ESPGHAN goes Africa Course

Cape Town 29 September-6 October 2015

Failure To Thrive

Jan Taminiau

Failure To Thrive FTT

• Subnormal growth

• Subnormal weight gain or weight faltering

• Weight faltering is not a disease, but rather a description of a relatively common growth pattern Most commonly caused by under nutrition relative to a child’s specific energy requirement

Stunting related to low income

Perspective?

Failure To Thrive Increased in Africa along with population

Africa is slow to decline

Lancet series; 382: 427-478 August 3-9, 2013

RE Black and ZA Bhutta

Failure to thrive FTT

• Child under nutrition

– Stunting

– Wasting

• Gastro Intestinal contribution possible?

– Loss of nutritional calories due gastrointestinal disease

– Waste of calories causes unexplained weight loss or growth inhibition

– More malnourished observed relative to expected from intake

Failure To Thrive

Subnormal growth Subnormal weight gain or weight faltering Gradual or moment of acquiring disease

Inadequate intake

• Sufficient food offered • Micronutrients do not restore growth or malnutrition

– iron, zinc, vitamin A

• Ongoing stunting, malnutrition despite extra food

• Gastrointestinal cause possible? • Was more growth or weight gain expected from food

supply? • Not sure, increase food supply temporarily

Failure To Thrive

GASTROINTESTINAL CAUSES

• Inadequate intake

• Excessive losses

• Anorexia

• Defective digestion and absorption

Inadequate ingestion due to dysphagia

• Neuromuscular incöordination • Oesophageal atresia (repaired) • Oesophagitis (stricture) • Achalasia • Eosinophilic Esophagitis

• History of feeding

– Regurgitated food is acid or not – Aspiration – Dysphagia

Failure To Thrive

GASTROINTESTINAL CAUSES

• Inadequate intake

• Excessive losses

• Anorexia

• Defective digestion and absorption

Excessive nutrient losses

• Substantial nutrient loss caused by vomiting

– Gastro-esophageal reflux

– Eosinophilic esophagitis

– Pyloric stenosis

– Incomplete bowel obstruction

– History of feeding, estimate of vomit volume

Pyloric hypertrophy Clinical visible peristalsis after meal

Excessive vomiting

Excessive peristalsis

Failure To Thrive

GASTROINTESTINAL CAUSES

• Inadequate intake

• Excessive losses

• Anorexia

• Defective digestion and absorption

Energy requirements Normal healthy child

Total energy

requirements

Metabo-

lisable

energy

require-

ments

Resting energy

expenditure

Physical activity

Growth

Energy excretion

Energy requirements for children Anorexia due to inflammation = catabolism

Total energy

requirements

Metabo-

lisable

energy

require-

ments

Resting energy

expenditure depressed by anorexia

Physical activity

Growth

Energy excretion

Energy expenditure as waste

due to inflammation

Failure To Thrive GASTROINTESTINAL CAUSES

• Inadequate intake due to chronic inflammation with energy wastage lost for beneficial purposes (catabolism)

• Anorexia

– Symptoms due to inflammatory lesions

• Abdominal pain

• Discomfort

• Nausea

• Risk for organ damage

– Depressed resting energy expenditure

Examples of gastrointestinal inflammatory anorexia with failure to thrive

• Gastritis – Severe Helicobacter pylori gastritis – CMV gastritis

• Enteric infection – Intestinal tuberculosis – Parasitic inflammation – Acute gastroenteritis (with/without diarrhea)

• Inflammatory lesions in small intestine – Crohn’s Disease – Celiac disease (also malabsorption) – Tropical sprue (also malabsorption)

• Gastric or intestinal motility disorders

• Congenital urinary tract anomalies and infections along with GI

disorders

Examples of inflammatory anorexia

• Anorexia might be caused by inflammatory pain or discomfort after meals

• Abdominal pain

• Nausea

• Diarrhea not necessary

• No obvious malabsorption

• Weight loss and/or stunting

• Consider infectious gastritis

• Consider intestinal infections like tbc, parasites

• Consider intestinal inflammation without infection

10 year old Turkish boy with abdominal pain and

a swollen knee joint with fluctuating effusion in the knee

Miliary TB on chest X-Ray PCR intestinal biopsy, skin

test might be negative

Height SDS/Z-score in Crohn in children at presentation N= 120 at Sick Children Boston USA

One year therapy in Paediatric CD Normal growth velocity is 4-6 cm/year

Severity of gastrointestinal symptoms

0

1

2

3

4

5

6

7

Quiescent Mild

He

igh

t ve

loc

ity c

m/y

r

Gut 1994

Moderate Severe

8

9

10

14

54

23 9

Energy requirements for children Increased energy intake to improve growth

Treat inflammation to resume growth

Total energy

requirements

Metabo-

lisable

energy

require-

ments

Resting energy

expenditure depressed to anorexia

Physical activity

Growth

Energy excretion

Energy expenditure as waste

due to inflammation

Improve growth

Failure To Thrive

GASTROINTESTINAL CAUSES

• Inadequate intake

• Excessive losses

• Anorexia

• Defective digestion and absorption

Congenital and Acquired malabsorptionDefective Digestion and Absorption

Pancreatic Insufficiency Cystic Fibrosis Shwachman also bone marrow dysplasia Secondary due to villous atrophy Secondary due to tropical pancreatitis Intestinal Mucosal Disorders Celiac Disease Tropical sprue Short Gut Syndrome A-β-lipoproteinemia Bile Secretion Disorders Bile Duct Abnormalities Bile acid synthesis disorders Biliary dysfunction, liver abcesses Fasciola, Ascariasis, Salmonella Bacterial Overgrowth

Fatty acids induce Cholecystokinin and hydrogen ions Secretin release from the mucosa into the circulation and stimulate exocrine pancreatic secretion

In villus atrophy release of CCK and Secretin by

mucosal cells is diminished

CCK Secretin

Duodenum

Cystic Fibrosis: Chloride secretions in ducts are diminished with obstruction

Fat Malabsorption

Nutritional status

Malnutrition

Growth failure

Cystic Fibrosis

Failure to thrive

Chronic lung disease

Chronic liver disease

Black Carribean boy 12 years old hepatitis enlarged liver

Stunted growth Fatty stools

Diagnosis is Cystic Fibrosis

15 year old boy with chronic hepatitis History renewed:

Coughing Fatty stools

Diagnosis is Cystic Fibrosis

Diagnosis on sweat chloride Lick their forhead

Collect sweat and test chloride Cl < 30 mmol/L

Cystic fibrosis carrier frequencies in populations of African origin Frequency of the 3120+1G→A mutation in healthy black Africans

• Chiefdom Carrier frequency No of subjects No of carriers

• Southern Africa 728 8 1 in 91 • Nguni 157 0 0 • Zulu 57 0 0 • Xhosa 52 0 0 • Ndebele 23 0 0 • Swazi 25 0 0 • Sotho/Tswana 372 6 1 in 62 • Pedi/Northern Sotho 152 2 1 in 76 • Southern Sotho 100 4 1 in 25 • Tswana 120 0 0 • Tsonga 76 1 1 in 76 • Tsonga 53 1 1 in 53 • Shangaan 23 0 0 • Venda 45 1 1 in 45 • Random blacks 78 0 0

• Central Africa 315 1 1 in 315 • Central African Republic 218 0 0 • Pygmies 83 0 0 • Ubangian speakers 135 0 0 • Zambia 97 1 1 in 97 • West Africa 109 0 0 in 109 • Total 1152 9 1 in 128

30 CF Mutations tested for (SA)

Common names are given in brackets Together these mutations account for 91% and 74% of mutations in the local

Caucasian 60% -mixed ancestry population 30%-Blacks 10%

• p.Glu60X (E60X)

• p.Gly85Glu (G85E)

• p.Leu88IlefsX22 (394delTT)

• p.Tyr122X (Y122X)

• c.489+1G>T (621+1G>T)

• c.579+1G>T (711+1G>T)

• p.Phe316LeufsX12 (1078delT)

• p.Arg334Trp (R334W)

• p.Arg347Pro (R347P)

• p.Ala455Glu (A455E)

• p.Ile507del (ΔI507)

• p.Phe508del (ΔF508)

• c.1585-1G>A (1717-1G>A)

• p.Gly542X (G542X)

• p.Gly551Asp (G551D)

• p.Arg553X (R553X)

• c.1680-886A>G (1811+1.6kbA>G)

• p.Lys684SerfsX38 (2183AA>G)

• p.Trp846X (W846X)

• c.2657+5G>A (2789+5G>A)

• c.2988+1G>A (3120+1G>A)

• c.3140-26A>G (3272-26A>G)

• p.Tyr1092X (Y1092X(C>A)

• p.Arg1162X (R1162X)

• p.Lys1177SerfsX15 (3659delC)

• c.3718-2477C>T (3849+10kbC>T)

• p.Ser1251Asn (S1251N)

• p.Trp1282X (W1282X)

• p.Asn1303Lys (N1303K)

A-β-lipoproteinemia Fat cannot be transported out of enterocyte

Acanthocytes

Acrodermatits enteropathica Failure to thrive

Zinc

intestinal transport disorder

Symptoms at

weaning breast feeding

Therapy Oral Zinc

Small intestinal mucosal diseases that cause chronic diarrhea with malabsorption

Villous atrophy

• Tropical sprue

• Environmental enteropathy

• Drug associated enteropathy

• Ischaemic enteropathy

• Immunodeficiency sprue

• Whipple's disease

• HIV enteropathy

• Coeliac disease

• Collagenous sprue

• Infectious enteritis

• Tuberculosis

• Giardiasis (especially in immunodeficiency (IgA deficiency))

• Bacterial overgrowth

Tropical sprue

Consistent findings:

• Glossitis (sprue like tongue)

• Macrocytic anaemia

• Folate deficiency

• Partial intestinal villus atrophy

• Anorexia

• Nutrient malabsorption

• Improvement on folate therapy

• Folate deficiency causes villus atrophy!

Hypersegmentation Neutrophils

Folate deficiency

Tropical sprue or enteropathy

Small bowel biopsy

Normal small bowel biopsy

Tropical Sprue

• Compatible clinical presentation: Chronic diarrhea, malabsorption related, distended abdomen, anorexia, flatulence

• Demonstration of malabsorption of two unrelated substances abnormal small intestinal mucosal histology, which may be patchy

• Exclusion of other specific causes for MAS (except small-intestinal bacterial overgrowth [SIBO])

• Persistent response to treatment with antibiotics such as tetracycline and folic acid

Tropical sprue

• Reported from:

• Nigeria

• Zimbabwe

• South Africa

• Liberia

• Zambia

• Egypt

Total Sucrase of all enterocytes measured by Sucrose digestion reflects small intestinal surface area

Sucrose breath test to estimate small intestinal villous integrity and function

13CO2 recovered in breath after oral load of sucrose

cPDR90% = cumulative percentage dose recovery of sucrose at 90 minutes

Ritchie et al., Pediatrics 2009

Childhood Stunting

Child undernutrition, tropical enteropathy, toilets, and handwashing Humphrey JH Lancet 2009

Tropical Sprue in 2014: the New Face of an Old Disease Uday C. Ghoshal

Age-related association of small intestinal mucosal enteropathy with nutritional status in rural Gambian children

David I. Campbell 2002

Inadequate intake under sufficient supply

Anorexia due to intestinal inflammation

Intestinal malabsorption

Environmental enteropathy is an acquired disorder with

– Reduced intestinal absorptive capacity

– Altered barrier integrity

– Mucosal inflammation

– Relation to increased rate of infections, nutritional deficits and stunting is unclear

– Responds to antibiotics and folic acid supplementation

Does it make sense to know villus atrophy Endoscopy?

• All can be treated

• Celiac disease Gluten free diet

• Tropical sprue Folate, antibiotics

• Giardiasis Metronidazole

• Tuberculosis Treatment

• Bacterial overgrowth Antibiotics

• Secondary pancreatic Pancreatic enzymes

insufficiency

Nutrient malabsorption

By Organ related malabsorption • Small intestinal disease

– Protein-Fat-Carbohydrate malabsorption • Pancreatic disease

– Protein-Fat-Carbohydrate malabsorption • Biliary disease

– Fat malabsorption

• Signs: – Fatty stools Fat – Foul smelling stools Protein – Acidic smell of stools Carbohydrates

• Symptoms:

– Failure to thrive despite offering sufficient food intake for some days

Carbohydrate malabsorption • Lactase deficiency • Sucrase iso-maltase deficiency • Glucose galactose malabsorption

• Some calorie loss, but SCFA’s compensate • Minor brush border abnormalities • Does usually not cause FTT

• Signs:

– Diarrhea increases with sugars offered – Acidic smell of stools

• Tests:

– Carbohydrate breath test • Sucrose • Lactose • Glucose

– Stools for sugars

How to detect Pancreatic, biliary related digestion or small intestinal

malabsorption problems

Stool examination Parasites Culture Watery: Sugar malabsorption

pH, reducing substances Fatty stools: Fat malabsorption

Microscopy with Sudan staining Feces collection for fat (one to three days) With and without antibiotics With and without pancreatic supplements

Foul smelling: Protein malabsorption Fecal nitrogen Small bowel biopsy Plasma: Zinc, albumin, elastase, lipase IgA-Tissue transglutaminase (IgA-TTG) Blood: Acanthocytes Hyper segmentation leucocytes Sweat: Chloride

Triglycerides in stool Sudan red staining (unstained also visible)

Fatty acid crystals in stools

Diagrammatic representation of the detection of reducing substances in

stool (Ames Clinitest tablet, Fehling reaction)

Or when not available:

Boil feces sample in flame will liberate glucose from lactose, sucrose and

maltose

Add glucose stick?

Investigation indication condition being sought

Developing World approach

• Is this child not fitting into only malnutrition

• Any persistent weight faltering

• Moment of change of growth, weight

• Relative worse for degree of malnutrition

• Extra food offered

• Symptoms of dysphagia, vomiting, abnormal anorexia, abnormal diarrhea

• Challenge with food

– Symptoms diarrhea, fatty stools, abnormal smelly stools

– Signs erythema, edema, rickets, anemia, respiratory symptoms not fitting

• Any clue for specific disease

Microvillus

inclusion

Sub Saharan Africa Any of these diseases?