Post on 10-Mar-2018
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 ?