MICRONUTRITION FOR

TB PATIENT

Resti Yudhawati
Department of Pulmonology and Respiratory Medicine
Faculty of Medicine, Airlangga University
Dr. Soetomo Hospital Surabaya
 Introduction
Estimated TB incidence rates, 2015
• TB remains a major global public
health threat
• Over 1.4 million deaths reported in
2015

Global tuberculosis report, 2016

 Introduction
• Malnutrition and wasting are associated with TB
Ramakrishnan, 2008; Swaminathan, 2008

• Approximately two-thirds of TB patients presenting with dramatic

weight loss and malnutrition
Eddleston M, 2009, Fauci AS, 2008

• Nutritional status is significantly lower in patients with active

pulmonary tuberculosis in different studies in Indonesia, England,
India, and Japan Gupta, 2009; Karyadi E, 2000

• Malnutrition has been linked to impair immune responses

• Poor prognosis and is a major risk factor for mortality in TB patiens
Chang SW, 2013; Lubart E, 2007
 Innate immune cells;
macrophages,
neutrophils and dendritic

Adaptive immunity T-
lymphocytes (CD-8, CD-4)

Increased production of
cytokines

Kaufman SHE, 2010 Ernst JD, 2012

 TUBERCULOSIS
Macrophages (resting state)  activated state  increased cellular
turnover, essential nutrients, oxygen uptake, and protein synthesis
Akiibinu MO, 2009; Edem VF, 2016; Kominsky Dj, 2010

Inflammatory and immune response  cytokines  (IL-1, IL-6, IL- 8,

TNFα   altered metabolism, Leptin, lipolytic and proteolytic,
reduction in appetite Gupta, 2009, Paton NI, 2004, Sarraf P 1997, Verbon A, 1999

• Catabolisme 
• Reduced food intake
• Increased losses

Wasting -- Nutritional deficiencies  Micronutrition

 Micronutrients

• Micronutrients are dietary components referred to as vitamins and

minerals, only required by the body in small amounts
• Vital to development, disease prevention, and wellbeing.
• Micronutrients are not produced in the body and must be derived
from the diet CDC. 2015. Micronutrient Facts.
Low micronutrient status in TB patients

• Increased catabolism
• loss of appetite,
• Drug nutrient interactions
• Nausea and vomiting caused by anti-TB drugs
• Impaired absorption of nutrients

Edem VF; 2015, Karyadi E, 2000; NICUS; 2007

 Summary of studies investigating micronutrient status of patients
with pulmonary tuberculosis
Nutrient Findings Reference
Copper, zinc, selenium, iron ↑ Mean copper, ↓ Mean zinc, ↓ Mean
Kassu, 2006
Ethiopia selenium, ↓ Mean iron i
• Conclusively,
Vitamin B6 (pyridoxine) the results
90% low B6 indicated
at initiationthat patients
tx, 100% ↓ B6 with
Visser,. 2004
South tuberculosis
Africa have ataltered
one weekprofile of vitamin (A, B6, C, D, E)
Vitaminand
A, E,trace
zinc, selenium
elementsdeficient in vitaminzinc,
(Selenium, A, E, zinc
ironand) in their sera
Van Lettow, 2005
Malawi selenium
Vit A, zinc, Indonesia ↓ Mean vitamin A, zinc, in TB patients Karyadi, 2002
Vitamin D deficiency associated with
Vitamin D, England Wilkinson , 2000
active TB (OR 2.9; 95% CI 1.3-6.5)
Vitamin C, Vitamin E, India ↓ Mean vitamin C and E in TB patients Vijayamalini, 2004
Serum selenium levels ↓in pulmonary
Ramakrishnan K,
Selenium tuberculosis l with and without
2009
HIV/AIDS.
Ramakrishnan K,
↓ levels of zinc in blood sample of TB
Zinc 2008, Bacelo AC,
and TB- HIV infected patients 2015
Role of micronutrients in TB
 Summary of the sites of action of
micronutrients on the immune system

Epithelial barriers Cellular immunity Antibody production

Vitamin A Vitamin A Vitamin A

Vitamin C Vitamin B6 Vitamin B6
Vitamin E Vitamin B12 Vitamin B12
Zinc Vitamin C Vitamin D
Vitamin D Asam Folat
Vitamin E Zinc
Asam folat Tembaga
Iron Selenium
Zinc
Copper
Selenium

Maggini et al., 2007

 Micronutrients and the
immune system

Institute of Medicine National Academy of Scienec, 1999

 Micronutrients and the
immune system

Institute of Medicine National Academy of Scienec, 1999

 Micronutrients
Vitamins Minerals

Thiamin (vitamin B1) Calcium

Riboflavin (vitamin B2) Copper
Vitamin B6 (pyridoxine) Iodine
Vitamin B12 Iron
Folate (vitamin B9) Magnesium
Choline Manganese
Vitamin C Phosphorus
Vitamin A Potassium
Vitamin D
Selenium
Vitamin E
Sodium (Chloride)
Vitamin K
Zinc
Cochrane Database of Systematic Reviews 2016
 SELENIUM
• Reactive oxygen  species and  antioxidant activities in
pulmonary tuberculosis patients  enzymes glutathione peroxidase
(GPx)
• Maintaining the immune processes and thus may have a critical role
in clearance of mycobacteria
Seyedrezazadeh E, 2007; Richie et al., 2012 , Wu 6, 2016

ZINC
• Zinc is used by the cells of the immune system to destroy bacteria
such as tubercle bacilli
Botella et al, 2011; Stensland et al, 2015
 IRON
• The role of iron in the pathogencity, growth and metabolism of M. TB
depends on the acquisition of iron from host resources
Meneghetti ET AL, 2016; Ratledge C. 2004

• M. TB ability in multiplication within host macrophages depends on the

available iron.
• The iron deficiency in TB infected patients could be due to the M.TB iron
consumption. Agarwal et 1l, 2016; Boelaert et al, 2007; Mwandumba et al, 2004

COPPER
• copper are components of an enzyme (superoxide dismutase) 
production of hydrogen peroxide, a potent factor of intracellular killing
mechanism by phagocytes (macrophages and neutrophils)
Edem et al, 2015

• serum Cu/Zn ratio has been reported in patients with tuberculosis.

• The serum copper/zinc after anti-tuberculosis treatment.
Mohan Gl, 2006; Sepehri et al, 2017
 VITMIN D
• Vitamin D is known to be essential to M.TB containment and killing
through activation of 25-hydroxyvitamin D receptors (VDRs) present
on all immune cells.
• Binding of 1,25(OH)2 D3 activates VDRs and induces cathelicidin-
mediated killing of Mycobacteria.
Liu et al, 2006; Liu et al, 2007

VITAMIN C and E

• Vitamins C (ascorbic acid) and E (alpha tocopherol) act as potent and

the most important hydrophilic and lipophilic antioxidants respectively.
• Vitamin C scavenges superoxide radical, while vitamin E converts
superoxide radical to less reactive forms Vijayamalini, M 2004
 VITAMIN A
• Vitamin A helps in the normal function of immune cells and also
enhances the synthesis essential cytokines with antitubercular activity
Chakraborty et al, 2014

• invivo study  attenuates the severity of tuberculosis

• in vitro study  Inhibition of multiplication M.TB
Crowle AJ, 1989; Yamada et al, 2007

VITMIN B
• The direct association between TB and vitamin-B deficiency is not
known
• Administration of Pyrazinamide, isoniazid  vitamin B6 deficiency
• Vitamin-B supplementation is well recommended in order to avert
several neurological complications in tuberculosis patients
Chakraborty et al , 2014; Maggini et al, 2007
Micronutrient supplementation
in TB
 Dietary reference intake (DRI)
Mikronutrien DRI untuk laki-laki 19-70 DRI untuk perempuan 19-
tahun 70 tahun
Vit A 900 μg 700 μg
(3000IU) (2200IU)
B1 (Thiamine) 1.2 mg 1.1 mg
B2 (Riboflavin) 1.3 mg 1.1 mg
B3(Niacin) 16 mg 14 mg
B6 1.3 - 1.7mg 1.3 - 1.5mg
(Pyridoxine)
B9(FolicAcid) 400 μg 400 μg
B12 2.4 μg 2.4 μg
Vit C 90 mg 75 mg
Vit D 15-20 μg 15-20 μg
Vit E 15 mg 15 mg
Selenium 55 μg 55 μg
Copper 0.9 mg 0.9 mg
Zinc 11 mg 8 mg
Iodine 150 μg 150 μg
Calcium 1000-1200 mg 1000-1200 mg
Manganese 2.3 mg 1.8 mg
Magnesium 410 – 420mg 310 – 320mg
Fe 8 mg 8-18 mg
Dietary Reference Intake (DRI). Bethesda: NIH; 2011
 Vitamin A (DRI 2200-3000 IU/DAY)

• Hanekom 1997  200.000 IU at day 0 and 1

VITAMIN A • Pakasi et al. tahun 2010  5000 IU/ day.

• Armijos 2010  5000 IU/day

• Pakasi et al. 2010  5000 IU/day
+ ZINC • Lawson 2010  5000 IU/day
• Visser 2011  200.000 IU at day 1

• Range et al. 2005  5000 IU/day

MULTI • Semba 2007  5000 IU/day
NUTRIENTS •
•
Vilamor  8000 IU/day
Praygod 2011  5000 IU/day

Fails to reduce sputum conversion, improved

treatment outcomes, and body weight
 Zinc (DRI 8-11 mg/day)
• Range et al. 2005 45 mg/day
ZINC • Lawson 2010 90 mg/day
• Pakasi et al. 2010  15 mg/day

• Armijos 2010 50 mg/ day

+ VIT A •
•
Lawson 2010  90 mg /week
Pakasi et al. 2010 15 mg/day
• Visser 2011  15 mg 5 x / week

MULTI • Range et al.2005 zinc  45 mg/day

• Lawson 2010  90 mg zinc/week
NUTRIENTS • Pakasi et al. 2010  15 mg zinc/day

Fails to reduce sputum conversion, improved

treatment outcomes, and body weight
 VITAMIN A and Zinc

• Karyadi et al. 2002 Zinc 15 mg/hari + vitamin A

5000 IU/ day for 6 month
 Vitamin D (DRI 15-20 μg/day)
VITAMIN D vs • Morcos 1998 1000 IU/hi (8th initial week)
PLASEBO • Nursyam et al., 2006 250 µg/day (6th initial week )

Nursyam et al., 2006 250 µg/day (6th initial week

•showWesje 2008 difference
a significant 100.000 IUin at 5 and conversion
sputum 8 months after the
compared
VITAMIN D withstart of treatment
placebo. The percentage of radiological improvement
was also higher in the vitamin D group.

MULTI • Range et al. 2005  5 µg/day

NUTRIENTS • Semba 2007 10 µg/day

Fails to reduce sputum conversion, improved

treatment outcomes, and body weight
 Vitamin D (High doses)

Supplementation with high doses of vitamin D (600,000 IU of

Intramuscular )  accelerated clinical, radiographic improvement in
all TB patients.
Salahuddin et al.2013

Administration of four doses of 2.5 mg vitamin D3 elevated serum 25-

hydroxyvitamin D concentrations and reduced time to sputum culture
conversion in participants with the tt genotype of the TaqI VDR
polymorphism.
Martineau et al.2011
 VITAMIN C

The efficacy of the antioxidative therapy in tuberculosis. Besides

chemotherapeutic drugs, the administration of alpha-tocopherol, vitamin C
and sodium nucleinate brings about higher rates of smear-negative cases
and shorter period of cavity closure.
Safarian et al, 1990

VITAMIN E
• Vitamin E supplementation, alone or in combination with other vitamins 
improve plasma levels of vitamin E, but this has not been shown to have
clinically important benefits.
Sinclair et al., 2011
 SELENIUM

• Seyedrezazadeh E, 2007  vitamin E: 140 mg alpha-tocopherol and

Selenium: 200 microg

• A 2-month intervention with vitamin E and selenium supplementation

reduces oxidative stress and enhances total antioxidant status in patients
with pulmonary TB treated with standard chemotherapy
• Highly recommended in pulmonary tuberculosis patients
 IRON
•  iron intake is associated with developing active tuberculosis infection
and its mortality.
• M. TB ability in multiplication within host macrophages depends on the
available iron
Boelaert et al, 2007; Patel et al, 2016

•  dietary iron was associated with a 3.5-fold increase in the estimated

odds of developing pulmonary TB and with a trend toward higher
mortality among the patients with pulmonary TB.
Gangaidzo 2001
 MULTIVITAMIN and MINERAL

A (2-3x DRI), vitamin B (1-10x DRI), vitamin C (1-5xDRI), vitamin D

(1xDRI), vitamin E (1-10 x DRI), zinc (1-5 x DRI ), selenium (1-4x DRI)

• Range et al. 2005

• Semba 2007
• Praygod 2011
• Vilamor 2008
• Metha 2010
Fails to reduce sputum conversion, improved
treatment outcomes, and body weight
 MULTIVITAMIN and MINERAL

A (2-3x DRI), vitamin B (1-10x DRI), vitamin C (1-5xDRI), vitamin D

(1xDRI), vitamin E (1-10 x DRI), zinc (1-5 x DRI ), selenium (1-4x DRI)

• Range et al. 2005

 • Cochrane researchers  After searching for relevant studies up to 4
February 2016, they included 35 relevant studies with 8283
participants.

• Routinely providing multi-micronutrient supplements may have little

or no effect on deaths in HIV-negative people with tuberculosis
• No studies have assessed the effect on quality of life

Cohcrane; 2016
 WHO. Guideline
• There is insufficient evidence whether multi micronutrients have a
beneficial effect on mortality in TB – HIV (-), but probably have little
or no effect on mortality in TB – HIV (+)
• No studies have assessed the effects of multi-micronutrients on TB
cure, or completion of TB treatment.
• Multiple micronutrient supplements may have little or no efect on
the proportion of TB patients remaining sputum positive during
the first 8 weeks, and probably have no efect on weight gain during
treatment.
• There is insufficient evidence whether routinely providing free food
or energy supplements results in better TB treatment outcomes or
improved quality of life

WHO, 2013. Guideline: Nutritional Care and Support for Patient with Tuberculosis.
 Micronutrient supplementation
• A daily multiple micronutrient supplement at 1× recommended
nutrient intake should be provided in situations where fortifed or
supplementary foods should have been provided in accordance with
standard management of moderate undernutrition
• All pregnant women with active TB should receive multiple
micronutrient supplements that contain iron and folic acid and
other vitamins and minerals,
• For pregnant women with active TB in settings where calcium
intake is low, calcium supplementation as part of antenatal care is
recommended for the prevention of pre-eclampsia
• All lactating women with active TB should be provided with iron
and folic acid and other vitamin and minerals

WHO, 2013. Guideline: Nutritional Care and Support for Patient with Tuberculosis.
Nutrition assessment -- BMI
 Summary
• Micronutrients status is significantly lower in patients with active
pulmonary tuberculosis
• Micronutrients supplementation was shown to increase immune
function
• There is insufficient evidence whether multi micronutrients have a
beneficial effect on reduced duration of seputum conversion,
improved treatment outcomes, quality of life and body weight in TB
patient
• WHO recommended A daily multiple micronutrient supplement as
standard management on moderate undernutrition, pregnant women,
and lactating women with active TB
• Micronutrients supplementation providing Dietary Reference Intake
35
 Iron deficiency anemia
Normal Iron deficiency anemia Anemia of chronic disease

plasma Fe (mg/L) 70-90 30 30

Total iron binding 250-400 >450 <200
capacity

percent saturation 30 70 15
The content of Fe in ++ - +++
macrophages

serum ferritin 20-200 10 150

Serum transferrin 8-28 >28 8-28
receptor

Supandiman et al., 2014

 Nutrition assessment

Adapted from WHO, 1995; WHO, 2000 and WHO, 2004