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©2012 MFMER | slide-1 Beriberi Treatment: What a medical student can teach us all Philip Fischer, M.D., and Samuel Porter Global Missions Health Conference.

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Presentation on theme: "©2012 MFMER | slide-1 Beriberi Treatment: What a medical student can teach us all Philip Fischer, M.D., and Samuel Porter Global Missions Health Conference."— Presentation transcript:

1 ©2012 MFMER | slide-1 Beriberi Treatment: What a medical student can teach us all Philip Fischer, M.D., and Samuel Porter Global Missions Health Conference November 9 th, 2012

2 ©2012 MFMER | slide-2 Prey Veng Province, Cambodia

3 ©2012 MFMER | slide-3 Debbie Coats, FNP Svay Chrum Health Clinic Previously-healthy infants presenting with tachypnea, tachycardia, hepatomegaly, and no fever.

4 ©2012 MFMER | slide-4 Beriberi – a significant killer Verbal autopsy study in Prey Veng, Cambodia 1 45% of infants who died in their first year of life had signs and symptoms of beriberi Respiratory distress, dysphonia, irritability, vomiting Karen Refugees Record infant mortality (>20%) Majority were dying of beriberi 2 Reports from all over SE Asia 2 1: Kauffman, G., D. Coats, et al. (2011). "Thiamine deficiency in ill children." The American Journal of Clinical Nutrition 94(2): ; author reply : Luxemburger, C., N. J. White, et al. (2003). "Beri-beri: the major cause of infant mortality in Karen refugees." Transactions of the Royal Society of Tropical Medicine and Hygiene 97(2):

5 ©2012 MFMER | slide-5 “I cannot, I cannot” 1870  Marked increase in beriberi incidence in SE Asia 3 Polished rice Christiaan Eijkman “White rice can be poisonous!” (1896) 3 The “anti-beriberi” factor Gerrit Grijns Suggested dietary deficiency (1901) 4 3: "Christiaan Eijkman, Beriberi and Vitamin B1". Nobelprize.org. 11 Oct :Lanska, DJ. “Chapter 30: Historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins”, In: Michael J. Aminoff, François Boller and Dick F. Swaab, Editor(s), Handbook of Clinical Neurology, Elsevier, 2009, 95, p ,

6 ©2012 MFMER | slide-6 On a molecular level …

7 ©2012 MFMER | slide-7 Beriberi in infants Thiamine-deficient mother due to polished rice Breast-fed infant does not get enough thiamine Picture of Rice Mill (from Dr. Fischer)

8 ©2012 MFMER | slide-8 Japanese Occupation of Singapore First observational study in infants , Archives of Disease in Children 139 cases, 55 % died 5: Haridas G. “Infantile beri-beri in Singapore during the latter part of the Japanese occupation.” Arch Dis Child Mar;22(109):23-33.

9 ©2012 MFMER | slide-9 What does beriberi in infants look like? 5,6,7 Previously healthy, 2-4 months old Vomiting, irritability over a few days but no fever Respiratory distress, tachycardia Hepatomegaly Dysphonia, hoarseness Cyanosis and grunting Cold extremities, mottled skin Death within a few days 5:Haridas G. “Infantile beri-beri in Singapore during the latter part of the Japanese occupation.” Arch Dis Child Mar;22(109): :Thanangkul, O. and J. Whitaker (1966). "Childhood thiamin deficiency in Northern Thailand." American Journal of Clinical Nutrition 18: : Luxemburger, C., N. J. White, et al. (2003). "Beri-beri: the major cause of infant mortality in Karen refugees." Transactions of the Royal Society of Tropical Medicine and Hygiene 97(2):

10 ©2012 MFMER | slide-10 How do we treat it? Replace the thiamine: 50 mg IM. Signs and symptoms resolve within hours. “Infantile beriberi is a readily-preventable disease that nearly disappeared in the first half of the 20 th century.” 2 And yet, it remains “an important cause of infant mortality in rural areas of [southeast Asia].” 2 2: Luxemburger, C., N. J. White, et al. (2003). "Beri-beri: the major cause of infant mortality in Karen refugees." Transactions of the Royal Society of Tropical Medicine and Hygiene 97(2):

11 ©2012 MFMER | slide-11 Back to Prey Veng Province … Do these infants have beriberi? Why are they so young? (1-2 months) Could there be an environmental or dietary exacerbation of thiamine deficiency?

12 ©2012 MFMER | slide-12 Medical Student #1: Kelsey Shelton-Dodge 27 beriberi cases & mothers 27 healthy controls (Cambodia) & mothers 20 healthy controls (USA) & mothers Blood draw Survey

13 ©2012 MFMER | slide-13 Results 27 beriberi cases & mothers 27 healthy controls (Cambodia) & mothers 20 healthy controls (USA) & mothers Thiamine: Low Thiamine: Normal NO difference in thiamine levels =

14 ©2012 MFMER | slide-14 Results (cont.) No association between environmental and dietary factors and thiamine levels Symptoms of beriberi resolved quickly after treatment, but hepatomegly and vital signs were slower to resolve

15 ©2012 MFMER | slide-15 Implications If all the Cambodian infants are thiamine- deficient, why do only some get beriberi? If clinical criteria don’t correlate to thiamine- levels, how are we going to diagnose beriberi?

16 ©2012 MFMER | slide-16 Medical Student #2: Liz Keating 50 infants presenting with tachypnea Blood draw Clinical & Lab Variables

17 ©2012 MFMER | slide-17 Results No clinical or lab data correlates to thiamine levels Even infants not treated with thiamine had improved thiamine levels at discharge.

18 ©2012 MFMER | slide-18 Implications How do we diagnose beriberi?

19 ©2012 MFMER | slide-19 What about response to thiamine treatment as a diagnostic criteria? Well … Acute infection could be simply running its course, and would have resolved even without thiamine administration. Thiamine deficiency may predispose infants to more severe infections, and repletion helps them overcome the infection. Lima ICU study (Brazil) 8 Mayxay Malaria study (Laos) 9 8: Lima, L. F., H. P. Leite, et al. (2011). "Low blood thiamine concentrations in children upon admission to the intensive care unit: risk factors and prognostic significance." The American Journal of Clinical Nutrition 93(1): : Mayxay, M., A. M. Taylor, et al. (2007). "Thiamin deficiency and uncomplicated falciparum malaria in Laos." Tropical Medicine & International Health : TM & IH 12(3):

20 ©2012 MFMER | slide-20 Medical Student #3: Sam Porter Beriberi will show right-sided heart failure 10,11 What do hearts of Debbie’s sick kids vs. apparently healthy infants look like? How do sick kids’ hearts change after thiamine administration? At what thiamine level do we start seeing cardiac dysfunction? N-type Pro-BNP 12 10: Khowsathit, P., B. Pongpanich, et al. (1990). "Cardiac beri-beri. Report of a case with an echocardiographic study." Japanese Heart Journal 31(2): :Rao, S. N. and G. R. Chandak (2010). "Cardiac beriberi: often a missed diagnosis." Journal of Tropical Pediatrics 56(4): : Lowenthal, A., B. V. Camacho, et al. (2012). "Usefulness of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide as biomarkers for heart failure in young children with single ventricle congenital heart disease." The American Journal of Cardiology 109(6):

21 ©2012 MFMER | slide-21 Methods 20 beriberi cases 45 healthy controls Blood draw: Day 0 & 2 Echocardiogram: Day 0, 1 & 2 Blood draw: Day 0 Echocardiogram: Day 0

22 ©2012 MFMER | slide-22 Working with a team

23 ©2012 MFMER | slide-23 Fitting into the culture (not vice versa)

24 ©2012 MFMER | slide-24 The Protocol

25 ©2012 MFMER | slide-25 Preliminary results Beriberi: short axisHealthy control: short axis

26 ©2012 MFMER | slide-26 Preliminary results (cont) Beriberi: 4 chamber w/ Doppler Healthy control: 4 chamber w/ Doppler

27 ©2012 MFMER | slide-27 Preliminary results (cont) Beriberi: Day 0 Short-axis Beriberi 24 hours after thiamine treatment

28 ©2012 MFMER | slide-28 Preliminary results (cont) Beriberi: Day 0 4 Chamber Beriberi 24 hours after thiamine treatment

29 ©2012 MFMER | slide-29 Demographic Data of Beriberi Cases 20 beriberi cases 60% male, 40% female Mean age: 10.8 weeks (std. dev: 7.7) Age range: 3 – 31 weeks 30% pure beriberi, 70% mixed

30 ©2012 MFMER | slide-30 The questions continue … How do we predict which thiamine-deficient children will succumb to beriberi? How do we improve thiamine levels on a population scale?

31 ©2012 MFMER | slide-31 Summary Beriberi in infants presents as heart failure and respiratory distress, and is caused by thiamine- deficiency In SE Asia, mothers are thiamine-deficient due to staple diet of polished rice, and their infants do not get enough thiamine from their breast-milk Thiamine deficiency is extremely common among infants and mothers in Prey Veng Province, Cambodia, in both apparently-healthy and sick populations Thiamine deficiency is not related to environmental factors There may be a relationship between thiamine levels and infectious disease, thus making beriberi difficult to diagnose

32 ©2012 MFMER | slide-32

33 ©2012 MFMER | slide-33 Clinician?Teacher? Researcher?

34 ©2012 MFMER | slide-34 Heal the sick. Advance the science.

35 ©2012 MFMER | slide-35 Grants This project was supported by CTSA Grant Number UL1 TR from the National Center for Advancing Translational Science (NCATS), the Benjamin H. Kean Traveling Fellowship in Tropical Medicine from the American Society of Tropical Medicine & Hygiene (ASTMH), and the Hubert Trust Scholarship from Baptist Medical Dental Fellowship (BMDF). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH, ASTMH, or BMDF.

36 ©2012 MFMER | slide-36 References 1: Kauffman, G., D. Coats, et al. (2011). "Thiamine deficiency in ill children." The American Journal of Clinical Nutrition 94(2): ; author reply : Luxemburger, C., N. J. White, et al. (2003). "Beri-beri: the major cause of infant mortality in Karen refugees." Transactions of the Royal Society of Tropical Medicine and Hygiene 97(2): : "Christiaan Eijkman, Beriberi and Vitamin B1". Nobelprize.org. 11 Oct :Lanska, DJ. “Chapter 30: Historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins”, In: Michael J. Aminoff, François Boller and Dick F. Swaab, Editor(s), Handbook of Clinical Neurology, Elsevier, 2009, 95, p , 5: Haridas G. “Infantile beri-beri in Singapore during the latter part of the Japanese occupation.” Arch Dis Child Mar;22(109): :Thanangkul, O. and J. Whitaker (1966). "Childhood thiamin deficiency in Northern Thailand." American Journal of Clinical Nutrition 18: : Luxemburger, C., N. J. White, et al. (2003). "Beri-beri: the major cause of infant mortality in Karen refugees." Transactions of the Royal Society of Tropical Medicine and Hygiene 97(2): : Lima, L. F., H. P. Leite, et al. (2011). "Low blood thiamine concentrations in children upon admission to the intensive care unit: risk factors and prognostic significance." The American Journal of Clinical Nutrition 93(1): : Mayxay, M., A. M. Taylor, et al. (2007). "Thiamin deficiency and uncomplicated falciparum malaria in Laos." Tropical Medicine & International Health : TM & IH 12(3): : Khowsathit, P., B. Pongpanich, et al. (1990). "Cardiac beri-beri. Report of a case with an echocardiographic study." Japanese Heart Journal 31(2): :Rao, S. N. and G. R. Chandak (2010). "Cardiac beriberi: often a missed diagnosis." Journal of Tropical Pediatrics 56(4): : Lowenthal, A., B. V. Camacho, et al. (2012). "Usefulness of B-type natriuretic peptide and N- terminal pro-B-type natriuretic peptide as biomarkers for heart failure in young children with single ventricle congenital heart disease." The American Journal of Cardiology 109(6):

37 ©2012 MFMER | slide-37 Questions?


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