©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

©2012 MFMER | slide-1

Beriberi Treatment: What a medical student can teach us all

Philip Fischer, M.D., and Samuel Porter

Global Missions Health ConferenceNovember 9th, 2012


Prey Veng Province, Cambodia


Debbie Coats, FNP

• Svay Chrum Health Clinic

• Previously-healthy infants presenting with tachypnea, tachycardia, hepatomegaly, and no fever.


Beriberi – a significant killer

• Verbal autopsy study in Prey Veng, Cambodia1

• 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 beriberi2

• Reports from all over SE Asia2

1: Kauffman, G., D. Coats, et al. (2011). "Thiamine deficiency in ill children." The American Journal of Clinical Nutrition 94(2): 616-617; author reply 617.2: 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): 251-255.


“I cannot, I cannot”

• 1870 Marked increase in beriberi incidence in SE Asia3

• 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 2012 http://www.nobelprize.org/educational/medicine/vitamin_b1/eijkman.html 4: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 445-476,


On a molecular level …


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)


Japanese Occupation of Singapore

• First observational study in infants 5

• 1947, 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. 1947 Mar;22(109):23-33.


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 days5:Haridas G. “Infantile beri-beri in Singapore during the latter part of the Japanese occupation.” Arch Dis Child. 1947 Mar;22(109):23-33. 6:Thanangkul, O. and J. Whitaker (1966). "Childhood thiamin deficiency in Northern Thailand." American Journal of Clinical Nutrition 18: 275-277.7: 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): 251-255.


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 20th 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): 251-255.


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?


Medical Student #1: Kelsey Shelton-Dodge

27 beriberi cases & mothers

27 healthy controls

(Cambodia) & mothers

20 healthy controls (USA) & mothers

Blood draw Blood draw

Blood drawSurvey Survey


Results

27 beriberi cases & mothers

27 healthy controls

(Cambodia) & mothers

20 healthy controls (USA) & mothers

Thiamine: Low

Thiamine: Low

Thiamine: Normal

NO difference

in thiamine

levels

=


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


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?


Medical Student #2: Liz Keating

50 infants presenting with tachypnea

Blood draw

Clinical & Lab

Variables


Results

• No clinical or lab data correlates to thiamine levels

• Even infants not treated with thiamine had improved thiamine levels at discharge.


Implications

• How do we diagnose beriberi?


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): 57-61.9: Mayxay, M., A. M. Taylor, et al. (2007). "Thiamin deficiency and uncomplicated falciparum malaria in Laos." Tropical Medicine & International Health : TM & IH 12(3): 363-369.


Medical Student #3: Sam Porter

• Beriberi will show right-sided heart failure10,11

• 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-BNP12

10: Khowsathit, P., B. Pongpanich, et al. (1990). "Cardiac beri-beri. Report of a case with an echocardiographic study." Japanese Heart Journal 31(2): 265-269.11:Rao, S. N. and G. R. Chandak (2010). "Cardiac beriberi: often a missed diagnosis." Journal of Tropical Pediatrics 56(4): 284-285.12: 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): 866-872.


Methods

20 beriberi cases

45 healthy controls

Blood draw: Day 0 & 2

Echocardiogram:

Day 0, 1 & 2

Blood draw: Day 0

Echocardiogram:

Day 0


Working with a team


Fitting into the culture (not vice versa)


The Protocol


Preliminary results

Beriberi: short axis Healthy control: short axis


Preliminary results (cont)

Beriberi: 4 chamber w/

Doppler

Healthy control: 4 chamber w/

Doppler



Beriberi: Day 0

Short-axis

Beriberi 24 hours after thiamine

treatment



Beriberi: Day 0

4 Chamber

Beriberi 24 hours after thiamine

treatment


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


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?


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



Clinician? Teacher? Researcher?


Heal the sick. Advance the science.


Grants

This project was supported by CTSA Grant Number UL1 TR000135 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.


References 1: Kauffman, G., D. Coats, et al. (2011). "Thiamine deficiency in ill children." The American Journal of Clinical

Nutrition 94(2): 616-617; author reply 617.2: 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): 251-255.3: "Christiaan Eijkman, Beriberi and Vitamin B1". Nobelprize.org. 11 Oct 2012

http://www.nobelprize.org/educational/medicine/vitamin_b1/eijkman.html 4: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 445-476,

5: Haridas G. “Infantile beri-beri in Singapore during the latter part of the Japanese occupation.” Arch Dis Child. 1947 Mar;22(109):23-33.

6:Thanangkul, O. and J. Whitaker (1966). "Childhood thiamin deficiency in Northern Thailand." American Journal of Clinical Nutrition 18: 275-277.

7: 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): 251-255.

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): 57-61.

9: Mayxay, M., A. M. Taylor, et al. (2007). "Thiamin deficiency and uncomplicated falciparum malaria in Laos." Tropical Medicine & International Health : TM & IH 12(3): 363-369.

10: Khowsathit, P., B. Pongpanich, et al. (1990). "Cardiac beri-beri. Report of a case with an echocardiographic study." Japanese Heart Journal 31(2): 265-269.

11:Rao, S. N. and G. R. Chandak (2010). "Cardiac beriberi: often a missed diagnosis." Journal of Tropical Pediatrics 56(4): 284-285.

12: 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): 866-872.


Questions?

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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