Vitamin B1 deficiency is a clinical diagnosis and can present in several ways depending on the cause of deficiency, presence of comorbidities, age, and general susceptibility.[7]Polegato BF, Pereira AG, Azevedo PS, et al. Role of thiamin in health and disease. Nutr Clin Pract. 2019 Aug;34(4):558-64.
http://www.ncbi.nlm.nih.gov/pubmed/30644592?tool=bestpractice.com
Patient history may include excessive alcohol consumption and poor nutritional status. Enquire about the patient’s medical history (e.g., bariatric surgery, chemotherapy). Drug history should be reviewed; diuretic therapy (e.g., furosemide) has been associated with vitamin B1 deficiency.[49]Katta N, Balla S, Alpert MA. Does long-term furosemide therapy cause thiamine deficiency in patients with heart failure? A focused review. Am J Med. 2016 Jul;129(7):753.e7-11.
https://www.amjmed.com/article/S0002-9343(16)30171-1/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/26899752?tool=bestpractice.com
[50]Bicer I, Dizdar OS, Dondurmacı E, et al. Furosemide-related thiamine deficiency in hospitalized hypervolemic patients with renal failure and heart failure. Nefrologia (Engl Ed). 2023 Jan-Feb;43(1):111-9.
https://www.revistanefrologia.com/es-linkresolver-furosemide-related-thiamine-deficiency-in-hospitalized-S2013251422001389
http://www.ncbi.nlm.nih.gov/pubmed/36437201?tool=bestpractice.com
[51]Gundogan K, Akbudak IH, Bulut K, et al. Thiamin status in adults receiving chronic diuretic therapy prior to admission to a medical intensive care unit: a pilot study. Nutr Clin Pract. 2019 Aug;34(4):565-71.
http://www.ncbi.nlm.nih.gov/pubmed/30644614?tool=bestpractice.com
As the presenting symptoms are non-specific, it is important to ascertain whether the patient has any risk factors for vitamin B1 deficiency. There should be a low threshold for the initiation of treatment.[1]Berger MM, Shenkin A, Schweinlin A, et al. ESPEN micronutrient guideline. Clin Nutr. 2022 Jun;41(6):1357-424.
https://www.clinicalnutritionjournal.com/article/S0261-5614(22)00066-8/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/35365361?tool=bestpractice.com
[55]Sriram K, Manzanares W, Joseph K. Thiamine in nutrition therapy. Nutr Clin Pract. 2012 Feb;27(1):41-50.
http://www.ncbi.nlm.nih.gov/pubmed/22223666?tool=bestpractice.com
Patients at risk of vitamin B1 deficiency and those presenting with signs and symptoms of Wernicke's encephalopathy, wet beriberi, or dry beriberi should be treated with thiamine replacement therapy immediately and the response to treatment recorded while investigations to exclude other diagnoses are ongoing.[44]Smith TJ, Johnson CR, Koshy R, et al. Thiamine deficiency disorders: a clinical perspective. Ann N Y Acad Sci. 2021 Aug;1498(1):9-28.
https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.14536
http://www.ncbi.nlm.nih.gov/pubmed/33305487?tool=bestpractice.com
Clinical improvement with thiamine replacement therapy suggests a diagnosis of vitamin B1 deficiency.[7]Polegato BF, Pereira AG, Azevedo PS, et al. Role of thiamin in health and disease. Nutr Clin Pract. 2019 Aug;34(4):558-64.
http://www.ncbi.nlm.nih.gov/pubmed/30644592?tool=bestpractice.com
Clinical features
Patient signs and symptoms may suggest the following.
Subclinical deficiency
Early stages of vitamin B1 deficiency present with non-specific symptoms, such as fatigue and muscle aches.[41]Marrs C, Lonsdale D. Hiding in plain sight: modern thiamine deficiency. Cells. 2021 Sep 29;10(10):2595.
https://www.mdpi.com/2073-4409/10/10/2595
http://www.ncbi.nlm.nih.gov/pubmed/34685573?tool=bestpractice.com
Wernicke's encephalopathy
Characterised by the classic triad of altered mental status, ataxia, and ocular abnormalities (e.g., nystagmus and strabismus), although vague presenting features may also be seen.[56]Isen DR, Kline LB. Neuro-ophthalmic manifestations of Wernicke encephalopathy. Eye Brain. 2020 Jun 30;12:49-60.
https://www.dovepress.com/neuro-ophthalmic-manifestations-of-wernicke-encephalopathy-peer-reviewed-fulltext-article-EB
http://www.ncbi.nlm.nih.gov/pubmed/32636690?tool=bestpractice.com
[57]Chamorro AJ, Rosón-Hernández B, Medina-García JA, et al. Differences between alcoholic and nonalcoholic patients with Wernicke encephalopathy: a multicenter observational study. Mayo Clin Proc. 2017 Jun;92(6):899-907.
http://www.ncbi.nlm.nih.gov/pubmed/28578781?tool=bestpractice.com
The classic triad of symptoms was present in 39% of patients in one retrospective cohort study of patients in Spain.[57]Chamorro AJ, Rosón-Hernández B, Medina-García JA, et al. Differences between alcoholic and nonalcoholic patients with Wernicke encephalopathy: a multicenter observational study. Mayo Clin Proc. 2017 Jun;92(6):899-907.
http://www.ncbi.nlm.nih.gov/pubmed/28578781?tool=bestpractice.com
Wernicke’s encephalopathy is the most common form of thiamine deficiency in adults and older children.[10]Whitfield KC, Bourassa MW, Adamolekun B, et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci. 2018 Oct;1430(1):3-43.
https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.13919
http://www.ncbi.nlm.nih.gov/pubmed/30151974?tool=bestpractice.com
Wet beriberi
Cardiac sequelae in wet beriberi can occur with acute or chronic deficiency. These can manifest as high-output cardiac failure with peripheral vasodilation, dependent oedema, dyspnoea, and orthopnoea. Shoshnin beriberi occurs less frequently, and is characterised by low-output cardiac failure with lactic acidosis (due to hypoperfusion).[7]Polegato BF, Pereira AG, Azevedo PS, et al. Role of thiamin in health and disease. Nutr Clin Pract. 2019 Aug;34(4):558-64.
http://www.ncbi.nlm.nih.gov/pubmed/30644592?tool=bestpractice.com
Dry beriberi
Presents as a symmetrical distal peripheral polyneuropathy (particularly of the legs).[7]Polegato BF, Pereira AG, Azevedo PS, et al. Role of thiamin in health and disease. Nutr Clin Pract. 2019 Aug;34(4):558-64.
http://www.ncbi.nlm.nih.gov/pubmed/30644592?tool=bestpractice.com
Characterised by paraesthesia, reduced knee jerks and other tendon reflexes, and progressive severe weakness with muscle wasting.
Gastrointestinal (GI) beriberi
Presents with abdominal pain and minimal clinical findings on examination.
Infantile beriberi
Mostly occurs in infants exclusively breastfed by vitamin B1-deficient mothers, and exists in three forms: cardiogenic (cardiac failure and cyanosis), aphonic (vocal-cord paralysis), and pseudo-meningitic (clinical meningismus with negative cerebrospinal fluid [CSF] findings).[10]Whitfield KC, Bourassa MW, Adamolekun B, et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci. 2018 Oct;1430(1):3-43.
https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.13919
http://www.ncbi.nlm.nih.gov/pubmed/30151974?tool=bestpractice.com
In younger infants (<4 months), early signs are non-specific, including irritability, refusal to breastfeed, tachycardia and tachypnoea, vomiting, and incessant crying.[10]Whitfield KC, Bourassa MW, Adamolekun B, et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci. 2018 Oct;1430(1):3-43.
https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.13919
http://www.ncbi.nlm.nih.gov/pubmed/30151974?tool=bestpractice.com
As the disease progresses, signs and symptoms of congestive heart failure begin to appear (e.g., shortness of breath, hepatomegaly, and cyanosis).[10]Whitfield KC, Bourassa MW, Adamolekun B, et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci. 2018 Oct;1430(1):3-43.
https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.13919
http://www.ncbi.nlm.nih.gov/pubmed/30151974?tool=bestpractice.com
Pulmonary hypertension has also been reported.[58]Qureshi UA, Bhat AS, Qureshi U, et al. Infantile thiamine deficiency: Redefining the clinical patterns. Nutrition. 2021 Apr;84:111097.
http://www.ncbi.nlm.nih.gov/pubmed/33461052?tool=bestpractice.com
[59]Sastry UMK, M J, Kumar RK, et al. Thiamine-responsive acute severe pulmonary hypertension in exclusively breastfeeding infants: a prospective observational study. Arch Dis Child. 2021 Mar;106(3):241-6.
https://adc.bmj.com/content/106/3/241.long
http://www.ncbi.nlm.nih.gov/pubmed/32883659?tool=bestpractice.com
Older infants may present with predominant neurological symptoms, including loss of appetite, nystagmus, bulging fontanelle, and loss of consciousness.[10]Whitfield KC, Bourassa MW, Adamolekun B, et al. Thiamine deficiency disorders: diagnosis, prevalence, and a roadmap for global control programs. Ann N Y Acad Sci. 2018 Oct;1430(1):3-43.
https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.13919
http://www.ncbi.nlm.nih.gov/pubmed/30151974?tool=bestpractice.com
Consider thiamine metabolism dysfunction syndrome when clinical presentation cannot otherwise be explained.
Thiamine metabolism dysfunction syndrome (THMD) comprises rare genetic disorders that impact vitamin B1 metabolism. Thiamine-responsive megaloblastic anaemia (TRMA) syndrome is characterised by thiamine-responsive anaemia, diabetes, and deafness. It is caused by recessively inherited mutations in the SLC19A2 gene.[28]Marcé-Grau A, Martí-Sánchez L, Baide-Mairena H, et al. Genetic defects of thiamine transport and metabolism: a review of clinical phenotypes, genetics, and functional studies. J Inherit Metab Dis. 2019 Jul;42(4):581-97.
http://www.ncbi.nlm.nih.gov/pubmed/31095747?tool=bestpractice.com
[29]Habeb AM, Flanagan SE, Zulali MA, et al. Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome. Diabetologia. 2018 May;61(5):1027-36.
https://link.springer.com/article/10.1007/s00125-018-4554-x
http://www.ncbi.nlm.nih.gov/pubmed/29450569?tool=bestpractice.com
Mutations in SLC19A3, TPK1, and SLC25A19 genes predominantly result in neurological sequelae with episodic encephalopathy, often triggered by febrile illness or infection.[27]Ortigoza-Escobar JD, Alfadhel M, Molero-Luis M, et al. Thiamine deficiency in childhood with attention to genetic causes: survival and outcome predictors. Ann Neurol. 2017 Sep;82(3):317-30.
http://www.ncbi.nlm.nih.gov/pubmed/28856750?tool=bestpractice.com
[28]Marcé-Grau A, Martí-Sánchez L, Baide-Mairena H, et al. Genetic defects of thiamine transport and metabolism: a review of clinical phenotypes, genetics, and functional studies. J Inherit Metab Dis. 2019 Jul;42(4):581-97.
http://www.ncbi.nlm.nih.gov/pubmed/31095747?tool=bestpractice.com
Further investigations
While vitamin B1 deficiency is associated with lactic acidosis and a raised lactate, their presence is not diagnostic and their absence does not exclude the deficiency.[44]Smith TJ, Johnson CR, Koshy R, et al. Thiamine deficiency disorders: a clinical perspective. Ann N Y Acad Sci. 2021 Aug;1498(1):9-28.
https://nyaspubs.onlinelibrary.wiley.com/doi/10.1111/nyas.14536
http://www.ncbi.nlm.nih.gov/pubmed/33305487?tool=bestpractice.com
Depending on the context, it may be appropriate to investigate other possible causes of metabolic acidosis (e.g., salicylate toxicity, diabetic ketoacidosis, uraemia).
All patients presenting in high-output cardiac failure should have urgent thyroid function tests to rule out thyrotoxicosis.[60]Anand IS. High-output heart failure revisited. J Am Coll Cardiol. 2016 Aug 2;68(5):483-6.
https://www.sciencedirect.com/science/article/pii/S0735109716332600
http://www.ncbi.nlm.nih.gov/pubmed/27470456?tool=bestpractice.com
Thyrotoxicosis is represented by raised free thyroxine (T4)/triiodothyronine (T3) and suppressed thyroid-stimulating hormone (TSH). It may be appropriate to investigate other possible causes of high-output cardiac failure, depending on the presentation.[60]Anand IS. High-output heart failure revisited. J Am Coll Cardiol. 2016 Aug 2;68(5):483-6.
https://www.sciencedirect.com/science/article/pii/S0735109716332600
http://www.ncbi.nlm.nih.gov/pubmed/27470456?tool=bestpractice.com
Magnetic resonance imaging (MRI) of the brain is useful to support a diagnosis of Wernicke's encephalopathy.[13]Galvin R, Bråthen G, Ivashynka A, et al. EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol. 2010 Dec;17(12):1408-18.
https://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2010.03153.x
http://www.ncbi.nlm.nih.gov/pubmed/20642790?tool=bestpractice.com
[61]Manzo G, De Gennaro A, Cozzolino A, et al. MR imaging findings in alcoholic and nonalcoholic acute Wernicke's encephalopathy: a review. Biomed Res Int. 2014;2014:503596.
https://onlinelibrary.wiley.com/doi/10.1155/2014/503596
http://www.ncbi.nlm.nih.gov/pubmed/25050351?tool=bestpractice.com
In Wernicke’s encephalopathy, sensitivity is 53% and specificity is 93%.[13]Galvin R, Bråthen G, Ivashynka A, et al. EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol. 2010 Dec;17(12):1408-18.
https://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2010.03153.x
http://www.ncbi.nlm.nih.gov/pubmed/20642790?tool=bestpractice.com
[62]Chung SP, Kim SW, Yoo IS. Magnetic resonance imaging as a diagnostic adjunct to Wernicke's encephalopathy in the ED. Am J Emerg Med. 2003 Oct;21(6):497-502.
http://www.ncbi.nlm.nih.gov/pubmed/14574661?tool=bestpractice.com
MRI changes in Wernicke's encephalopathy are often described as bilateral and symmetrical lesions in the thalamus, mammillary bodies, tectal plate, and periaqueductal region on T2-weighted imaging or fluid-attenuated inversion recovery (FLAIR) sequence.[13]Galvin R, Bråthen G, Ivashynka A, et al. EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy. Eur J Neurol. 2010 Dec;17(12):1408-18.
https://onlinelibrary.wiley.com/doi/10.1111/j.1468-1331.2010.03153.x
http://www.ncbi.nlm.nih.gov/pubmed/20642790?tool=bestpractice.com
[61]Manzo G, De Gennaro A, Cozzolino A, et al. MR imaging findings in alcoholic and nonalcoholic acute Wernicke's encephalopathy: a review. Biomed Res Int. 2014;2014:503596.
https://onlinelibrary.wiley.com/doi/10.1155/2014/503596
http://www.ncbi.nlm.nih.gov/pubmed/25050351?tool=bestpractice.com
Echocardiography may be useful for diagnosis of wet beriberi and to help guide management.[7]Polegato BF, Pereira AG, Azevedo PS, et al. Role of thiamin in health and disease. Nutr Clin Pract. 2019 Aug;34(4):558-64.
http://www.ncbi.nlm.nih.gov/pubmed/30644592?tool=bestpractice.com