Baylor Research Institute

Schiffmann, R., D. A. Hughes, G. E. Linthorst, A. Ortiz, E. Svarstad, D. G. Warnock, M. L. West and C. Wanner (2017). “Screening, diagnosis, and management of patients with fabry disease: Conclusions from a “kidney disease: Improving global outcomes” (kdigo) controversies conference.” Kidney Int 91(2): 284-293.

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Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized.

Schiller, L. R., D. S. Pardi and J. H. Sellin (2017). “Chronic diarrhea: Diagnosis and management.” Clin Gastroenterol Hepatol 15(2): 182-193.e183.

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Chronic diarrhea is a common problem affecting up to 5% of the population at a given time. Patients vary in their definition of diarrhea, citing loose stool consistency, increased frequency, urgency of bowel movements, or incontinence as key symptoms. Physicians have used increased frequency of defecation or increased stool weight as major criteria and distinguish acute diarrhea, often due to self-limited, acute infections, from chronic diarrhea, which has a broader differential diagnosis, by duration of symptoms; 4 weeks is a frequently used cutoff. Symptom clusters and settings can be used to assess the likelihood of particular causes of diarrhea. Irritable bowel syndrome can be distinguished from some other causes of chronic diarrhea by the presence of pain that peaks before defecation, is relieved by defecation, and is associated with changes in stool form or frequency (Rome criteria). Patients with chronic diarrhea usually need some evaluation, but history and physical examination may be sufficient to direct therapy in some. For example, diet, medications, and surgery or radiation therapy can be important causes of chronic diarrhea that can be suspected on the basis of history alone. Testing is indicated when alarm features are present, when there is no obvious cause evident, or the differential diagnosis needs further delineation. Testing of blood and stool, endoscopy, imaging studies, histology, and physiological testing all have roles to play but are not all needed in every patient. Categorizing patients after limited testing may allow more directed testing and more rapid diagnosis. Empiric antidiarrheal therapy can be used to mitigate symptoms in most patients for whom a specific treatment is not available.

Shen, J. S., E. Arning, M. L. West, T. S. Day, S. Chen, X. L. Meng, S. Forni, N. McNeill, O. Goker-Alpan, X. Wang, P. Ashcraft, D. F. Moore, S. H. Cheng, R. Schiffmann and T. Bottiglieri (2017). “Tetrahydrobiopterin deficiency in the pathogenesis of fabry disease.” Hum Mol Genet: 2017 Feb [Epub ahead of print].

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Fabry disease is caused by deficient activity of α-galactosidase A and subsequent accumulation of glycosphingolipids (mainly globotriaosylceramide, Gb3), leading to multisystem organ dysfunction. Oxidative stress and nitric oxide synthase (NOS) uncoupling are thought to contribute to Fabry cardiovascular diseases. We hypothesized that decreased tetrahydrobiopterin (BH4) plays a role in the pathogenesis of Fabry disease. We found that BH4 was decreased in the heart and kidney but not in the liver and aorta of Fabry mice. BH4 was also decreased in the plasma of female Fabry patients, which was not corrected by enzyme replacement therapy (ERT). Gb3 levels were inversely correlated with BH4 levels in animal tissues and cultured patient cells. To investigate the role of BH4 deficiency in disease phenotypes, 12-month-old Fabry mice were treated with gene transfer-mediated ERT or substrate reduction therapy (SRT) for 6 months. In the Fabry mice receiving SRT but not ERT, BH4 deficiency was restored, concomitant with ameliorated cardiac and renal hypertrophy. Additionally, glutathione levels were decreased in Fabry mouse tissues in a sex-dependent manner. Renal BH4 levels were closely correlated with glutathione levels and inversely correlated with cardiac and kidney weight. In conclusion, this study showed that BH4 deficiency occurs in Fabry disease and may contribute to the pathogenesis of the disease through oxidative stress associated with a reduced antioxidant capacity of cells and NOS uncoupling. This study also suggested dissimilar efficacy of ERT and SRT in correcting pre-existing pathologies in Fabry disease.

Singer, A. J., M. P. Than, S. Smith, P. McCullough, T. W. Barrett, R. Birkhahn, M. Reed, H. C. Thode, W. D. Arnold, L. B. Daniels, C. de Filippi, G. Headden and W. F. Peacock (2017). “Missed myocardial infarctions in ed patients prospectively categorized as low risk by established risk scores.” Am J Emerg Med: 2017 Jan [Epub ahead of print].

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STUDY OBJECTIVES: Few studies have prospectively compared multiple cardiac risk prediction scores. We compared the rate of missed acute myocardial infarction (AMI) in chest pain patients prospectively categorized as low risk by unstructured clinical impression, and by HEART, TIMI, GRACE, and EDACS scores, in combination with two negative contemporary cardiac troponins (cTn) available in the U.S. METHODS: We enrolled 434 patients with chest pain presenting to one of seven emergency departments (ED). Risk scores were prospectively calculated and included the first two cTn. Low risk was defined for each score as HEART

Schiffmann, R., D. A. Hughes, G. E. Linthorst, A. Ortiz, E. Svarstad, D. G. Warnock, M. L. West and C. Wanner (2016). “Screening, diagnosis, and management of patients with fabry disease: Conclusions from a “kidney disease: Improving global outcomes” (kdigo) controversies conference.” Kidney Int: 2016 Dec [Epub ahead of print].

Full text of this article.

Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized.