 (N = 321), and 2004 (N = 323). Recent concerns about donor safety and ethical considerations have made careful analysis of donor availability and selection criteria critically important. We conducted a retrospective review of our active liver transplant recipient registry (N = 251) and compared it to our living donor registry (N = 231), which included all potential living donors before the selection process. Fifteen percent of recipients accounted for the majority (53%) of donor evaluations, whereas 42% of recipients did not have even a single donor evaluation. Recipient diagnosis appears to have a significant impact on donor availability, with donors rarely evaluated for patients with alcoholic cirrhosis. Careful and stringent selection criteria rule out 67% of potential donors.

Race and comorbid factors predict nonalcoholic fatty liver disease histopathology in severely obese patients.

PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is a common and potentially serious form of chronic liver disease. Although NAFLD is known to be associated with obesity and some comorbid conditions, less is known about the severity of NAFLD among different racial groups. METHODS: We prospectively studied 237 consecutive morbidly obese patients presenting for bariatric surgery. All patients underwent intraoperative liver biopsy and chart review. After excluding subjects who reported alcohol use (n = 37) or who had missing biopsy data (n = 11), 189 patients were available for analysis. Clinical and laboratory associations with each of the histological components of NAFLD were assessed using multiple logistic regression analysis. RESULTS: The mean age was 43.1 years, 84% were female, and 13% were African American. It was found that 88% had steatosis, including 35% with moderate to severe steatosis (> 33% of hepatocytes involved). Of these patients, 67% had inflammation, 46% had fibrosis, and 45% met Brunt's criteria for NASH. Compared with Caucasians and after adjustment, African Americans had significantly lower odds of severe hepatic pathology, with adjusted odds ratios of 0.1 (P = .02) for the presence of moderate or severe steatosis, 0.2 for inflammation (P = .006), 0.3 for fibrosis (P = .05), and 0.2 for NASH (P = .02). In addition, participants with one or more features of the metabolic syndrome (ie, diabetes, hypertension, or dyslipidemia) or elevated aminotransferase levels had significantly higher odds of severe hepatic histopathology. CONCLUSION: Among obese patients presenting for bariatric surgery, NAFLD is more common in Caucasians, patients with features of the metabolic syndrome, and those with elevated aminotransferase levels.

Clinical utility of breath ammonia for evaluation of ammonia physiology in healthy and cirrhotic adults.

Blood ammonia is routinely used in clinical settings to assess systemic ammonia in hepatic encephalopathy and urea cycle disorders. Despite its drawbacks, blood measurement is often used as a comparator in breath studies because it is a standard clinical test. We sought to evaluate sources of measurement error and potential clinical utility of breath ammonia compared to blood ammonia. We measured breath ammonia in real time by quartz enhanced photoacoustic spectrometry and blood ammonia in 10 healthy and 10 cirrhotic participants. Each participant contributed 5 breath samples and blood for ammonia measurement within 1 h. We calculated the coefficient of variation (CV) for 5 breath ammonia values, reported medians of healthy and cirrhotic participants, and used scatterplots to display breath and blood ammonia. For healthy participants, mean age was 22 years (±4), 70% were men, and body mass index (BMI) was 27 (±5). For cirrhotic participants, mean age was 61 years (±8), 60% were men, and BMI was 31 (±7). Median blood ammonia for healthy participants was within normal range, 10 µmol L(-1) (interquartile range (IQR), 3-18) versus 46 µmol L(-1) (IQR, 23-66) for cirrhotic participants. Median breath ammonia was 379 pmol mL(-1) CO2 (IQR, 265-765) for healthy versus 350 pmol mL(-1) CO2 (IQR, 180-1013) for cirrhotic participants. CV was 17 ± 6%. There remains an important unmet need in the evaluation of systemic ammonia, and breath measurement continues to demonstrate promise to fulfill this need. Given the many differences between breath and blood ammonia measurement, we examined biological explanations for our findings in healthy and cirrhotic participants. We conclude that based upon these preliminary data breath may offer clinically important information this is not provided by blood ammonia.

N-acetylcysteine treats intravenous amiodarone induced liver injury.

We report a case of intravenous (IV) amiodarone drug induced liver injury (DILI). The patient received IV N-acetylcysteine (NAC) which resulted in a rapid improvement in liver enzymes. While the specific mechanisms for the pathogenesis of IV amiodarone DILI and the therapeutic action of IV NAC are both unknown, this case strongly implies at least some commonality. Because IV amiodarone is indicated for the treatment of serious cardiac arrhythmias in an intensive care unit setting, some degree of ischemic hepatitis is likely a cofactor in most cases.

Fast and accurate exhaled breath ammonia measurement.

This exhaled breath ammonia method uses a fast and highly sensitive spectroscopic method known as quartz enhanced photoacoustic spectroscopy (QEPAS) that uses a quantum cascade based laser. The monitor is coupled to a sampler that measures mouth pressure and carbon dioxide. The system is temperature controlled and specifically designed to address the reactivity of this compound. The sampler provides immediate feedback to the subject and the technician on the quality of the breath effort. Together with the quick response time of the monitor, this system is capable of accurately measuring exhaled breath ammonia representative of deep lung systemic levels. Because the system is easy to use and produces real time results, it has enabled experiments to identify factors that influence measurements. For example, mouth rinse and oral pH reproducibly and significantly affect results and therefore must be controlled. Temperature and mode of breathing are other examples. As our understanding of these factors evolves, error is reduced, and clinical studies become more meaningful. This system is very reliable and individual measurements are inexpensive. The sampler is relatively inexpensive and quite portable, but the monitor is neither. This limits options for some clinical studies and provides rational for future innovations.

Changes in the concentration of breath ammonia in response to exercise: a preliminary investigation.

Breath ammonia has proven to be a difficult compound to measure accurately. The goal of this study was to evaluate the effects that the physiological intervention, exercise, had on the levels of breath ammonia. The effects of vigorous exercise (4000 m indoor row) in 13 participants were studied and increases in breath ammonia were observed in all participants. Mean pre-exercise concentrations of ammonia were 670 pmol ml(-1) CO2 (SD, 446) and these concentrations increased to post-exercise maxima of 1499 pmol ml(-1) CO2 (SD, 730), p < 0.0001. The mean increase in ammonia concentrations from pre-exercise to maximum achieved in conditioned (1362 pmol ml(-1) CO2) versus non-conditioned rowers (591 pmol ml(-1) CO2) were found to be statistically different, p = 0.029. Taken together, these results demonstrate our ability to repeatedly measure the influence of exercise on the concentration of breath ammonia.

Factors influencing breath ammonia determination.

Amongst volatile compounds (VCs) present in exhaled breath, ammonia has held great promise and yet it has confounded researchers due to its inherent reactivity. Herein we have evaluated various factors in both breath instrumentation and the breath collection process in an effort to reduce variability. We found that the temperature of breath sampler and breath sensor, mouth rinse pH, and mode of breathing to be important factors. The influence of the rinses is heavily dependent upon the pH of the rinse. The basic rinse (pH 8.0) caused a mean increase of the ammonia concentration by 410 ± 221 ppb. The neutral rinse (pH 7.0), slightly acidic rinse (pH 5.8), and acidic rinse (pH 2.5) caused a mean decrease of the ammonia concentration by 498 ± 355 ppb, 527 ± 198 ppb, and 596 ± 385 ppb, respectively. Mode of breathing (mouth-open versus mouth-closed) demonstrated itself to have a large impact on the rate of recovery of breath ammonia after a water rinse. Within 30 min, breath ammonia returned to 98 ± 16% that of the baseline with mouth open breathing, while mouth closed breathing allowed breath ammonia to return to 53 ± 14% of baseline. These results contribute to a growing body of literature that will improve reproducibly in ammonia and other VCs.

Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetes.

OBJECTIVE: Weight loss through lifestyle changes is recommended for nonalcoholic fatty liver disease (NAFLD). However, its efficacy in patients with type 2 diabetes is unproven. RESEARCH DESIGN AND METHODS: Look AHEAD (Action for Health in Diabetes) is a 16-center clinical trial with 5,145 overweight or obese adults with type 2 diabetes, who were randomly assigned to an intensive lifestyle intervention (ILI) to induce a minimum weight loss of 7% or a control group who received diabetes support and education (DSE). In the Fatty Liver Ancillary Study, 96 participants completed proton magnetic resonance spectroscopy to quantify hepatic steatosis and tests to exclude other causes of liver disease at baseline and 12 months. We defined steatosis >5.5% as NAFLD. RESULTS: Participants were 49% women and 68% white. The mean age was 61 years, mean BMI was 35 kg/m(2), mean steatosis was 8.0%, and mean aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were 20.5 and 24.2 units/l, respectively. After 12 months, participants assigned to ILI (n = 46) lost more weight (-8.5 vs. -0.05%; P < 0.01) than those assigned to DSE and had a greater decline in steatosis (-50.8 vs. -22.8%; P = 0.04) and in A1C (-0.7 vs. -0.2%; P = 0.04). There were no significant 12-month changes in AST or ALT levels. At 12 months, 26% of DSE participants and 3% (1 of 31) of ILI participants without NAFLD at baseline developed NAFLD (P < 0.05). CONCLUSIONS: A 12-month intensive lifestyle intervention in patients with type 2 diabetes reduces steatosis and incident NAFLD.

Hepatic 31P magnetic resonance spectroscopy: a hepatologist's user guide.

Hepatic phosphorus magnetic resonance spectroscopy (31P MRS) offers the exciting potential of studying metabolic processes in the human liver in vivo. Many investigators have utilized 31P MRS to research a broad range of metabolic questions, and there is outstanding potential for this imaging modality in the future. However, at times it is difficult to appreciate this potential because most published series have been small, and comparisons between studies are difficult. Indeed, the published literature contains significant variation in data acquisition and data analysis techniques and, perhaps most importantly, the interpretation of the data itself. As MR technology continues to evolve and more studies are being performed, perhaps a greater consensus of study techniques and endpoints will emerge. This review summarizes the present literature on human hepatic 31P MRS.