Gastroenterology A-ZDR AMIN SHEIKHPAEDIATRIC GASTROENTEROLOGIST & HEPATOLOGISTSTARSHIP CHILDREN’S HOSPITAL, AUCKLAND

FRACP EXAM COURSE, NOVEMBER 2017

APC gene

Adenomatosis polyposis coli gene (chromosome 5) Tumour suppressor gene Germline mutations Phenotypic spectrum of polyposis syndromes FAP (familial adenomatosis polyposis)

Most common

Average age of onset of polyps = 16 years

100% of patients develop malignancy

Average age of onset of Colorectal Ca = 39 years

FAP associated with other cancers HEPATOBLASTOMA

Also - Gastric, thyroid, pancfreatic, adrenal, rectal Ca

Other syndromes on the FAP phenotypic spectrum

Gardiner syndrome Autosomal DOMINANT

Colonic polyps + extracolonic manifestations

Osteomas (skull, mandible, long bones), epidermal cysts, thyroid Ca, epidermal cysts, pancreatic adenoCa, CHRPE (congenital hypertrophy of retinal pigmented epithelium), desmoid tumours

Turcot syndrome Autosomal RECESSIVE

Colononic polyps (malignant before 30 years)

CNS tumours (glioblastoma, medulloblastoma)

Spot diagnosis… Peutz-Jeghers syndrome

Lip freckling Gastric polyps

Breath tests

Reported diagnostic indications:• Carbohydrate malabsorption

• Lactose, fructose• Bacterial overgrowth (SIBO / SBBOG)• Functional disorders

• Irritable bowel syndrome

• Use is controversial • In paediatrics – use is becoming less

clinically relevant• Culture of aspirates from SB – gold

standard for SIBO• Trial avoidance for CHO malabsorption

Breath tests

Calprotectin

“The ESR/CRP of the gut” 24 kDa dimer of calcium binding proteins S100A08 & S100A09 Present in cytoplasm of neutrophils Not degraded by intestinal enzymes or bacteria Normal levels <50 µg/g Neonates have higher levels (up to 200) Non-specific marker of GI inflammation

Good screening test for IBD (Sens & Spec >90%)

Also elevated with NSAIDs

Distal intestinal obstruction syndrome

DIOS – GI manifestation of CF (15% of al CF cases)

Common in adolescents & adults

63% of patients have history of meconium ileus Cardinal features

Cramping RLQ pain

Palpable mass

Reduced stool frequency

Exact aetiology unknown More common with pancreatic insufficiency (despite adequate enzyme

replacement)

DIOS

Management hydrate,

laxatives,

bowel washout,

prokinetics, &

(rarely) surgery

Other GI manifestations of CF

Rectal prolapse (~ 20%)

Increased risk of GI tract tumours

Fibrosing colonopathy Colonic strictures with mucosal & submucosal fibrosis, destruction of the

muscularis mucosa

Increased risk with high dose pancreratic enzyme replacement

Amenable to surgical resection if localised

CF associated liver disease

Most common non-respiratory cause of CF mortality

Spectrum of disease (mild transaminitis to multilobular cirrhosis)

Presentation Frequency (%)Asymptomatic ↑ in liver enzymes 10-35Hepatic steatosis 30-60Focal biliary cirrhosis 11-70Neonatal cholestasis <2Multilobular biliary cirrhosis 5-15

CFLD: Associations/risk factors

Male gender Pancreatic insufficiency Severe genotype ?History of meconium ileus ?Age at diagnosis Alpha-1-Antitrypsin heterozygosity

CFLD: Natural History

Develops before puberty Slow progression from focal biliary cirrhosis to multilobular cirrhosis Approximately 5-10% may develop multilobular cirrhosis Progressive portal hypertension Synthetic dysfunction rare and late event

Mean duration of survival after development of cirrhosis is 4.5 years1

Liver transplant accepted treatment of end-stage chronic liver disease with 5 year survival rate >90%2

Feigelson J, et al. Liver cirrhosis in cystic fibrosis-therapeutic implications and long term follow up. Arch Dis Child 1993;68:653-7

Utterson EC, et al. Biliary atresia: clinical profiles, risk factors, and outcomes of 755 patients listed for liver transplantation. J Pediatr 2005;147:180-185

Exocrine pancreatic insufficiency

Most common cause – Cystic Fibrosis

3 other syndromes associated with EPI: Shwachman-Diamond syndrome

Pearson syndrome

Johanson-Blizzard syndrome

Testing: Steatocrit / 72 hour faecal fat

Faecal elastase or chymotrypsin False positives with diarrhoea (enzyme diluted by stool)

Shwachman-Diamond syndrome

Autosomal recessive (SBDS gene, chromosome 7) Triad of

Pancreatic insufficiency agenesis of pancreatic acinar cells, replaced by fatty tissue

Bone marrow dysfunction (neutropaenia 98%, anaemia 42%, thrombocytopaenia 34%, pancytopaenia 19%)

Skeletal abnormalities dysplasias, oseteoporosis

2nd most common cause of EPI 3rd most common inherited bone marrow dysfunction syndrome (after Fanconi

& Diamond-Blackfan)

Pearson syndrome

Differentiated from Shwachman –Diamond by:

Pancreatic fibrosis (not fatty tissue) Vacoulated erythropoeitic precursors No skeletal abnormalities

Johanson-Blizzard syndrome

Hypoplasia of nasal alae

Fish oils (omega-3 fatty acids) Lipid content of IVN (PN)

Lipid content of IVN (PN)

IFALD (intestinal failure associated liver disease) Old name = TPN cholestasis

Complication on long-term IVN /PN

Type of lipid in IVN impacts on developmemnt and progression of IFALD

Lipid content of IVN (PN)

IFALD (intestinal failure associated liver disease) Old name = TPN cholestasis

Complication on longterm IVN /PN

Type of lipid in IVN impacts on developmemnt and progression of IFALD

Venick. 2011. CurrOpinOrgan Transpl; 16: 306‐311

Risk factors for IFALD

Prematurity & low birth weight

Primary gastrointestinal disease

Lack of enteral nutrition

Catheter-related bloodstream infections

Small bowel bacterial overgrowth (SBBOG)

Prolonged IVN

Excessive IV glucose, amino acids or omega-6 fatty acids

Approach to managing IFALD

Early addition of omega-3 fatty acids for abnormal liver function Cycling of IVN

Introduce breaks in infusion rate

Use of ursodeoxycholic acid Advancement of enteral feeding Prompt treatment of sepsis Ethanol & antibiotic line locks Rotating antibiotic prophylaxis for SBBOG

GLP-2 analogues (Teduglutide)

trophic hormone secreted by enteroendocrine L cells (ileum and right colon)

shown to increase villous height in SBS patients & increase serum citrullinelevels

clinical trials shown to reduce PN requirements in SBS1,2

FDA approved for use in adults

clinical trials in pediatrics underway

1O’Keefe SJ et al. Clin Gastroenterol Hepatol. 2013;11:815-8232Jeppesen PB et al. Gastroenterology. 2012;143:1473-1481

Haemophagocytic Lymphohistiocytosis

Rare, potentially fatal disorder

Overwhelming activation of normal T lymphocyte & histiocytes

Precise underlying pathyophysiology poorly understood

Primary (familial) & Secondary forms

Primary HLH Multiple sub types (various different mutations identified)

PFP (perforin) gene, STX11(syntaxin 11) gene, UNC13D, STXBP-2 (syntaxin binding protein-2) gene

PRF1, Rab27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, XMEN, HPS

Secondary HLH EBV – most common infective trigger

Diagnostic criteria of HLH

Molecular identification of HLH-associated gene OR 5 out of the following 9 findings:

1. Fever >38.5 C2. Spleenomegaly

3. Peripheral cytopaenias (at least 2 cell lines)4. Raised triglycerides5. Low fibrinogen6. Haemophagocytosis in either liver, spleen, lymph node, or bone marrow7. Low/absent NK cell activity8. Raised Ferritin (in the thousands)9. Elevated CD25 (soluble IL-2 receptor)

Intestinal Failure

Definition No international consensus

Multiple definitions – variations on length of residual bowel or duration on PN/IVN dependence

“reduction in gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous

supplementation is required to maintain health and/or growth”

Intestinal Failure

Definition No international consensus

Multiple definitions – variations on length of residual bowel or duration on PN/IVN dependence

Canadian association of Pediatric Surgery definition

“anatomical loss of >75% of expected small bowel length for gestational age”OR

“total parenteral nutrition dependence for >42 days”

AETIOLOGY of IF – 4 categories

1. Critical reduction in the intestinal mass

Short bowel syndrome NEC

small bowel atresias

abdominal wall defects (gastroschisis)

volvulus

AETIOLOGY of IF – 4 categories

1. Critical reduction in the intestinal mass

2. Poor tolerance of feeds

Motility disorders Gastroschisis

Chronic intestinal pseudo-obstruction (CIPO)

Hirschprungs

AETIOLOGY of IF – 4 categories

1. Critical reduction in the intestinal mass

2. Poor tolerance of feeds

3. Abnormal enterocyte function

Congenital enteropathies Microvillous inclusion disease

Tufting enteropathy

AETIOLOGY of IF – 4 categories

1. Critical reduction in the intestinal mass

2. Poor tolerance of feeds

3. Abnormal enterocyte function

4. Multi-system disease

IPEX

Mitochondrial disorders

Congenital glycosolation defects

Jeans

Jeans Jeans

Gene SPINK1

NOTCH2

Serpina1

STK11

RET

ATP7B

UGTP81

SBDS

Disease / Syndrome Familial pancreatitis

Alagille syndrome

A1AT deficiency

Peutz-Jeghers syndrome

Hirschsprungs

Wilsons disease

Gilberts syndrome

Schwachman-Diamond

Kcals

Energy content of 3 major food groups:

1. Carbohydrates = 4 cal/gm

2. Protein = 4 cal/gm

3. Fat = 9 cal/gm

RULE OF 4-4-9

Lactose intolerance

Lactose (disaccharide) glucose + galactose (by lactase)

Lactose – unique to mammalian milk

Lactose “intolerance”

“result of a genetically programmed progressive loss of the activity of the enzyme lactase”

Do not confuse with Cow’s Milk Protein Intolerance (CMPI)“milk protein allergy”

Different types

CONGENITAL Congenital lactase deficiency

Very rare

Autosomal recessive

LCT gene (chromosome 2)

ACQUIRED Natural, age-related decline in

lactase

Transient (post-infectious, coeliac related etc)

Lactase deficiency

Marked racial differences in prevalance

Scandanavia & Northwest Europe 3-8%

Southeast Asia close to 100% Southern Italy & Turkey 70%

Breath testing for lactose intolerance

Feed lactose measure expired H2

Rise in 10-20 ppm positive test

Usually peaks at 2-4 hours

Earlier peak (within 1 hour) may reflect Rapid bowel transit time

Bacterial ovewrgrowth

Substrate fermentation by oral flora

CarbohydrateDigestion Starches,

sucrose, lactose

Salivary amylase

Pancreatic amylase

maltose, isomaltose, glucose polymers, sucrose, lactose

Brush border enzymes

MaltoseIsomaltose

MaltoseIsomaltose

GlucoseGlucoseSucrase-isomaltase

Brush border enzymes

Glucose polymersGlucose polymers

GlucoseGlucoseglucoamylase

Brush border enzymes

SucroseSucroseGlucoseFructoseGlucoseFructose

sucrase

Brush border enzymes

LactoseLactoseGlucose

GalactoseGlucose

Galactoselactase

Monosaccharide transporters

Glucose, galactose

Na+

SGLT1

NaKATPase

Apical membrane Basolateral membrane

enterocyte

Glucose-galactose malabsorption

Gut lumen circulation

Monosaccharide transporters

Glucose, fructose

Fructose

GLUT2

Apical membrane Basolateral membrane

enterocyte

Fructose malabsorption

Gut lumen circulation

GLUT5

Fructose intolerance from defective enterocyte transporters

NOT THE SAME AS

Hereditary Fructose IntoleranceRare, autosomal recessive disorder

fructose 1-phosphate aldolase deficiency(metabolism of fructose)

Mycophenolate mofetil Mycophenolate mofetil

Side effects:

Diarrhoea Cytopaenias (neutropaenia, anemia) Nausea, vomiting

Thrombosis/thrombophlebitis (IV formulation)

Mechanism of action:

Inhibits synthesis of guanosine monophosphate nucleotides

blocks purine synthesis, preventing proliferation of T and B cells

Case

3 week old baby girl

Frequent small non-bilious vomits for past 3 days

O/E: Non-dysmorphic

Not jaundiced

Breathless

Distended abdomen

Normal bowel sounds

Neonatal haemangiomas Neonatal haemangiomas

Most common benign hepatic tumour in children

Typically regress without intervention

Can use propanolol

Emobolisation (interventional radiology)

Massive hepatic haemangiomas associated with hypothyroidism tumor expresses type 3 iodothyronine deiodinase

results in an increased rate of inactivation of thyroid hormone

Orofacial granulomatosis

Granulomatous inflammation of the oral +/- maxillofacial region

Can be present in isolation

But also a rare manifestation of Crohn’s disease

Orofacial granulomatosis

Initially – painless swelling of lips Usually lower lip

Can progress fissuring disease

Orofacial granulomatosis

Apthous ulcers in the mouth

Investigate for Crohn’s

Treat if Crohn’s (usual therapies)

Topical steroids / tacrolimus

Cinamon & benzoate free diet

Protein losing enteropathy

Aeitology of PLE – 3 broad categories

1. lymphatic obstruction Lymhangictesia, constrictive pericarditis

2. mucosal erosion or ulceration Infection, inflammation

3. epithelial cell dysfunction in the absence of macroscopic compromise Congenital glycosolation defects

Protein losing enteropathy

PLE is a symptom, not a disease Treat underlying condition

PLE post Fontan procedure Exact mechanism poorly understood; proposed mechanisms include:

early elevations of postoperative central venous pressure,

low pulmonary vascular compliance, and

elevated serum hepatocyte growth factor

Very difficult to treat Low fat diets, oral budesonide, octreotide

Quality over Quantity Short Bowel Syndrome

Most common cause of IF in pediatrics1

NEC - 30% of all cases

Remaining neonatal causes: intestinal atresias

abdominal wall defects

malrotation/volvulus

long segment Hirschprungs

1Christison-Lagay et al. Seminars in Ped Surg 2010

Management of SBS Adaptation in SBS

Tappenden KA, JPEN J Parenter Enteral Nutr. 2014;38(suppl 1):23S-31S

Enteral autonomy

Factors that promote enteral autonomy:

residual small bowel length

intact ICV

primary diagnosis of NEC

>50% residual colon

no small bowel ostomy

decreased serum conjugated bilirubin at referral

care & follow-up at the same center

Citrulline

Amino acid produced by small bowel enterocytes

Biomarker of remnant small bowel mass and function

Low serum levels noted in conditions with low small bowel mass and/or function Short gut syndrome, villous atrophy

Note: levels can be elevated with co-existing renal impairment

Recurrent acute pancreatitis

Acute pancreatitis in children

Idiopathic (25%) abdominal trauma (23%) anomalies of the pancreaticobiliary system (15%) multisystem disease (14%) drugs and toxins (12%)

azathioprine, tetracycline, L-asparagine, valproic acid, steroids, and immunosuppressive agents

viral infections (10%) hereditary disorders (2%), and metabolic disorders (2%)

hypertriglyceridemia, hypercalcemia, cystic fibrosis

Hereditary pancreatitis

Candidate gene and genetic linkage studies have identified polymorphisms in

1. Cationic trypsinogen gene (PRSS1)

2. Serine protease inhibitor kazal type 1(SPINK1),

3. Cystic fibrosis trans-membrane conductance regulator (CFTR) gene,

4. Chymotrypsinogen C (CTRC),

5. Cathepsin B (CTSB) and

6. Calcium sensing receptor (CASR)

Kanth RV et al. World J Gastrointest Pathophysiol 2014 Nov 15;5(4):427-37

Serpina1 gene (A1AT def)

120 different alleles on chromosome 4

125 different single nucleotide polymorphisms for Serpina1 identified

Low serum level of A1AT Due to intracellular retention of the defective protein (within hepatocytes)

Loss of protection from various proteases such as neutrophil elastase Emphysema in lungs &

Hepatocyte destruction

The Z variant - allele overwhelmingly associated with liver disease (PiZZphenotype)

• Photomicrograph of human Pi*ZZ liver• Human Pi*ZZ liver stained with H&E (left

panel) and • Periodic Acid-Schiff with digestion (PAS

with digestion, right panel) • Showing inclusions (“globules”) of AAT

mutant Z polymerized protein visible within some hepatocytes (arrows)

A1AT deficiency

Liver biopsy findings may be highly variable in infants including giant cell transformation, lobular hepatitis, significant steatosis, fibrosis,

hepatocellular necrosis, bile duct paucity or bile duct proliferation

gold standard for the diagnosis of AATD is the analysis of the “phenotype” of AAT protein (NOT level, A1AT is an acute phase protein)

80% of Pi*ZZ patients presenting with neonatal cholestasis are healthy and free of chronic disease by age 18 years

overall risk of life-threatening liver disease in childhood is about 5%

Teckman JH, COPD 2013 Mar;10 Suppl 1:35-43

Tacrolimus

Tacrolimus (side-effects)

Nephrotoxicity

Hypertension

Low magnesium

Neurotoxicity Headaches, paraesthesias

Arrythmias

CYCLOSPORIN Renal impairment (worse than tac) Gingival hypertrophy Hirsutism

Unconjugated hyperbilirubinaemia

Crigler-Najjar Syndrome -1

Autosomal recessive

Absent enzyme (bilirubin uridine diphosphate glucoronosyltrsnsferaseenzye) – UGTA1A gene

High levels of serum Bili kernicterus, neruological impairment

Prompt treatment – phototherapy, exchange transfusion

Liver transplantation – only definitive cure

Unconjugated hyperbilirubinaemia

Crigler-Najjar Syndrome -2

Autosomal dominant transmission with variable penetrance and autosomal recessive transmission have both been reported

Milder phenotype

Often asymptomatic

Lower levels (<10% of normal) of UGDT enzyme levels

Bili levels respond to treatment with Phenobarbital

Unconjugated hyperbilirubinaemia

Gilbert’s syndrome Same spectrum of disease at Crigler-Najjar

Normal amounts of UGDT enzyme (but reduced activity)

Mild disease phenotype (compared to CN-1)

Dubin Johnson syndrome

Rotor syndrome

VEO-IBD (very early onset IBD)

Often significant perianal disease Eg: IL-10 deficiency

BMT curative option for some (not all) Depending on genetic defect

Kelsen JR, Current Opinion in Pediatrics. 29(5):566–571, OCT 2017Zhu L et al. Gastroenterology Res.. 2017 Apr; 10(2): 65–69

Worms Worms

Based on numerous reports in the literature, a rough estimate of the occurrence (percent of total complications) of complications is as follows: Intestinal obstruction - 63% Bile duct obstruction - 23% Perforation, peritonitis, or both - 3.2% Volvus - 2.7% Hepatic abscess - 2.1% Appendicitis - 2.1% Pancreatitis - 1% Cerebral encephalitis - 1% Intussusception - 0.5%

Worms

The World Health Organization (WHO) recommends 4 drugs in helminithicinfection control (ie, ascariasis, hookworm infection, pinworm infection, strongyloidiasis, and trichuriasis):

1. albendazole, 2. levamisole, 3. mebendazole, and 4. pyrantel embonate.

All four have a cure rate of more than 90% in patients with ascariasis.

IPEX

Immunedysregulation Polyendocrinopathy Enteropathy X-linked syndrome

Most commonly manifests with early onset, insulin-dependent diabetes mellitus; severe watery diarrhea, (often with accompanying FTT) and dermatitis.(other phenotypic variations exist)

Mutations in FOXP3 gene Most children die (if untreated) before 2 years HSCT only curative option

Yersinia

CAN MIMIC ACUTE APPENDICITIS(RIF PAIN)

Zinc deficiency

In infancy periorificial and acral dermatitis diarrhoea behavioral changes neurologic disturbances

In older children Failure to thrive anorexia, alopecia, nail dystrophy repeated infections

Acrodermatitis enteropatica

BEFORE TREATMENT AFTER TREATMEMNT

QUESTIONS ?