micronutrition for tb...

MICRONUTRITION FOR

TB PATIENT

Resti Yudhawati

Department of Pulmonology and Respiratory Medicine

Faculty of Medicine, Airlangga University

Dr. Soetomo Hospital Surabaya

Introduction

• TB remains a major global public health threat

• Over 1.4 million deaths reported in 2015

Estimated TB incidence rates, 2015

Global tuberculosis report, 2016

• Malnutrition and wasting are associated with TB

Ramakrishnan, 2008; Swaminathan, 2008

Introduction

• Approximately two-thirds of TB patients presenting with dramatic weight loss and malnutrition

• 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

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 JapanGupta, 2009; Karyadi E, 2000

Innate immune cells; macrophages,

neutrophils and dendritic

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

Increased production of cytokines

Ernst JD, 2012Kaufman SHE, 2010

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

TUBERCULOSIS

• 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 dietCDC. 2015. Micronutrient Facts.

• 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

Low micronutrient status in TB patients

Summary of studies investigating micronutrient status of patients with pulmonary tuberculosis

Nutrient Findings Reference

Copper, zinc, selenium, iron

Ethiopia

↑ Mean copper, ↓ Mean zinc, ↓ Mean

selenium, ↓ Mean iron iKassu, 2006

Vitamin B6 (pyridoxine)

South Africa

90% low B6 at initiation tx, 100% ↓ B6

at one week Visser,. 2004

Vitamin A, E, zinc, selenium

Malawi

deficient in vitamin A, E, zinc and

selenium Van Lettow, 2005

Vit A, zinc, Indonesia ↓ Mean vitamin A, zinc, in TB patients Karyadi, 2002

Vitamin D, England Vitamin D deficiency associated with

active TB (OR 2.9; 95% CI 1.3-6.5) Wilkinson , 2000

Vitamin C, Vitamin E, India ↓ Mean vitamin C and E in TB patients Vijayamalini, 2004

Selenium

Serum selenium levels ↓in pulmonary

tuberculosis l with and without

HIV/AIDS.

Ramakrishnan K,

2009

Zinc↓ levels of zinc in blood sample of TB

and TB- HIV infected patients

Ramakrishnan K,

2008, Bacelo AC,

2015

• Conclusively, the results indicated that patients with

tuberculosis have altered profile of vitamin (A, B6, C, D, E)

and trace elements (Selenium, zinc, iron ) in their sera

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 C

Vitamin E

Zinc

Vitamin A

Vitamin B6

Vitamin B12

Vitamin C

Vitamin D

Vitamin E

Asam folatIron

ZincCopper

Selenium

Vitamin A

Vitamin B6

Vitamin B12

Vitamin D

Asam Folat

Zinc

Tembaga

Selenium

Maggini et al., 2007

Institute of Medicine National Academy of Scienec, 1999

Micronutrients and the

immune system

Micronutrients and the

immune system

Institute of Medicine National Academy of Scienec, 1999

Micronutrients

Vitamins

Thiamin (vitamin B1)

Riboflavin (vitamin B2)

Vitamin B6 (pyridoxine)

Vitamin B12

Folate (vitamin B9)

Choline

Vitamin C

Vitamin A

Vitamin D

Vitamin E

Vitamin K

Minerals

Calcium

Copper

Iodine

Iron

Magnesium

Manganese

Phosphorus

Potassium

Selenium

Sodium (Chloride)

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 bacilliBotella 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

• 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.

Meneghetti ET AL, 2016; Ratledge C. 2004

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.TBCrowle AJ, 1989; Yamada et al, 2007

• 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

VITMIN B

Micronutrient supplementation

in TB

Mikronutrien DRI untuk laki-laki 19-70

tahun

DRI untuk perempuan 19-

70 tahun

Vit A 900 μg

(3000IU)

700 μg

(2200IU)

B1 (Thiamine) 1.2 mg 1.1 mg

B2 (Riboflavin) 1.3 mg 1.1 mg

B3(Niacin) 16 mg 14 mg

B6

(Pyridoxine)

1.3 - 1.7mg 1.3 - 1.5mg

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

Dietary reference intake (DRI)

Vitamin A (DRI 2200-3000 IU/DAY)

VITAMIN A

+ ZINC

MULTI NUTRIENTS

• Armijos 2010 5000 IU/day

• Pakasi et al. 2010 5000 IU/day

• Lawson 2010 5000 IU/day

• Visser 2011 200.000 IU at day 1

• Range et al. 2005 5000 IU/day

• Semba 2007 5000 IU/day• Vilamor 8000 IU/day

• Praygod 2011 5000 IU/day

• Hanekom 1997 200.000 IU at day 0 and 1

• Pakasi et al. tahun 2010 5000 IU/ day.

Fails to reduce sputum conversion, improved

treatment outcomes, and body weight

ZINC

+ VIT A

MULTI NUTRIENTS

• Armijos 2010 50 mg/ day

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

• Visser 2011 15 mg 5 x / week

• Range et al.2005 zinc 45 mg/day

• Lawson 2010 90 mg zinc/week

• Pakasi et al. 2010 15 mg zinc/day

• Range et al. 2005 45 mg/day

• Lawson 2010 90 mg/day

• Pakasi et al. 2010 15 mg/day



Zinc (DRI 8-11 mg/day)

VITAMIN A and Zinc

• Karyadi et al. 2002 Zinc 15 mg/hari + vitamin A 5000 IU/ day for 6 month

VITAMIN D vs

PLASEBO

VITAMIN D

MULTI NUTRIENTS

• Wesje 2008 100.000 IU at 5 and 8 months after the

start of treatment

• Range et al. 2005 5 µg/day

• Semba 2007 10 µg/day

• Morcos 1998 1000 IU/hi (8th initial week)

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



Vitamin D (DRI 15-20 μg/day)

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

show a significant difference in sputum conversion compared

with placebo. The percentage of radiological improvement

was also higher in the vitamin D group.

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

Intramuscular ) accelerated clinical, radiographic improvement in

all TB patients.

Salahuddin et al.2013

Vitamin D (High doses)

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

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.

VITAMIN C

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

• 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

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

Selenium: 200 microg

• 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.

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

Gangaidzo 2001

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



MULTIVITAMIN and MINERAL

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

• 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

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

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

• 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

Summary

Iron deficiency anemia

Normal Iron deficiency anemia Anemia of chronic disease

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

Total iron binding

capacity

250-400 >450 <200

percent saturation 30 70 15

The content of Fe in

macrophages

++ - +++

serum ferritin 20-200 10 150

Serum transferrin

receptor

8-28 >28 8-28

Supandiman et al., 2014

Nutrition assessment

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

micronutrition for tb...

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