Research Spotlight

Brown, M., P. Ashcraft, E. Arning, T. Bottiglieri, W. McClintock, F. Giancola, D. Lieberman, N. S. Hauser, R. Miller, J. B. Roullet, P. Pearl and K. M. Gibson (2019). “Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female.” Mol Genet Genomic Med Mar 4: e629. [Epub ahead of print]: e629.

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BACKGROUND: We present a patient with Rett syndrome (RTT; MECP2) and autosomal-recessive succinic semialdehyde dehydrogenase deficiency (SSADHD; ALDH5A1 (aldehyde dehydrogenase 5a1 = SSADH), in whom the current phenotype exhibits features of SSADHD (hypotonia, global developmental delay) and RTT (hand stereotypies, gait anomalies). METHODS: gamma-Hydroxybutyric acid (GHB) was quantified by UPLC-tandem mass spectrometry, while mutation analysis followed standard methodology of whole-exome sequencing. RESULTS: The biochemical hallmark of SSADHD, GHB was increased in the proband’s dried bloodspot (DBS; 673 microM; previous SSADHD DBSs (n = 7), range 124-4851 microM); control range (n = 2,831), 0-78 microM. The proband was compound heterozygous for pathogenic ALDH5A1 mutations (p.(Asn418IlefsTer39); maternal; p.(Gly409Asp); paternal) and a de novo RTT nonsense mutation in MECP2 (p.Arg255*). CONCLUSION: The major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), is increased in SSADHD but normal in RTT, although there are likely regional changes in GABA receptor distribution. GABAergic anomalies occur in both disorders, each featuring an autism spectrum phenotype. What effect the SSADHD biochemical anomalies (elevated GABA, GHB) might play in the neurodevelopmental/epileptic phenotype of our patient is currently unknown.

Brahmania, M., M. Lombardero, B. E. Hansen, N. A. Terrault, A. S. Lok, R. P. Perrillo, S. H. Belle, A. M. Di Bisceglie, J. J. Feld, W. M. Lee, M. W. Fried and H. L. A. Janssen (2019). “Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection.” Clin Gastroenterol Hepatol Feb 8. [Epub ahead of print].

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BACKGROUND & AIMS: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous groups of patients in North America. METHODS: We collected data from the Hepatitis B Research Network-an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). RESULTS: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th-75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. CONCLUSION: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.

Baron, S. J., K. Wang, J. A. House, E. A. Magnuson, M. R. Reynolds, R. Makkar, H. C. Herrmann, S. Kodali, V. H. Thourani, S. Kapadia, L. Svensson, M. J. Mack, D. L. Brown, M. J. Russo, C. R. Smith, J. Webb, C. Miller, M. B. Leon and D. J. Cohen (2019). “Cost-Effectiveness of Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis at Intermediate Risk.” Circulation 139(7): 877-888.

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BACKGROUND: In patients with severe aortic stenosis (AS) at intermediate surgical risk, treatment with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) results in similar rates of death or stroke at 2 years. Whether TAVR is cost-effective compared with SAVR for intermediate-risk patients remains uncertain. METHODS: Between 2011 and 2014, 3110 intermediate-risk AS patients were treated with TAVR or SAVR in the PARTNER 2 trial (Placement of Aortic Transcatheter Valves 2). A total of 2032 patients were randomized to receive TAVR using the SAPIEN XT valve (XT-TAVR) or SAVR in the PARTNER 2A trial, whereas the PARTNER S3i registry included an additional 1078 patients treated with TAVR using the SAPIEN 3 valve (S3-TAVR), which offers a lower delivery profile and sealing skirt designed to reduce paravalvular regurgitation compared with XT-TAVR. Procedural costs were estimated using measured resource utilization. Other in-trial costs were assessed by linkage of trial data with Medicare claims (n=2333) or by linear regression models for unlinked patients (n=682). Health utilities were estimated using the EQ-5D at baseline and 1, 12, and 24 months. Using a Markov model informed by in-trial costs, utilities, and survival data, lifetime cost-effectiveness from the perspective of the US healthcare system was estimated in terms of cost per quality-adjusted life-year gained. RESULTS: Although procedural costs were approximately $20 000 higher with TAVR than SAVR, total cost differences for the index hospitalization were only $2888 higher with XT-TAVR ( P=0.014) and were $4155 lower with S3-TAVR ( P<0.001) owing to reductions in length of stay with TAVR. Follow-up costs were significantly lower with XT-TAVR (Delta=-$9304; P<0.001) and S3-TAVR (Delta=-$11 377; P<0.001) than with SAVR. Over a lifetime horizon, TAVR was projected to lower total costs by $8000 to $10 000 and to increase quality-adjusted survival by 0.15 to 0.27 years. XT-TAVR and S3-TAVR were found to be economically dominant compared with SAVR in 84% and 97% of bootstrap replicates, respectively. CONCLUSIONS: Among intermediate-risk AS patients, TAVR is projected to be economically dominant from the perspective of the US healthcare system by providing both greater quality-adjusted life expectancy and lower long-term costs than SAVR. If long-term data demonstrate comparable late mortality with TAVR and SAVR, these findings suggest that TAVR might be the preferred treatment strategy for intermediate-risk AS patients based on both clinical and economic considerations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01314313.

Asrani, S. K. and J. Hasse (2019). “Reply: Bariatric Surgery and Liver Transplantation.” Liver Transpl 25(3): 516.

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We appreciate the interest by Yildiz in our work that looked at the association between bariatric surgery and outcomes among patients evaluated for liver transplantation. We share the sentiment that some of the outcomes noted in the study may be related to malabsorptive rather than restrictive weight reduction surgery. As reflected in the results, rates of delisting or death were high for gastric bypass versus non–gastric bypass patients (44% versus 16.7%; P = 0.04). However, rates of moderate or severe malnutrition were similar between the groups (68% versus 57%; P = 0.5). Hence, in this analysis of historical data, it is hard to assess whether it is the surgery itself or a consequence of malnutrition regardless of surgery type that is driving the effect. In an independent population–based cohort, we are currently evaluating the impact of bariatric surgery on the natural history of compensated and decompensated cirrhosis. To our knowledge, there are no longitudinal prospective data collected looking at longterm outcomes (beyond 1‐2 years) starting from the time of surgery. Such efforts are needed to assess the absolute impact of the surgery type on outcomes in patients with or without recognized liver disease. Portal vein thrombosis remains an important complication of bariatric surgery. Reliable data on portal vein thrombosis among all patients with bariatric surgery evaluated for transplantation were not available. However, among those who underwent liver transplantation, only 1 patient had portal vein thrombosis. (Full text of this letter.)

Arnold, S. V., Y. Zhang, S. J. Baron, T. C. McAndrew, M. C. Alu, S. K. Kodali, S. Kapadia, V. H. Thourani, D. C. Miller, M. J. Mack, M. B. Leon and D. J. Cohen (2019). “Impact of Short-Term Complications on Mortality and Quality of Life After Transcatheter Aortic Valve Replacement.” JACC Cardiovasc Interv 12(4): 362-369.

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OBJECTIVES: The aim of this study was to examine the independent association of short-term complications of transcatheter aortic valve replacement (TAVR) with survival and quality of life at 1 year. BACKGROUND: Prior studies have examined the mortality and cost implications of various complications of TAVR. However, many of these complications may primarily affect patients’ quality of life after TAVR, which has not been previously studied. METHODS: Among patients at intermediate or high surgical risk who underwent TAVR as part of the PARTNER (Placement of Aortic Transcatheter Valve) 2 studies and survived 30 days, the association between complications within the 30 days after TAVR and mortality and quality of life at 1 year was examined. Quality of life was assessed using the Kansas City Cardiomyopathy Questionnaire and the Short-Form 12. Complications assessed included major and minor stroke, life-threatening and major bleeding, vascular injury, stage 3 acute kidney injury, new pacemaker implantation, and mild and moderate or severe paravalvular leak (PVL). Multivariable models that included all complications as well as baseline clinical factors were used to examine the independent association of each complication with outcomes. RESULTS: Among 3,763 TAVR patients, major stroke and stage 3 acute kidney injury were associated with markedly increased risk for 1-year mortality, with adjusted hazard ratios of 5.4 (95% confidence interval [CI]: 3.1 to 9.5) and 4.9 (95% CI: 2.7 to 8.8), respectively, as well as poorer quality of life among survivors (reductions in 1-year Kansas City Cardiomyopathy Questionnaire overall summary score of 15.1 points [95% CI: 24.8 to 5.3 points] and 14.7 points [95% CI: 25.6 to 3.8 points], respectively). Moderate or severe PVL, life-threatening bleeding, and major bleeding were each associated with a more modest increase in mortality and decrement in quality of life, whereas mild PVL was associated with a small decrease in quality of life. After adjusting for baseline characteristics and other complications, need for a new pacemaker, minor stroke, and vascular injury were not independently associated with poor outcomes. CONCLUSIONS: Among patients undergoing TAVR, similar events are associated with increased mortality and impaired quality of life at 1 year. These results suggest that despite considerable progress, efforts to further reduce stroke, acute kidney injury, bleeding, and moderate or severe PVL are likely to yield important clinical benefits and remain key targets for device iteration and procedural improvement.