• 1.

    Whitfield KC et al. 2018. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci 1430: 343.

    • Search Google Scholar
    • Export Citation
  • 2.

    Nazir M, Lone R, Charoo BA, 2019. Infantile thiamine deficiency: new insights into an old disease. Indian Pediatr 56: 673681.

  • 3.

    Whitfield KC et al. 2017. High prevalence of thiamine (vitamin B1) deficiency in early childhood among a nationally representative sample of Cambodian women of childbearing age and their children. PLoS Negl Trop Dis 11: e0005814.

    • Search Google Scholar
    • Export Citation
  • 4.

    Barennes H, Sengkhamyong K, René JP, Phimmasane M, 2015. Beriberi (thiamine deficiency) and high infant mortality in northern Laos. PLoS Negl Trop Dis 9: e0003581.

    • Search Google Scholar
    • Export Citation
  • 5.

    Bhat JI et al. 2017. Shoshin beriberi-thiamine responsive pulmonary hypertension in exclusively breastfed infants: a study from northern India. Indian Heart J 69: 2427.

    • Search Google Scholar
    • Export Citation
  • 6.

    Rao SN, Chandak GR, 2010. Cardiac beriberi: often a missed diagnosis. J Trop Pediatr 56: 284285.

  • 7.

    Saya RP, Baikunje S, Prakash PS, Subramanyam K, Patil V, 2012. Clinical correlates and outcome of shoshin beriberi. N Am J Med Sci 4: 503506.

  • 8.

    Cerroni MP et al. 2010. Outbreak of beriberi in an Indian population of the upper Amazon region, Roraima State, Brazil, 2008. Am J Trop Med Hyg 83: 10931097.

    • Search Google Scholar
    • Export Citation
  • 9.

    Imamura T, Kinugawa K, 2015. Shoshin beriberi with low cardiac output and hemodynamic deterioration treated dramatically by thiamine administration. Int Heart J 56: 568570.

    • Search Google Scholar
    • Export Citation
  • 10.

    Coats D et al. 2013. Thiamine pharmacokinetics in Cambodian mothers and their breastfed infants. Am J Clin Nutr 98: 839844.

  • 11.

    Allen LH, 2012. B vitamins in breast milk: relative importance of maternal status and intake, and effects on infant status and function. Adv Nutr 3: 362369.

    • Search Google Scholar
    • Export Citation
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Case Report: Fulminant Infantile Beriberi: A Report of Six Cases

Madhusudan SamprathiRainbow Children’s Hospital, Bannerghatta Road, Bangalore, India

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Faisal MohammadRainbow Children’s Hospital, Bannerghatta Road, Bangalore, India

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Sridhar MRainbow Children’s Hospital, Bannerghatta Road, Bangalore, India

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Prakash RamachandraRainbow Children’s Hospital, Bannerghatta Road, Bangalore, India

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Prakash VemgalRainbow Children’s Hospital, Bannerghatta Road, Bangalore, India

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Abstract.

Thiamine deficiency disorders are an under-recognized public health problem in low- and middle-income countries. Infantile beriberi, the most important symptom for children, is suspected to significantly contribute to infant mortality and lifelong neurodevelopmental morbidity. Lack of awareness, varied clinical presentation, and lack of a readily available diagnostic marker lead to frequent misdiagnoses. We report six thriving infants who presented with an acute fulminant illness with varied clinical manifestations mimicking common childhood illnesses like pneumonia and sepsis. Four of them presented with the severe cardiovascular form, called Shoshin beriberi, and severe pulmonary arterial hypertension. Empirical intravenous thiamine administered to four of the six infants resulted in dramatic recovery. Awareness of the clinical definition of infantile beriberi and treatment with empirical thiamine can be lifesaving.

INTRODUCTION

Thiamine deficiency disorders are an under-recognized public health problem in low- and middle-income countries.1 We report six infants with a fulminant illness. Of the six infants, four recovered dramatically with intravenous thiamine. Awareness, a high level of suspicion, and empirical treatment with thiamine can be lifesaving.

CASE SERIES

  • Case 1 was a 2-month-old boy who presented to a pediatrician with fever and vomiting for 2 days. He experienced lethargy, fast breathing, and seizures on day 5. He was diagnosed with sepsis and meningitis. His heart rate was 120/min, respiratory rate was 60/min, saturation (SpO2) was 80% on room air, and Glasgow coma scale score was 4/15. He had hypotensive cold shock, acidotic breathing, hepatomegaly, severe high anion gap metabolic acidosis, and hyperlactatemia. He was treated in the pediatric intensive care unit with mechanical ventilation, vasoactive drugs, sodium bicarbonate infusion, and antibiotics. Investigations revealed multi-organ dysfunction syndrome (Table 1). Sepsis and inborn error of metabolism (IEM) were considered. An echocardiogram showed a dilated right atrium and right ventricle and moderate tricuspid regurgitation with a gradient of 50 mm Hg, suggesting severe pulmonary arterial hypertension (PAH). Despite high-frequency oscillation and inhaled nitric oxide, he died of worsening shock and hypoxemia within 12 hours.

  • Case 2 was a 2.5-month-old boy who presented with excessive crying, reduced feeding, and peripheral cyanosis for 1 day. He was born at term and weighed 2.3 kg at birth. His heart rate was 172/minute, respiratory rate was 65/minute, SpO2 was 86%, and Glasgow coma scale score was 11/15. He had acidotic breathing and hepatomegaly. Clinical possibilities that were considered were IEM and cyanotic congenital heart disease. His respiratory distress worsened; therefore, he required mechanical ventilation. An echocardiogram showed a dilated right atrium and right ventricle and moderate tricuspid regurgitation with a gradient of 55 mm Hg, suggesting severe PAH. Intravenous sildenafil and oral bosentan were started as treatment. His condition worsened on day 4, with new-onset fever and shock. He died on day 6.

  • Case 3 was a 2-month-old boy with reduced feeding, vomiting, and fast breathing for 1 day. He was diagnosed with pneumonia. He was born at term and weighed 3.5 kg at birth. He had been exclusively breastfed. His heart rate was 186/min, respiratory rate was 50/min, SpO2 was 85% on room air, and SpO2 was 92% on oxygen. He had respiratory distress, hepatomegaly, lethargy, and hypotonia. Blood gas test results indicated severe high anion gap metabolic acidosis and hyperlactatemia. The echocardiogram indicated normal results, with no evidence of PAH. An IEM was suspected. A blood sample was tested using tandem mass spectrometry, with normal results. Intravenous thiamine resulted in a dramatic response and his acidosis resolved within 12 hours.

  • Case 4 was a 3-month-old girl who presented to a pediatrician with vomiting, fast breathing, and seizures for 2 days. She was intubated for respiratory failure and referred to us. She was born at term and weighed 3 kg at birth. Her development was normal. Her heart rate was 146/min and SpO2 was 96% on the ventilator. The examination results indicated hepatomegaly. She was treated in the pediatric intensive care unit with ventilation and epinephrine infusion for shock. Blood gas test results showed mixed metabolic and respiratory acidosis. Her serum procalcitonin level was 0.32. Her echocardiogram was normal. An IEM was suspected. Her blood sugar level, serum electrolyte level, ammonia level, and liver function test results were normal. Empirical intravenous thiamine was administered and she showed a dramatic response. She was extubated within 19 hours. Her tandem mass spectrometry results were subsequently normal.

  • Case 5 was a 3.5-month-old boy born at term. He was exclusively breastfed and developmentally normal. He presented to the outpatient department with vomiting for 7 days. An ultrasonogram of the abdomen ruled out idiopathic hypertrophic pyloric stenosis. Oral ondansetron and domperidone were started. Lansoprazole was added to his treatment because of the suspicion of gastroesophageal reflux disease. He presented to the emergency department the next day with persistent vomiting and fast breathing. His heart rate was 144/minute, respiratory rate was 60/minute, breathing was acidotic, and SpO2 was 82%. He had hepatomegaly. The other examination results were unremarkable. SpO2 failed to improve with oxygen administered through nasal prongs at 2 L/minute. Blood gas test results indicated compensated metabolic acidosis. His echocardiogram showed severe PAH, right ventricular dysfunction, and a small patent foramen ovale with right to left shunt. Intravenous furosemide 1 mg/kg and intravenous thiamine 400 mg were administered. Within 6 to 8 hours, tachypnea resolved, SpO2 was > 94% on room air, and liver size regressed. He was discharged within 24 hours. Echocardiogram repeated 4 weeks later yielded normal results.

  • Case 6 was a 3.5-month-old boy who presented to the emergency department with mild fever, fast breathing, and excessive crying for 1 day. He was born at term and weighed 2.7 kg at birth. He had been exclusively breastfed. His development was normal. At admission, his temperature was 37°C, heart rate was 210/minute, respiratory rate was 50/minute, SpO2 was 83% on room air, capillary refill time was prolonged, extremities were cold, and mean arterial pressure was in the 50th percentile. He had hepatomegaly. Viral pneumonia with myocarditis and sinus tachycardia were considered. Oxygen at 2 L/minute failed to improve the SpO2. Because the respiratory examination and chest X-ray examination results were normal, cyanotic congenital heart disease was suspected. The echocardiogram showed a massively dilated right atrium and right ventricle, tricuspid regurgitation with a gradient of 60 mm Hg, right ventricular dysfunction, and patent foramen ovale with right to left shunt, which are features of severe PAH. Intravenous furosemide 1 mg/kg and empirical intravenous thiamine were administered. Over the next 12 hours, respiratory distress settled, SpO2 was 100% on room air, and he was discharged within 12 hours on oral thiamine, multivitamins, and furosemide. An echocardiogram repeated 4 weeks later indicated normal results.

Table 1

Salient clinical and laboratory features of the six patients

Case 1Case 2Case 3Case 4Case 5Case 6
Age, months/sex2/M2.5/M2/M3/F3/M3.5/M
Duration of illness5 days1 day1 day4 days7 days6 hours
Referral diagnosisSepsis with meningitisCyanotic congenital heart diseasePneumoniaMeningitisGastroesophageal reflux disease
PresentationRespiratory failureRespiratory distressRespiratory distressStatus epilepticusRespiratory distressRespiratory distress
ShockCyanosisEncephalopathyCyanosisCyanosis
EncephalopathyAcidotic breathingRespiratory failureAcidotic breathingAcidotic breathing
Blood count results
Hemoglobin, g%7.448.110.67.412.111.6
Total leukocyte count, /mm331,60015,70019,00011,700930012,000
Differential count N/L, %79/1848/4648/4452/4023/7136/41
Platelets, /mm3470,000480,000650,000630,0001,001,000520,000
Creatinine, mg/dL1.50.60.50.20.40.4
AST/ALT, U/L767/345207/7214/1935/27
C-reactive protein, mg/L0.33231
Blood cultureSterileSterile
Blood gasSevere HAGMASevere HAGMASevere HAGMAHAGMAMetabolic acidosisMild acidosis
EchocardiogramSevere PAHSevere PAHNormalNormalSevere PAHSevere PAH
Ammonia, μmol/L3256
Lactate, mmol/L12Not evaluated230.5Not evaluated5
Urine ketonesNoNoNoNoNot evaluatedNot evaluated
Empirical thiamineNoNo500 mg IV400 mg IV400 mg IV400 mg IV
OutcomeDiedDiedSurvivedSurvivedSurvivedSurvived
Current statusNormalNormalNormalNormal

ALT = alanine aminotransferase; AST = aspartate transaminase; F = female; HAGMA = high anion gap metabolic acidosis; IV = intravenous; M = male; PAH = pulmonary arterial hypertension.

DISCUSSION

Thiamine deficiency disorders comprise the spectrum of clinical presentations caused by thiamine deficiency across all ages.1 Beriberi is the clinical syndrome for children caused by dietary thiamine deficiency. Beriberi can be wet (predominantly affecting the cardiovascular system) or dry (predominantly affecting the peripheral nervous system). Infantile beriberi is the most important presentation for children.

Thiamine deficiency disorders have a reported prevalence of 27% to 78% for mothers and 15% to 58% for children.14 Nonspecific clinical features, varied organ involvement, inadequate awareness, and nonavailability of diagnostic markers lead to frequent misdiagnoses.

As seen in all six patients, infantile beriberi classically occurs after 2 months of life. The thiamine content of breast milk depends on the maternal thiamine status. Thiamine levels are higher in newborns and decline rapidly during the third month of life.1

All six patients had multiple risk factors, including increased demand for thiamine caused by pregnancy and lactation, high consumption of thiamine-deficient staple foods (especially polished rice), faulty practices (washing rice multiple times before cooking, food taboos in the postpartum period) and consumption of thiamine-destroying substances (tea, betel nut, raw fish). In an exclusively breastfed baby with these risk factors, fever (because of infection or vaccination) can acutely increase the demand for thiamine and precipitate the fulminant form of infantile beriberi.1

All these patients were well-thriving, exclusively breastfed infants who presented with a fulminant illness. Infantile beriberi can mimic pneumonia, sepsis with multi-organ dysfunction syndrome, cyanotic congenital heart disease, and IEM; these diseases can also present concurrently with infantile beriberi, thereby complicating the diagnosis. Most infants present with tachypnea, tachycardia, shock, hepatomegaly, and lactic acidosis.46

Erythrocyte transketolase assays and thiamine diphosphate levels in whole blood or erythrocytes can be used to assess the thiamine status; however, their cost, difficulty, and lack of availability and standardization limit their routine use.1 A clinical definition has been proposed for early suspicion1; the response to thiamine (50–100 mg intravenous) is the gold standard for diagnosis. The cases of all six of these patients fulfilled this definition. The four patients who were administered empirical thiamine recovered dramatically.

The fulminant form of cardiovascular beriberi, called Shoshin beriberi is common for adults but rare for infants; however, four of these six patients had Shoshin beriberi.7––9 The presence of all of the following is diagnostic for cardiac beriberi: cardiomegaly with normal sinus rhythm; metabolic acidosis; no other evident cause; and prompt response to thiamine.5,6 Two of the four infants who were administered thiamine recovered completely and fulfilled all of the aforementioned criteria. The other two who died were not administered thiamine because of a lack of clinical suspicion. Their diagnoses were inconclusive, but their presentations satisfied the clinical definition and were prototypical of warranting a therapeutic challenge of thiamine.1

Thiamine deficiency preferentially injures tissues with a high metabolic requirement. The pathogenesis of cardiac beriberi is not clear. Impaired myocardial energy production and myocardial damage causing increased left ventricular end diastolic pressure are possible mechanisms.2,5

The four infants who survived and their mothers are using oral thiamine supplementation and are thriving well. Long-term maternal thiamine supplementation can improve thiamine concentrations in breast milk.10,11 These infants need careful follow-up because persistent cognitive and motor deficits can occur.1 Food fortification, supplementation, optimizing dietary intake, and health education are important preventive strategies.

Infantile beriberi should be suspected for all acutely ill infants, especially when they present with PAH and lactic acidosis in the absence of congenital heart disease. Prompt recovery with empirical thiamine can confirm the diagnosis and avoid unnecessary investigations and therapy. Timely recognition and treatment can be lifesaving and life-changing. Treatment is simple and inexpensive; however, awareness and a high level of suspicion are crucial.

Acknowledgment:

The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses.

REFERENCES

  • 1.

    Whitfield KC et al. 2018. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci 1430: 343.

    • Search Google Scholar
    • Export Citation
  • 2.

    Nazir M, Lone R, Charoo BA, 2019. Infantile thiamine deficiency: new insights into an old disease. Indian Pediatr 56: 673681.

  • 3.

    Whitfield KC et al. 2017. High prevalence of thiamine (vitamin B1) deficiency in early childhood among a nationally representative sample of Cambodian women of childbearing age and their children. PLoS Negl Trop Dis 11: e0005814.

    • Search Google Scholar
    • Export Citation
  • 4.

    Barennes H, Sengkhamyong K, René JP, Phimmasane M, 2015. Beriberi (thiamine deficiency) and high infant mortality in northern Laos. PLoS Negl Trop Dis 9: e0003581.

    • Search Google Scholar
    • Export Citation
  • 5.

    Bhat JI et al. 2017. Shoshin beriberi-thiamine responsive pulmonary hypertension in exclusively breastfed infants: a study from northern India. Indian Heart J 69: 2427.

    • Search Google Scholar
    • Export Citation
  • 6.

    Rao SN, Chandak GR, 2010. Cardiac beriberi: often a missed diagnosis. J Trop Pediatr 56: 284285.

  • 7.

    Saya RP, Baikunje S, Prakash PS, Subramanyam K, Patil V, 2012. Clinical correlates and outcome of shoshin beriberi. N Am J Med Sci 4: 503506.

  • 8.

    Cerroni MP et al. 2010. Outbreak of beriberi in an Indian population of the upper Amazon region, Roraima State, Brazil, 2008. Am J Trop Med Hyg 83: 10931097.

    • Search Google Scholar
    • Export Citation
  • 9.

    Imamura T, Kinugawa K, 2015. Shoshin beriberi with low cardiac output and hemodynamic deterioration treated dramatically by thiamine administration. Int Heart J 56: 568570.

    • Search Google Scholar
    • Export Citation
  • 10.

    Coats D et al. 2013. Thiamine pharmacokinetics in Cambodian mothers and their breastfed infants. Am J Clin Nutr 98: 839844.

  • 11.

    Allen LH, 2012. B vitamins in breast milk: relative importance of maternal status and intake, and effects on infant status and function. Adv Nutr 3: 362369.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Madhusudan Samprathi, Rainbow Children’s Hospital, Bannerghatta Road, Bangalore, India. E-mail: madhu_1511@yahoo.com

Authors’ addresses: Madhusudan Samprathi, Faisal Mohammad, Sridhar M, Prakash Ramachandra, and Prakash Vemgal, Rainbow Children’s Hospital, Bannerghatta Road, Bangalore, India, E-mails: madhu_1511@yahoo.com, faisal20_1897@yahoo.co.in, docsridhara@gmail.com, drprakashr@gmail.com, and pvemgal@hotmail.com.

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