Beriberi (Thiamine Deficiency)

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Practice Essentials

Thiamine deficiency, or beriberi, refers to the lack of thiamine pyrophosphate, the active form of the vitamin known as thiamine (also spelled thiamin), or vitamin B-1 (see the image below). Thiamine pyrophosphate, the biologically active form of thiamine, acts as a coenzyme in carbohydrate metabolism through the decarboxylation of alpha ketoacids. It also takes part in the formation of glucose by acting as a coenzyme for the transketolase in the pentose monophosphate pathway. (See Treatment and Medication.)



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Beriberi in an adult patient.

See 21 Hidden Clues to Diagnosing Nutritional Deficiencies, a Critical Images slideshow, to help identify clues to conditions associated with malnutrition.

Thiamine is a water-soluble vitamin that is absorbed in the jejunum by 2 processes. When the thiamine level in the small intestines is low, an active transport portal is responsible for absorption. When the thiamine concentration is high, a passive mucosal process takes place. Up to 5 mg of thiamine is absorbed through the small intestines. The small intestine is where phosphorylation of thiamine takes place.[1]

The body cannot produce thiamine and can only store up to 30 mg of it in tissues. Thiamine is mostly concentrated in the skeletal muscles. Other organs in which it is found are the brain, heart, liver, and kidneys. The half-life of thiamine is 9-18 days. It is excreted by the kidney.[2, 3, 4, 5]

Persons may become deficient in thiamine by not ingesting enough vitamin B-1 through the diet or may become deficient through excess use; the latter may result from hyperthyroidism, pregnancy, lactation, or fever. Prolonged diarrhea may impair the body's ability to absorb vitamin B-1, and severe liver disease impairs its use. (See Pathophysiology, Etiology, Presentation, and Workup.)[6, 7]

Dietary thiamine

Food that are rich in thiamine are as follows[1] (see Table 1, below):

Thiamine is not present in fats or highly refined sugars and is present sparingly in cassava. Foods containing thiaminases, such as milled rice, shrimp, mussels, clams, fresh fish, and raw animal tissues, decrease absorption.[8]

Cassava is a staple in many developing countries and has been used in a variety of high-energy diets. Although it contains thiamine (0.05-0.225 mg of thiamine per 100 g of cassava, depending on the crop), the high carbohydrate load of a diet rich in cassava actually consumes more thiamine than it offers the body. This can produce a thiamine deficiency through the same mechanism observed when dextrose is administered to a person with limited supplies of the vitamin.

Table. Nutritional Needs for Specific Age Groups[9]



View Table

See Table

Patient education

Include education regarding Korsakoff syndrome (which arises from thiamine deficiency) for patients being treated for alcohol dependency, one of the causes of thiamine deficiency. As with any substance abuse treatment program, education needs to be combined with a serious, multidisciplinary team approach to have any chance of success.

With other causes of beriberi, once the primary problem has been addressed, an appropriate diet providing more-than-adequate thiamine levels should be adopted by the patient.

Diagnosis

For practical reasons, replacing thiamine as an initial test may be most feasible. If the patient responds to treatment, it is safe to assume that a measure of thiamine deficiency was responsible for the condition.

If laboratory confirmation is needed, measure blood thiamine, pyruvate, alpha-ketoglutarate, lactate, and glyoxylate levels. Also, measure urinary excretion of thiamine and its metabolites. A scarcity of any of these chemicals strongly suggests thiamine deficiency.[10]

In conjunction with whole blood or erythrocyte transketolase activity preloading and postloading, a thiamine loading test is the best indicator of thiamine deficiency. An increase of more than 15% in enzyme activity is a definitive marker of deficiency. However, this test is expensive and time consuming; it is performed only for criterion-standard proof of deficiency.

Measure urinary methylglyoxal; also measure serum thyroid-stimulating hormone (TSH), to rule out thyrotoxicosis-induced high-output heart failure, if applicable.

Management

In suspected cases of thiamine deficiency, prompt administration of parenteral thiamine is indicated. The recommended dose is 50 mg given intramuscularly for several days. The duration of therapy depends on the symptoms, and therapy is indicated until all symptoms have disappeared. Maintenance is recommended at 2.5-5 mg per day orally unless a malabsorption syndrome is suspected.

Most outpatient care is targeted at delivering thiamine in a bioavailable form to rehabilitated patients. Clinical follow-up with measurement of thiamine diphosphate activity may be warranted if relapse or noncompliance is suspected.

Pathophysiology

When healthy individuals are deprived of thiamine, thiamine stores are depleted within 1 month. However, within a week after thiamine intake stops, healthy people develop a resting tachycardia, weakness, and decreased deep tendon reflexes; some people develop a peripheral neuropathy.

Dry beriberi

Thiamine deficiency with nervous system involvement is termed dry beriberi.[11] This presentation usually occurs when poor caloric intake and relative physical inactivity are present. The neurologic findings can be peripheral neuropathy characterized by symmetrical impairment of sensory, motor, and reflex functions of the extremities, especially in the distal lower limbs. Histologic analysis has shown that the lesions arise from a degeneration of the myelin in the muscular sheaths without inflammation.

Another presentation of neurologic involvement is Wernicke encephalopathy,[12] in which an orderly sequence of symptoms occurs, including vomiting, horizontal nystagmus, palsies of the eye movements, fever, ataxia, and progressive mental impairment leading to Korsakoff syndrome.[13, 14, 15, 16] Improvement can be achieved at any stage by the addition of thiamine, unless the patient is in frank Korsakoff syndrome. Only half of the patients treated at this stage recover significantly.

Wet beriberi

Wet beriberi is the term used for thiamine deficiency with cardiovascular involvement. The chronic form of wet beriberi consists of 3 stages. In the first stage, peripheral vasodilation occurs, leading to a high cardiac output state. This leads to salt and water retention mediated through the renin-angiotensin-aldosterone system in the kidneys. As the vasodilation progresses, the kidneys detect a relative loss of volume and respond by conserving salt. With the salt retention, fluid is also absorbed into the circulatory system. The resulting fluid overload leads to edema of the dependent extremities.

By the time significant edema occurs, the heart has been exposed to a severely high workload in order to pump the required cardiac output needed to satisfy end organ requirements. Parts of the heart muscle undergo overuse injury, which results in the physical symptoms of tachycardia, edema, and high arterial and venous pressures. These changes can lead to myocardial injury, expressed as chest pain.

A more rapid form of wet beriberi is termed acute fulminant cardiovascular beriberi, or Shoshin beriberi. The predominant injury is to the heart, and rapid deterioration follows the inability of the heart muscle to satisfy the body's demands because of its own injury. In this case, edema may not be present. Instead, cyanosis of the hands and feet, tachycardia, distended neck veins, restlessness, and anxiety occur. Treatment with thiamine causes low-output cardiac failure, because systemic vasoconstriction is reinstated before the heart muscle recovers. Support of heart function is an added requirement at this stage, and recovery is usually fairly quick and complete if treatment is initiated promptly. However, if no treatment is available, death occurs just as rapidly (within hours or days).

Etiology

Lack of thiamine intake

Lack of thiamine intake can occur via diets consisting mainly of the following:

The following diet-related factors can also cause reduced thiamine intake:

Increased consumption states

Increased metabolic consumption of thiamine can result from the following:

Increased depletion

Increased thiamine depletion can result from the following[23] :

Loss of thiamine through renal excretion can occur with most, if not all, diuretics. It has been seen with the use of such diuretics as mannitol, acetazolamide, chlorothiazide, amiloride, and loop diuretics.[25] Thiamine loss is associated with the increase in urine flow rate, but it is not related to sodium excretion. This suggests that patients with polyuria, even if the condition is unrelated to diuretics, may benefit from thiamine supplementation.

One cross-sectional observational study showed that up to 33% of patients admitted with a diagnosis of congestive heart failure (CHF) had a thiamine deficiency due to chronic loop diuretic use, usually for more than 1 month.[26] (However, thiamine deficiency found in patients with heart failure has been present in up to 98% of patients in other studies.[1] )

Risk factors for the development of thiamine deficiency in the study's patients consisted of the following:

Repletion of thiamine in patients with CHF has been shown to improve left ventricular function.

Decreased absorption

The following factors can result in decreased thiamine absorption:

Bariatric weight-loss surgery

In a study of 59 superobese patients who underwent bariatric weight-loss surgery, Aasheim et al concluded that the risk of thiamine deficiency in the first months following a duodenal switch procedure may be higher than it is after a gastric bypass, while the risk of vitamin A and D deficiencies following duodenal switch surgery may be greater in the first year than it is after gastric bypass.

The investigators compared the vitamin status of individuals who underwent laparoscopic Roux-en-Y gastric bypass to that of patients in whom laparoscopic biliopancreatic diversion with duodenal switch was performed.[27] The investigators found that following surgery, a steeper drop in thiamine levels occurred in the duodenal switch patients than in the patients who underwent gastric bypass. In addition, mean concentrations of vitamin A and 25-hydroxyvitamin D were lower in the duodenal switch group. Follow-up examinations were conducted at 6 weeks, 6 months, and 1 year after surgery.

The term bariatric beriberi is coined from this etiology.[22]

Folate deficiency

Thiamine serves as a coenzyme (in the form of thiamine pyrophosphate) in a variety of metabolic processes. In these processes, thiamine pyrophosphate is regenerated via the donation of a proton from the reduced form of nicotinamide adenine dinucleotide (NADH).

Folic acid is essential to having enough dihydrofolate reductase to regenerate NADH from its oxidative form. This regeneration allows NADH to continue to be present to regenerate thiamine pyrophosphate without being consumed in the process.

If folic acid is deficient in cells, it causes an indirect thiamine deficiency, because thiamine is present but cannot be activated.

Infantile beriberi

Infantile beriberi occurs in infants aged 2-4 months who are fed only breast milk and whose mothers are thiamine deficient.[28, 29]

Other

A retrospective study by Nath et al indicated that obesity is a risk factor for clinical thiamine deficiency, with such deficiency found in 66 out of 400 patients with a body mass index of 35 kg/m2 or above (16.5%).[30]

Epidemiology

Occurrence in the United States

Beriberi is observed in developed nations in persons with alcoholism, people on fad diets, persons on long-term peritoneal dialysis without thiamine replacement, persons undergoing long-term starvation, or persons receiving intravenous fluids with high glucose concentration. No accurate statistics are available on the incidence of this condition.

International occurrence

Developing countries are known to have more vitamin deficiency problems in general, but there has been a lack of accurate statistics for thiamine deficiency. Beriberi has been reported among refugees who are relying on emergency food aid.[31] This is due to the lack of available micronutrition supplementation.

A study by Whitfield et al found a high incidence of thiamine deficiency in Cambodia among mothers and their young children. Using a nationally representative population sample of women of childbearing age and their young offspring, as well as an erythrocyte thiamine diphosphate concentration cutoff of under 120 nmol/L as a designation of thiamine deficiency, the investigators found such deficiency in 27% of mothers and 15% of children. Using a cutoff of under 180 nmol/L, thiamine deficiency rates reached 78% in mothers and 58% in their children. A particularly high prevalence of thiamine deficiency (38%) was found in infants aged 6-12 months (38%), as measured using the cutoff of less than 120 nmol/L.[32]

Prognosis

Beriberi can be quickly fatal or can slowly rob an individual of almost all energy for even the simplest of daily activities. However, it is one of the most easily treatable conditions, with a remarkable recovery being possible even in severe cases. Thus, the patient prognosis for beriberi is usually good, unless patients have established Korsakoff syndrome. When patients have progressed to this stage, the degree of damage is only minimally reversible.

In cases of wet beriberi, clinical improvement can be observed within 12 hours of treatment, with normalization of heart function and size occurring in 1 or 2 days. The recovery is so dramatic that treatment with thiamine is a diagnostic test, which can be used in cases of acute heart failure and insidious peripheral neuropathy.

A retrospective study by Harel et al indicated that thiamine deficiency in infancy can lead to long-term motor function problems. The study looked at children aged 5-6 years who, during the first 2 years of life, had been fed a faulty milk substitute that was deficient in thiamine, comparing them with age-matched controls. The Movement Assessment Battery for Children and the Zuk Assessment indicated that motor function difficulties existed in 56% and 59%, respectively, of the thiamine-deficient formula group, compared with 10% and 3%, respectively, of the control group. The results suggested that infantile thiamine deficiency affects gross and fine motor function, as well as balance skills.[33]

History and Physical Examination

Most patients have no symptoms and signs of thiamine deficiency; therefore, it must be suspected in the appropriate clinical setting. Early symptoms and signs are often nonspecific and vague, such as fatigue. However, high-output cardiac failure should prompt investigation of thiamine deficiency as a cause. The same applies to neuropathic symptoms, particularly in the distal extremities.

Neurologic symptoms of thiamine deficiency are as follows:

Cardiovascular symptoms are as follows:

Gastroenterologic symptoms are as follows:

Infantile beriberi symptoms are as follows[28] :

A study by Isenberg-Grzeda et al indicated that thiamine deficiency may be a frequent occurrence among inpatients with cancer, even in those who are of normal weight or overweight, lack other vitamin deficiencies, and are receiving multivitamin supplements. The single-center study found thiamine deficiency in 55.3% of 217 patients, with risk factors for the deficiency including active cancer treatment and fluorouracil-based chemotherapy.[36]

A literature review by Jain et al comparing the incidence of thiamine deficiency in patients with heart failure to that in controls reported an odds ratio of 2.53, with possible reasons for the deficiency in heart failure including diuretic use, dietary changes, and alterations in the absorption and metabolism of thiamine. The literature also indicated that thiamine supplementation may improve symptoms and ejection fraction in patients with heart failure.[37]

Alcoholism

Persons with chronic alcoholism have low thiamine intake, impaired thiamine uptake and storage, accelerated destruction of thiamine diphosphate, and varying degrees of energy expenditure. Alcohol is a direct neurotoxin. The effects on the body's supply of thiamine and on brain tissue are detrimental. Persons with known alcoholism should be administered parenteral thiamine as a routine action when they present to a medical facility.

Dieting

A patient’s dieting history also may hold a clue regarding thiamine deficiency. Fad diets often do not contain the necessary amounts of thiamine.

Dialysis and high energy consumption

Dialysis also robs thiamine from the circulation. In addition, states of high energy consumption, such as hyperthyroidism, pregnancy, or severe illness, require more thiamine and other nutrients.

Bariatric weight-loss surgery

Persons with a history of gastric bypass may also have beriberi.[19, 38, 39] For bariatric surgery patients, it is believed that a deficiency occurs primarily during the first 6 months after surgery, when individuals undergo the most rapid weight loss.

Approach Considerations

For practical reasons, replacing thiamine as an initial test may be most feasible. If the patient responds to treatment, it is safe to assume that a measure of thiamine deficiency was responsible for the condition. Thiamine is not toxic in high levels, which means that this route carries little risk. In addition, time is saved in treating the patient and money is saved in testing. (However, although observation of a patient's clinical response to thiamine administration remains the easiest, least expensive form of testing, clinicians usually miss the subclinical forms of beriberi.)

If laboratory confirmation is needed,[40] measure blood thiamine, pyruvate, alpha-ketoglutarate, lactate, and glyoxylate levels. Also, measure urinary excretion of thiamine and its metabolites. A scarcity of any of these chemicals strongly suggests thiamine deficiency.[10]

In conjunction with whole blood or erythrocyte transketolase activity preloading and postloading, a thiamine loading test is the best indicator of thiamine deficiency. An increase of more than 15% in enzyme activity is a definitive marker of deficiency. However, this test is expensive and time consuming; it is performed only for criterion-standard proof of deficiency.

Measure urinary methylglyoxal; also measure serum thyroid-stimulating hormone (TSH), to rule out thyrotoxicosis-induced high-output heart failure, if applicable.

An increase in troponin I has been found in heart failure due to thiamine deficiency.[41] Thiamine is an important enzymatic cofactor in several energy pathways. Its deficiency disrupts cellular processes and leads to myocardial death. Thiamine is also an important factor in the cellular production of glutathione, an antioxidant that myocardial cells need to counteract free radicals. In the absence of glutathione, these cells would die prematurely.

Metabolic acidosis can be seen in thiamine deficiency. This is due to increased lactic acid production from thiamine deficiency. Thiamine pyrophosphate (thiamine derivative) is the coenzyme for the conversion of pyruvate to acetyl coenzyme A. Without it, pyruvate is under used and converts to lactate. It is important to consider thiamine deficiency in the presence of unexplained metabolic acidosis, specifically, lactic acidosis.[42, 22]

Gastrointestinal beriberi is a condition in which patients report abdominal pain due to lactic acidosis.[43]

A retrospective study by Wani et al indicated that cranial ultrasonography can be used in the diagnosis of infantile encephalitic beriberi, with a finding of hyperechogenicity of the basal ganglia having a sensitivity and specificity of 71% and 92%, respectively, for the disease.[44]

Approach Considerations

In suspected cases of thiamine deficiency, prompt administration of parenteral thiamine is indicated. The recommended dose is 50 mg given intramuscularly for several days. The duration of therapy depends on the symptoms, and therapy is indicated until all symptoms have disappeared. Maintenance is recommended at 2.5-5 mg per day orally unless a malabsorption syndrome is suspected.

Thiamine, even at high concentrations, is not toxic in a person with normal renal function. No cases of thiamine toxicity have been reported from the use of thiamine at the dosages indicated, even in patients in critical condition.

An optimal method for delivering the needed thiamine in a bioavailable form must be determined for the long-term treatment of each patient. Depending on the cause of the vitamin deficiency, a referral to an alcohol dependency clinic may be needed.

Most outpatient care is targeted at delivering thiamine in a bioavailable form to rehabilitated patients. Clinical follow-up with measurement of thiamine diphosphate activity may be warranted if relapse or noncompliance is suspected.

Support for cardiac function is necessary in cases of wet beriberi, because lack of cardiac support leads to low-output cardiac failure when the thiamine deficiency is corrected.

Follow-up care until delivery of current pregnancy, intensive care for advanced cardiomyopathy, definitive care for hyperthyroidism, or further workup of intestinal derangement may be warranted in patients with thiamine deficiency.

Activity

The level of activity and the presence of a high energy consumption state (eg, hyperthyroidism, pregnancy, lactation, severe disease) increase the daily requirements of thiamine.

Medication Summary

The goals of pharmacotherapy are to correct the vitamin deficiency, reduce morbidity, and prevent complications. Suspected cases of thiamine deficiency are treated with prompt administration of parenteral thiamine; therapy continues until all symptoms of the deficiency have disappeared. Even at high concentrations, thiamine is not toxic in a person with normal renal function. Most outpatient care is targeted at delivering thiamine in a bioavailable form to rehabilitated patients.

Thiamine

Clinical Context:  Thiamine is used to replenish the body's stores of the coenzyme thiamine pyrophosphate. The duration of parenteral thiamine therapy depends on the symptoms of thiamine deficiency; treatment is administered until all symptoms are gone.

Class Summary

Vitamins are essential for normal deoxyribonucleic acid (DNA) synthesis. Thiamine pyrophosphate, the biologically active form of thiamine (vitamin B-1), acts as a coenzyme in carbohydrate metabolism through the decarboxylation of alpha ketoacids. It also takes part in the formation of glucose by acting as a coenzyme for the transketolase in the pentose monophosphate pathway.

What is beriberi (thiamine deficiency)?What is thiamine and what causes a deficiency?Which foods are rich in thiamine?What is the role of thiaminases in the etiology of beriberi (thiamine deficiency)?What is the role of cassava in the etiology of beriberi (thiamine deficiency)?What should be included in patient education about beriberi (thiamine deficiency)?How is beriberi (thiamine deficiency) diagnosed?What are the treatment options for beriberi (thiamine deficiency)?What is the pathophysiology of beriberi (thiamine deficiency)?What is dry beriberi?What is wet beriberi?Which dietary factors result in reduced thiamine intake leading to beriberi (thiamine deficiency)?Which factors increase metabolic consumption of thiamine leading to beriberi (thiamine deficiency)?Which factors increase depletion of thiamine leading to beriberi (thiamine deficiency)?What is the role of diuretics in the etiology of beriberi (thiamine deficiency)?What are risk factors for the development of beriberi (thiamine deficiency)?Which factors decrease thiamine absorption leading to beriberi (thiamine deficiency)?What is the role of bariatric weight-loss surgery in the etiology of beriberi (thiamine deficiency)?What is the role of folic acid in the etiology of beriberi (thiamine deficiency)?What is infantile beriberi?What is the role of obesity in the etiology of beriberi (thiamine deficiency)?Which patient groups are at highest risk for beriberi (thiamine deficiency) in developed countries?What is the global prevalence of beriberi (thiamine deficiency)?What is the prognosis of beriberi (thiamine deficiency)?How does dieting contribute to the development of beriberi (thiamine deficiency)?What are the early symptoms of beriberi (thiamine deficiency)?What are the neurologic symptoms of beriberi (thiamine deficiency)?What are the cardiovascular symptoms of beriberi (thiamine deficiency)?What are the gastroenterologic symptoms of beriberi (thiamine deficiency)?What are the symptoms of infantile beriberi?What is the prevalence of beriberi (thiamine deficiency) in cancer patients?Why are patients with heart failure at an increased risk of beriberi (thiamine deficiency)?How does alcoholism contribute to the development of beriberi (thiamine deficiency)?Which conditions increase the risk for beriberi (thiamine deficiency)?How does bariatric weight-loss surgery contribute to the development of beriberi (thiamine deficiency)?Which conditions should be included in the differential diagnoses of beriberi (thiamine deficiency)?Why should beriberi (thiamine deficiency) be suspected in patients with thyrotoxicosis?What are the differential diagnoses for Beriberi (Thiamine Deficiency)?How is beriberi (thiamine deficiency) diagnosed?What is the role of thyroid testing in the evaluation for beriberi (thiamine deficiency)?What is the role of troponin testing in the evaluation of beriberi (thiamine deficiency)?What is included in the treatment of beriberi (thiamine deficiency)?Which factors affect the daily requirements of thiamine to treat beriberi (thiamine deficiency)?What are the goals of drug treatment for beriberi (thiamine deficiency)?Which medications in the drug class Vitamins are used in the treatment of Beriberi (Thiamine Deficiency)?

Author

Dieu-Thu Nguyen-Khoa, MD, FACP, Associate Clinical Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician Specialist, Department of Primary Care and Community Medicine, ValleyCare Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Ginette V Busschots, MD, Assistant Professor, Department of Emergency Medicine, Foote Hospital, University of Michigan Medical School

Disclosure: Nothing to disclose.

Phyllis A Vallee, MD, Associate Program Director, Department of Emergency Medicine, Henry Ford Hospital

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Additional Contributors

Dennis W Cope, MD, FACP, Emeritus Professor of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Chief, Department of Internal Medicine, Olive View-UCLA Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Stanley Wallach, MD Executive Director, American College of Nutrition; Clinical Professor, Department of Medicine, New York University School of Medicine

Stanley Wallach, MD is a member of the following medical societies: American College of Nutrition, American Society for Bone and Mineral Research, American Society for Clinical Investigation, American Society for Clinical Nutrition, American Society for Nutritional Sciences, Association of American Physicians, and Endocrine Society

Disclosure: Nothing to disclose.

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Beriberi in an adult patient.

Beriberi in an adult patient.

Population Age Allowance, mg/day
Recommended Dietary Allowances (RDAs)
Boys9-13 years0.9
Men>14 years1.2
Girls9-13 years0.9
Women14-18 years1.0
Women>19 years1.1
Pregnant/lactating women. . .1.4
Children1-3 years0.5
Children4-8 years0.6
Adequate Intakes (AIs)
Infant0-6 months0.2
Infant7-12 months0.3