Gastroenterology Flashcards
Which syndromes associated with Wilms tumor
WAGR
Denys Drash syndrome
BWS
Hemihypertrophy
Cryptorchidism
Hypospadias
Diet in nephrogenic DI should be low in?
salt and protein
Rumination syndrome
The Rumination syndromes diagnostic criteria is as follows: (must include all of the following)
Persistent or recurrent regurgitation of recently ingested food into the mouth with subsequent spitting or remastication and swallowing
Regurgitation is not preceded by retching.
*The criteria must be fulfilled for the last three months with symptom onset at least six months prior to diagnosis.
Supportive criteria for Rumination syndrome:
Effortless regurgitation events are usually not preceded by nausea
Regurgitant contains recognisable food which may have a pleasant taste
The process tends to cease when the regurgitated material becomes acidic
Gilbert syndrome
mildly reduced activity of UDP glucoronyl transferase
isolated unconjugated hyperbilirubinemia
jaundice in times of periods of illness/stress/dehydration
neonatal unconjugated hyperbilirubinemia
pre hepatic
Increased bilirubin load:
- increased RBC breakdown (haemolytic and non hemolytic) - immune (Rh/ABO incompatibility), G6PD/pyruvate kinase def, hereditory spherocytosis, hemaglobinopathies (alpha thalassemia), polycythemia
- increased enterohepatic circulation (breast feeding jaundice, CF, hirshprungs)
- polycythemia
Impaired conjugation:
- hypothyroidism - reduced rate of conjugation and slowed gut motility
- crigler najjar syndrome- deficiency or impaired activity of UDP-glucoronyltransferase
- Breastfeeding jaundice: Infants who are breastfed receive only small volumes of colostrum in the first days of life, which leads to dehydration and increased uptake of conjugated bilirubin from the intestines)
- Breast milk jaundice: develops in the second week of life, lasts longer than physiologic jaundice, and has no other identifiable cause.
hepatic
reduced ability of liver to conjugate and thus excrete bili
- urea cycle defects, galatossaemia, FA oxidation defects
- TORCH infections
post hepatic - impaired excretion
biliary atresia (most common)
infection- sepsis/TORCH
Allagile
inborn errors metabolism
PFIC
CF
choledocal cyst
metabolic causes of neoantal hyperbilirubinemia
urea cycle defects
FA oxidation defects
galactossaemia
urine reducing substances tests for
galactosaemia
**but main test for galactosaemia is GALT activity
what does a hypoglycemia screen consist of
glucose, ketones (Beta-hydroxybutyrate), insulin, cortisol, Growth Hormone (GH), ammonia, lactate, free fatty acids, serum amino acids, acylcarnitines profile (Guthrie card) and urine for organic acids and ketones.
features of neonatal galactossemia
defect in the enzyme galactose-1-phosphate uridyl transferase (GALT), important in breakdown of galactose (from lactose) into glucose 6 phosphate –> accumulation of galactose-1-phosphate results in damage to the brain, liver, and kidney
feed intolorence - vomiting, hypoglycemia
weight loss
HEPATOMEGALY +/- splenomegaly
later –> cataracts
e. coli sepsis
Ix:
Raised LFTs , conjugated hyperbilirubinemia
Coagulopathy
+/- hypoglycemia
urine reducing substances
reduced GALT activity
genetics
causes conjugated hyperbilirubinemia
BA
Neonatal hepatitis
infectious eg sepsis, cmv
metabolic - eg galactosemia, tyrosinemia
A1AT deficiency
Allagille syndrome
choledocal cyst
bile plug- cystic fibsosis
TPN cholestasis
prolonged unconjugated hyperbili can lead to
SNHL
kernicterus
athetoid CP
more at risk if
- high level
- unwell, acidotic, hypoxemic
- prem, small
- low albumin
NOT Conjugated
biliary atresia
common cause of conjugated hyperbilirubinemia
extrahepatic bile ducts affected - poor bile flow- builds up causing damage (kasai cant fix damage to intrahepatic ducts from build up of bile by time of surgery)
need to diagnose by 6-8 weeks for kasai to be effective- but most go on to need liver Tx
Suspect if conjugated bili, elevated GGT, ALP (cholestasis). BSL/albumin/coags usually normal
pale stool, dark urine is not that common in real life
usually well appearing, and well grown (but can be small)
Firm hepatomegaly (NOT SPLENOMEGALY)
Initial Ix: ultrasound after 4 hour fast –> contracted or non visualised GB
gold standard ix: cholangiogram
Gestational alloimmune liver disease (GALD)
aka neonatal haemochromoatosis
rare cause of liver failure in neonates
Maternal antibodies that attack fetal hepatocytes. The fetal immune response to the antibodies causes liver damage
Ix: elevated ferritin, coagulopathy, hypoglycemia
pancreatic/liver iron accumulation
Rx: maternal IVIG in pregnancy
IVIG /exchange transfusion for baby
TPN leads to
death of enterocytes if no enteral feeding –> lose barrier function -> intestinal bacterial overgrowth
sepsis
cholestasis
Alpha 1 antitrypsin deficincy
A1AT = antiprotease
protects lungs from elastase secreted by neutrophils
mutated A1AT gets stuck in the liver and cant get out- accumulates in liver and causes liver damage; and cant reach lungs
Lack of A1AT in lungs lead to damage by neutrophil elastase
A1AT level
- unreliable as is an acute phase reactant (thus is normal when sick)
A1AT phenotype + genotype
Presentation: neonatal hepatitis with cholestasis beginning in the first few months of life, and approximately 65 percent of these have severe liver disease
-hepatomegaly
- can present later with isolated elevated aminotransferase levels
AAT-associated liver disease that presents in the neonatal period often resolves spontaneously, and this presentation is not necessarily associated with a worse prognosis compared with later presentation during childhood
Liver transplantation has improved the prognosis of infants with severe liver disease
ATP7B gene mutation.
Wilson’s disease
Perinatal chrons treatment
Metronidazole
Influximab
B2 (riboflavin) deficiency leads to
. Symptoms may include cheilosis, high sensitivity to sunlight, angular cheilitis, glossitis, dermatitis or pseudo-syphilis, or pharyngitis.
Allergic procrocolitis
Food protein-induced proctitis/proctocolitis is found almost exclusively in infants, who are either breastfed or fed standard cow’s milk- or soy-based formulas. Food protein-induced proctitis or proctocolitis has two peculiar clinical aspects.
First, that an orally ingested protein induces an inflammatory response limited to the rectum and distal sigmoid colon.
Secondly, that the vast majority of infants manifesting this condition are breastfed, with less common involvement in infants fed with cow’s milk or soy protein based formulas
Infants are generally healthy but pass blood-tinged stools and mucus; some may be fussy or have increased frequency of bowel movements, but frank diarrhoea is not typical. Indeed, the parent usually reports that otherwise the child is well.
The disorder typically presents between two and eight weeks of age, although there may be a history of bleeding several weeks prior to diagnosis that may have been erroneously attributed to anal fissures. Presentation as early as the first week of life has been described.
With complete elimination of the offending protein from the mother’s diet or formula, clinical bleeding typically clears within three days.
Best test to rule out coeliac disease
Negative predictive value of absence of both HLA DQ2 and HLA DQ8 is 100% (CI 98.4 – 100).
Negative predictive value of absence of Anti-tTG is 99.3% (CI 98.0 – 99.9).
Main function vit d
Increase intestinal absorption of calcium
Forms of vitamin d
It can be ingested, or synthesised from a cholesterol precursor as follows:
7-dehydrocholesterol is converted into vitamin-D3 under the influence of UV radiation.
In the liver, vitamin-D3 is converted into 25-hydroxyvitamin-D by 25-hydroxylase. This is relatively inactive.
In the kidney, 1-α-hydroxylase converts 25-hydroxyvitamin-D into 1,25-dihydroxyvitamin-D, otherwise known as calcitriol. This is metabolically active.
PTH increases calcium levels by
Increasing bone resorption: PTH binds to osteoblasts and upregulates the expression of a protein called RANKL. This stimulates pre-osteoclasts to differentiate into osteoclasts. Osteoclasts resorb bone and release calcium into the bloodstream
Increasing renal reabsorption of calcium: PTH upregulates the expression of specific channels in the distal convoluted tubule (DCT). This leads to increased reabsorption of calcium into the blood, and also increases excretion of phosphate.
Increasing synthesis of calcitriol: In the kidney, PTH upregulates the expression of 1-α-hydroxylase. This enzyme catalyses the conversion of the relatively inactive 25-hydroxycholecalciferol into calcitriol.
Additionally, PTH and calcitriol inhibit the secretion of PTH from the parathyroid gland. This negative feedback loop ensures blood calcium levels do not continue to rise and go beyond the normal range.
Hypocalcemia
Hypocalcaemia is defined as an adjusted calcium level of <2.20mmol/L.
Patients who develop hypocalcaemia acutely tend to be more symptomatic compared to patients who develop hypocalcaemia over a long period of time (chronic hypocalcaemia).
The symptoms of hypocalcaemia include peri-oral and peripheral numbness or tingling, cardiac arrythmias (prolonged QT interval on ECG), muscle spasms, and seizures. This is due to a reduction in the resting membrane potential, rendering the cell hyper-excitable.
Causes of hypocalcaemia include:
Hypoparathyroidism
Vitamin D deficiency
Hyperphosphatemia: Phosphate binds to calcium to form calcium phosphate, reducing free calcium.
Renal disease: Reduced calcitriol synthesis.
Acute pancreatitis: Free fatty acids bind calcium, reducing levels of free calcium.
Respiratory alkalosis: In alkalosis, calcium ions associate with albumin with greater affinity, thus reducing free and active calcium.
Hypercalcemia
Hypercalcaemia is defined as an adjusted calcium level of >2.60mmol/L.
Patients with mild hypercalcaemia tend to be asymptomatic, but when levels exceed 3mmol/L, symptoms include muscle weakness, cardiac arrhythmias (short QT interval), constipation, kidney stones and depression.
Causes of hypercalcaemia include:
Hyperparathyroidism
Malignant tumour – Some tumours secrete parathyroid-hormone related peptide (PTHrP). This mimics PTH, leading to hypercalcaemia.
Vitamin D intoxication – excess vitamin D causing increased intestinal absorption of calcium.
Thiazide diuretics – increase renal reabsorption of calcium causing excess calcium in blood.
Progressive familial intrahepatic cholestasis
mutation in bile salt transporter- accumulation of bile salts within hepatocytes (intrahepatic chlestasis)
type 1- presents early with hepatitis/cholestasis (ATP8B1 mutation)
type 2- presents later (ABCB11 mutation)
The onset of the disease is usually before age 2. Of the three entities, PFIC-1 usually presents earliest and is a multisystem disease.
Patients usually present in early childhood with cholestasis, jaundice, and failure to thrive. Intense pruritus is characteristic. Patients may have fat malabsorption, leading to fat soluble vitamin deficiency
PFIC1: + watery diarrhoea
Ix: elevated serum bile salts, elevated bili and ALP, GGT normal in type 1 and 2, high in type 3.
Liver biopsy= electron microscopy showing coarse granular bile and light microscopy showing bland cholestasis (type 1) or giant cell hepatitis (type 2) . Genetic testing is the only reliable way to distinguish between PFIC 1 and PFIC 2.
Type 2:
-higher risk of HCC in very young age than other conditions
- high incidence gallstones
no real treatment
eventually needs transplant
MYO5B mutation
microvillous inclusion disease
alpha 1 antitrypsin gene
SERPINA1
Hep b e antigen
corrolates with active replication and infectivity
HBe appears first, before HBs Ag
acute hep b phases
Replicant phase:
- HBeAg +
- high DNA viral load
- high transaminases
Inactive carrier state:
- HbeAg neg (implies low viral load)
- Normal liver enzymes
Resolution:
HbsAg neg
Anti HbsAb positive (immunity)
chronic hep b phases
immunotolorent
- normal liver enzymes
- high viral load
- HBeAg + due to replication
clearance
- abnorma liver enzymes
HBeAg neg
chronic HbsAg+ phase
-low viral replication
Hep B medications
Entacavir - nucleoside reverse transcriptase inhibitor
Tenofovir -nucleoside reverse transcriptase inhibitor
what type of virus is hep b
DNA
hep c transmission
blood
vertical
Hep C medications
sofosbuvir + ledipasvir
inhibitor of RNA polymerase - chain terminator
curative
Wilsons disease
AR
ATP7B gene
mutation: impaired function of the intracellular copper transporter. inability biliary copper excretion –> accumulation of copper in liver + brain + cornea
–> psychiatric symptoms, liver cirrhosis and failure
can present with neuropsychiatric disorder, chronic liver disease, or acute liver failure
KF rings have no impact on vision- diagnostic only
Rx: penicillamine, treatine if penicillamine not tolerated
Zinc- competes for copper absorption
If asymptomatic sibling without liver dieases- still start zinc to prevent liver damage
Wilsons investigations
ALP/AST usually mildly to moderately elevated in presymtomatic stage
hemolytic anemia (coombs positive)
elevated serum copper
low free ceruloplasmin (impaired hepatic incorporation of copper into ceruloplasmin, leading to a reduction in total circulating ceruloplasmin )
high urinary copper excretion , especially with penicillamine challenge
liver biopsy- high copper dry weight
eye review
Autoimmune hepatitis
Type 1- SMA positive, ANA positive
Type 2- LKN positive
- type 2 usually more severe, more treatment failure
clue- deranged LFTs including elevated conjugated bili (but may be normal), high AST/ALP, GGT but HIGH PROTEIN
Confirmed by liver biopsy
Rx: pred
2nd line- azathioprine/6MP
3rd line- mycophenolate
primary sclerosing cholangitis
inflammation (cholangitis) and scarring of bile ducts (sclerosis)
leads to progressive liver disease and cholestasis (jaundice, itch, abdo pain)
complications:
ascending cholangitis (fever, jaundice, RUQ pain)
portal HTN
risk colangiocarcinoma
Rx:
stenting strictures
liver transplant
if asociated with UC- colectomy may improve PSC
Fatty liver disease
simple steatosis (fat in liver)
steatohepatitis (fat causes inflammation)
cirrhosis
causes pancreatitis
PRSS1 and SPINK1 gene mutations
Cystic fibrosis
Adverse reaction from 6MP/azathioprine, valproate, ACEI, diuretics, asparaginase
gallstones (especialy bile pigment stones from hemolytic disease)
choledocal cyst
trauma
hyperlipidemia
Hypercalcemia
viral
rapid refeeding after starvation
antitrypsin deficiency
when to think metabolic or storage disease if hepatomegaly noted
associated splenomegaly
recurrent vomiting and FTT
hypoglycemia
unwell
portal HTN
> 12 mmHg
usuaully leads to splenomegaly due to congestion
management of upper GI bleed
ABC
IV PPI (improves platelet function)
IV antibiotics (sepsis precipitates variceal bleeding, bacterial infection present in up to 65% bleeders, may be SBP)
IV octreotide
Endscopy to band site of bleeding
action of lactulose in liver failure
prevents and treats encephalopathy
reduces intestinal production and absoprtion of ammonia
what is absorbed in duodenum
IRON and folic acid
what is absorbed in the jejunum
folic acid
carbs
water soluable vitamins
what is absorbed in the ileum
B12
bile salts
fatty acids
fat soluable vitamins
where are calcium/magnesium/phosphate absorbed
dupdenum + proximl jejunum
where are fat soluable vitamins absorbed
upper to mid small intestine
what is SGLT1 important for?
transporter on luminal side of enterocyte
absorption of glucose/galactose alongside sodium
= cotransporter
how is fructose absorbed?
GLUT5 transporter
what is GLUT2 important for in digestion
transporter on blood side of enterocyte
exit of sugars into the circulation
what nutritional deficiencies are associated with glossitis, cheilitis, stomatitis
B3
also B2, B12, iron
Stool investigations
pH <6 suggests osmotic diarrhoea/carbohydrate malabsorption
Reducing substances >0.5 is abnormal - carbohydrate maabsorption
Stool electrolytes- Na ~30, K ~75
High osmolar gap suggests osmotic diarrhoea
Low osmolar gap suggests secretory diarrhoea
osmotic diarrhoea
caused by non absorbed nutrients in the lumen dragging water out into gut
stops with fasting
high osmolar gap >100 (290-2xNa+K) ie low concentration of sodium and potassium in stool
reducing substances present
pH <5
eg
osmotic laxatives
Mucosal injury eg post rotavirus, IBD, coeliac
disaccharide deficiency
monosacharide transport defect
transport overload eg too much sugar or fruit00
secretory diarrhoea
drags water out into the gut with sodium (reduced absorbtion or increased secretion of electrolytes into gut lumen)
No effect to fasting
higher volume poo
low osmolar gap <50 as high stool electrolytes, Na >90
absent reducing substances
pH >6
eg. congenital transport and mucosal defects eg congenital chloride diarrhoea, microvillus inclsion, tufting enteropathy
bacterial toxins - cholera, E.coli, salmonella, shigella, c.diff, yesrsinia
Parasites: cryptosporidium
Hormone secreting tumor
bile acid malabsorption
short gut
rapid transport
fat globules or crystals in stool
Fat globules = intraluminal problem e.g. failure of enzyme process or bile to suspend fats = maldigestion
Fatty acid crystals = mucosal/brush border problem (fatty acid not absorbed) = malabsorption e.g. celiac disease, infection (Giardia), cows milk enteopathy
intestinal lymphangiectasia- broken down but not absorbed into lymphatics
Lymphangectasia
chronic protein losing enteropathy characterised by lymphatic vessel dilatation, chronic diarrhoea and loss of serum albumin/globulin oedema and ascites. Reduced lymph flow leads to malabsorbtion. Most commonly due to congenital malformation of the lymphatics
low Immunoglobulins and albumin
A1AT in stool
which sugars are non reducing
sucrose non reducing
all monosacharides, lactose, maltose are reducing
assessing malabsorption
stool electrolytes, pH, reducing sugars
Melanosis choli seen in
Laxative use
Eg senna
Cause early onset diarrhoea
Congenital chloride diarrhoea (chloride-losing diarrhoea) — rare recessive inherited disorder caused by mutations in a chromosome 7 gene. The chloride/bicarbonate transport mechanism in the distal ileum and colon is defective, causing severe watery diarrhoea, beginning at birth. Maternal polyhydramnios is common. Watery diarrhea leads to dehydration and a severe electrolyte disturbance characterized by hypokalemia, hypochloremia, and alkalosis, a most unusual pattern for an infant with chronic diarrhea. Other aspects of intestinal absorption are normal. Stools contain chloride in excess of the sum of sodium and potassium (125–150 mEq/L). Treatment does not alter diarrhoea but diminishes complications. All losses of electrolytes and water are at first replaced intravenously; oral solutions are usually tolerated after one month. If the diagnosis is made early in the neonatal period and adequate therapy started immediately, the affected infant will show perfect growth and development.
B: Fructose malabsorption, formerly named “dietary fructose intolerance,” is a digestive disorder in which absorption of fructose is impaired by deficient fructose carriers in the small intestine’s enterocytes. This results in an increased concentration of fructose in the entire intestine. Fructose malabsorption is found in up to 40% of the population of Western countries.
C: Glucose-galactose malabsorption. More than 30 different mutations of the sodium/glucose co-transporter gene (SGLT1) are identified. These mutations cause a rare autosomal recessive disorder of intestinal glucose and galactose/Na+ co-transport system that leads to osmotic diarrhoea. Presents with severe life-threatening diarrhoea and dehydration during the neonatal period. Since most dietary sugars are polysaccharides or disaccharides with glucose or galactose moieties, diarrhoea follows the ingestion of glucose, breast milk, or conventional formulas. Patients are symptomatic as long as their diet includes lactose or its hydrolysis products, glucose and galactose. The diagnosis is suspected if the diarrhoea resolves promptly when these sugars are eliminated, and confirmed by a positive glucose breath hydrogen test and normal intestinal biopsy. Treatment is with a fructose-based formula, and lifelong dietary restriction of the causative sugars.
E: Sucrase-isomaltase deficiency is a rare autosomal recessive disorder with a complete absence of sucrase and reduced maltase digestive activity. Symptoms of sucrase-isomaltase deficiency usually begin when the infant is exposed to sucrose or a glucose polymer diet. This can occur with ingestion of non–lactose based infant formula or on the introduction of pureed food, especially fruits and sweets. Diarrhea, abdominal pain, and poor growth are observed. Diagnosis of sucrase-isomaltase malabsorption requires acid hydrolysis of stool for reducing substances because sucrase is a nonreducing sugar. Alternatively, diagnosis can be achieved with hydrogen breath test or enzyme assay of small bowel biopsy. The mainstay of treatment is lifelong dietary restriction of sucrose-containing foods.
Peutz Jegher
D: STK11 mutation causes Peutz-Jegher, which manifests as GI hamartomatous polyposis and pigmented macules on the lips/gums.
calories in common formulas
Average length small intestine
adult- 6m
1 yo 3.8m
neonate 2.5 m
prem 28 week 1.5m
large intestine length in adult 1.5m
parietal cells of stomach
produce HCl and intrinsic factor
histamine produced by stomach mucosa, stimulates parietal cells to release HCl
chief cells of stomach
secrete pepsinogen
*pepsinogen is converted to pepsin in presence of HCll
G cells of stomach
neuroendocrine cells
secrete gastrin–> Increases secretion by gastric glands; promotes gastric emptying and intestinal contraction an relaxes ileocecal valve
cholecystokinin
CCK is synthesized and released by enteroendocrine cells in the mucosal lining of the small intestine (mostly in the duodenum and jejunum), called I cells, neurons of the enteric nervous system, and neurons in the brain.[5] It is released rapidly into the circulation in response to a meal. The greatest stimulator of CCK release is the presence of fatty acids and/or certain in the amino acids in the chyme entering the duodenum
Actions:
Inhibits gastric emptying
Stimulates contraction of gallbladder
Stimulates secretion of pancreatic enzymes
Satiety
EoE
- Primarily a food allergy
- Allergen presented to T cells in oesophagus -> inflammatory response by TH2 cells and IL 13 eosinophils and mast cells secretes proteases, cytokines and histamine tissue remodelling and inflammation fibrosis (strictures in severe cases)
- In older children, mainly presents as food impaction, dysphagia, odynophagia, reflux
- Younger children often present as reflux, vomiting, gagging, difficulty feeding
- Treatment: PPI, diet (remove allergen), steroids (topical- fluticasone, budesonide), biologics
- 30% of kids respond to PPI alone
Zollinger–Ellison syndrome
presence of gastrinoma, a neuroendocrine tumor that secretes a hormone called gastrin.[2] Too much gastrin in the blood (hypergastrinemia) results in the overproduction of gastric acid by parietal cells in the stomach.
—> peptic ulcers and chronic diarrhoea
25% occur as part of MEN1
Glucose-galactose Malabsorption
Mutations of the sodium/glucose co-transporter gene (SGLT1)—> osmotic diarrhoea.
Presents with severe life-threatening diarrhoea and dehydration during the neonatal period.
Diarrhoea follows the ingestion of glucose, breast milk, or conventional formulas. Patients are symptomatic as long as their diet includes lactose or its hydrolysis products, glucose and galactose. The diagnosis is suspected if the diarrhoea resolves promptly when these sugars are eliminated, and confirmed by a positive glucose breath hydrogen test and normal intestinal biopsy.
Treatment is with a fructose-based formula, and lifelong dietary restriction of the causative sugars.
herediotory fructose intolorence (aldose B deficiency)
Deficiency of fructose-1,6-bisphosphate aldolase is a severe condition of infants that appears with the ingestion of fructose-containing food (therefore start around 6 months of age) and is caused by deficiency of fructose aldolase B activity in the liver, kidney, and intestine.
Children present with hypoglycemia and vomiting following fructose ingestion Additional clinical manifestations include hepatomegaly, lactic acidosis, and failure to thrive. If exposure to fructose continues, the affected individual may develop liver failure and renal tubular dysfunction. Undiagnosed children may develop a self-protective aversion to fructose and sucrose-containing foods
first test for lactose intolorence
stool pH (<6) and reducing substances >0.5
MOA omeprazole
Omeprazole reversibly reduces gastric acid secretion by specifically inhibiting the gastric enzyme H+, K+-ATPase, the proton pump, in the acid environment of the intracellular canaliculi within the parietal cell.
This effect of omeprazole on the final step of the gastric acid formation process is dose dependent and effectively inhibits both basal acid secretion and stimulated acid secretion, irrespective of the stimulus to acid production.
MOA ranitidine
what stool tests can be used to screen for CF
elastase
chymotrypsin
trypsin
triad of vasocclusive disease
- weight gain caused by fluid retention
- tender hepatomegaly
- hyperbilirubinaemia
which antibiotics are assciated with c.diff
augmentin
refeeding syndrome is marked by:
§ Hypophosphatemia
§ Hypokalemia
§ Hypomagnesemia
§ Vitamin (e.g. thiamine) and trace mineral deficiencies
§ Volume overload
§ Oedema
Hypophosphatemia is the hallmark of the syndrome and predominant cause of the refeeding syndrome.
Serum PO4 < 0.5mmol/L results in weakness, rhabdomyolysis, neutrophil dysfunction, cardiorespiratory failure, arrhythmias, seizures, reduced level of consciousness. It results from a sudden shift from fat to CHO metabolism: sudden increase ininsulin levels results inincreasedcellular uptake of phosphate.
congenital chloride diarrhoea
The chloride/bicarbonate transport mechanism in the distal ileum and colon is defective, causing severe watery diarrhoea, beginning at birth. Maternal polyhydramnios is common. Watery diarrhea leads to dehydration and a severe electrolyte disturbance characterized by hypokalemia, hypochloremia, and metabolic ALKALOSIS (unusual pattern for diarrhoea) Stools contain very high chloride in excess of the sum of sodium and potassium (125–150 mEq/L).
Treatment does not alter diarrhoea but diminishes complications. All losses of electrolytes and water are at first replaced intravenously; oral solutions are usually tolerated after one month. If the diagnosis is made early in the neonatal period and adequate therapy started immediately, the affected infant will show perfect growth and development.
Sucrase-isomaltase deficiency
Rare autosomal recessive disorder with a complete absence of sucrase and reduced maltase digestive activity (cant break down sucrose or maltose to glucose).
Symptoms usually begin when the infant is exposed to sucrose or a glucose polymer diet. eg. introduction of pureed food, especially fruits and sweets.
Diarrhea, abdominal pain, and poor growth are observed.
Diagnosis of sucrase-isomaltase malabsorption requires acid hydrolysis of stool for reducing substances because sucrase is a nonreducing sugar. Alternatively, diagnosis can be achieved with hydrogen breath test or enzyme assay of small bowel biopsy.
The mainstay of treatment is lifelong dietary restriction of sucrose-containing foods.
Gilbert’s syndrome
It’s the commonest inherited cause of hyperbilirubinaemia, is autosomal recessive, and it’sbenign.
It presents as intermittent jaundice with no haemolysis or liver disease. The episodes maybe precipitated by fasting, dehydration, menstrual periods, stress e.g. Intercurrent illness, vigorous exercise. Patients may have vague abdo discomfort and fatigue but the episodes resolve spontaneously
It is caused by underactivity of conjugating enzyme system bilirubin-uridine diphosphate glucuronyl transferase (bilirubin-UGT)
LFTs arenormal except for an unconjugated hyperbilirubinaemia - intermittent unconjugated hyperbilirubinaemia and anormal full blood count, reticulocyte count and film, normal LFTs, and no other disease process.
causes osmotic diarrhoea
Non absorbable solutes in lumen dragging water into gut due to:
§ Glucose-galactose deficiency
§ Disaccharidase deficiencies (e.g. lactose intolorance)
§ Excess intake:carbonated fluids, sorbitol, lactulose, MgOH
lactulose
post rotavirus
IBD
Coeliac
transport overload eg excess sugar or fruit
Diarrhoea stops with fasting, acidic pH <6, Na <70, high osmotic gap, positve reducing substances
Elevated GGT with no other abnormalities
enzyme induction by alcohol or aromatic medications (phenobarbitone, phenytoin) in the absence of liver disease.
Meckel divirticulum
A remnant of the embryonic yolk-sac’s connection to the gut (vitelline or omphalomesenteric duct), produced by failure of involution during gestation. Most common congenital gastrointestinal anomaly, occurring in 2-3% of infants, appears as a 3-6 cm outpouching of the ileum. The rule of twos best describes Meckel’s diverticulum. It occurs in 2% of the population with a male-to-female ratio of 2:1, is found within two feet of the ileocecal valve, and is two inches long. Usually asymptomatic, but if symptoms occur they usually arise in the first 1-2 years of life, (can occur anywhere in the first decade). Most symptomatic diverticula are lined by ectopic mucosa, including an acid-secreting mucosa that causes painless rectal bleeding and ulceration of the adjacent mucosa -brick coloured or currant jelly stools.
Chyle
It progresses up from the lacteals to the cisterna chyli and into the thoracic duct where it joins the junction of the internal jugular and subclavian veins, and chlye flows into the venous system.
high protein and electroytes similar to serum
low cholesterol
high triglycrides
heaps of lymphocytes
NO MCT- as these are absorbed directly into the portal system
what hormone does hepatoblastoma secrete
Approximately 10% of hepatoblastomas secrete ectopic b-hCG. hCG, through its LH-like action, causes Leydig cell stimulation in the testes. In turn, testosterone levels reach those of a normal adult, and secondary sexual characteristics develop together with premature skeletal maturity.
The testes usually do not significantly enlarge – as Leydig cells only constitute about 25% of testicular volume; Sertoli cell hyperplasia or spermatogenesis is dependent on FSH.
Therefore boys with precocious puberty secondary to hCG production by tumours typically have only mildly enlarged testes, discordant with their degree of pubertal development.
Approximately 4% of boys with precocious puberty have hCG-producing tumours.
Causes raised AFP
neural tube defects
T21
T18
Tyrosinemia
Ataxia telangiectasia
Liver cirrhosis
Hepatoblastoma
HCC
Germ cell tumor
Wilsons disease
AR
ATP7B mutation
Mainly expressed in hepatocytes
Critical for biliary copper excretion and for copper incorporation into ceruloplasmin
Mutation results in reduced biliary copper excretion and diffuse accumulation of copper in cytosol of hepatocytes
Hepatocytes become overloaded and copper is redistributed to other tissues esp brain and kidneys causing toxicity
Asymptomatic hepatomegaly (+/- splenomegaly), steatosis, coombs negative hemolytic anemia, hepatitis, acute hepatic failure, cirrhosis, portal HTN, ascites, variceal bleeding, coagulation defects
Often misdiagnosed as steatosis or autoimmune hepatitis initially –> then fibrosisis and cirrhosis develop later
Neurologic/psychiatric symptoms- tremor, dysarthria, parkinsonism, deterioration in school performance, depression, psychosis, personality changes
Fanconi syndrome
The younger the patient the more likely hepatic involvement will be the predominant manifestation
Ix: consider in kids with unexplained acute or chronic liver disease, unexplained neurological symptoms, acute hemolysis, or bone disease
LOW CERULOPLASMIN (due to failure of incorporation of copper into ceruloplasmin) and elevated free copper level; increased urinary copper
If equivocal- 24 hour copper excretion with penacillamine challenge
Kayser Fleisher rings
Liver biopsy- hepatic copper content elevated
Low ALP
ceruoplasmin may be elevated in acute inflammation or low in celiac disease or autoimmune hepatitis
Rx: copper dietary restriction, copper chellation (penacillamine) or trientine, zinc (reduced copper intestinal absorption)
Autoimmune hepatitis
- Can be asymptomatic or present in liver failure
- Elevated transaminases
- Negative viral scren
- Elevated IgG
- ANA, anti - SMA (type 1), anti LKN (type 2)
Commonly associated with other autoimmune conditions
MoA of teduflutide for intestinal failure for short gut
GLP-2 analogue
mimic glucagon like peptide 2
maralixibat MoA
inhibits bile acid transport in the distal ilium
improves itch in Alagille syndrome
FAP
APC gene mutation (tumor suppressor gene)
Onset of polyps ~16 years but can be much younger
100% develop malignancy - need to screen
Average age of dx of colorectal cancer ~40 years
Associated with hepatoblastoma, other cancers, and cortical dysplasia (seizures etc)
Peutz-Jeghers syndrome
AD (positive family history)- but high rate of spontaenous mutations
Germline mutation
Mucocutaenous hyperpigmentation and extensive GI hamartomatous polyposis (mostly small intestine)
Present with bleeding and abdo cramping, intussusception
Carbohydrate malabsorption
Loose watery diarrhoea
Flatulence
Abdominal distension
Abdominal pain
Some children asymptomatic unless the malabsorbed carbohydrate is consumed in large amounts
Disaccharides, which are present on the brush border membrane of small bowel, can be deficient due to a genetic defect or secondary damage to bowel epithelium eg infection or inflammation
Unabsorbed carbs enter the large bowl and are fermented by intestinal bacteria, producing hydrogen and methane- cause discomfort and osmotic diarrhea ( acidic pH and presence of reducing or non reducing sugars in stool)
Hydrogen gas can be detected in the breath as a sign of fermentation of unabsorbed carbohydrates
Fructose malabsorption
- Reduced abundance of GLUT-5 transporter on the surface of the intestinal brush border membrane which occurs in 5% of the population
- Can present with IBD type symptoms
- Diagnosis with H2 breath test
Different to fructose intolerance
Hereditary fructose intolerance
aldose B enzyme deficiency
- results in fructose 1-phosphate accumulation in the liver. Consequently, gluconeogenesis and glycogenolysis are blocked, resulting in inhibition of protein synthesis
- Asymptomatic until fructose or sucrose (sucrose is broken down to fructose) is ingested when solids commenced
- Different patient can tolerate different amounts depending on degree of deficiency
- Early clinical manifestations are similar to galactosemia- lactic acidosis, jaundice, hepatomegaly, vomiting, lethargy, seizures
- Acute fructose ingestion- hypoglycemia, vomiting
- Chronic ingestion: kidney failure and liver failure –> death
Fructose-1,6-bisphosphatase deficiency
- Deficiency impairs formation of glucose (gluconeogenesis) from precursors
- Hypoglycemia occurs when glycogen reserves are limited or exhausted
- Presentation similar to GSDI
- Severe ketotic hypoglycaemia + lactic acidosis
- Hyperuricemia
- Hypertriglyceridemia
- Mild-mod hepatomegaly
- FTT
- Presentation in neonatal period or early infancy, often with metabolic crisis with fasting/illness
- Ix: enzyme deficiency in liver or intestinal biopsy
Rx: same as GSD1
Sucrase- Isomaltase deficiency
- Absence of sucrase and reduced maltase
- Symptoms occur with introduction of non lactose based milk or introduction of pureed food
- Ix: elevated stool reducing substances, hydrogen breath test, or direct enzyme assay of small bowel biopsy
Rx: avoidance of sucrose containing foods
Glucose galactose malabsorption
- SGLT1 (SCL5A1) mutation (sodium glucose transporter) which also cotransports galactose
- Diarrhoe with glucose or galactose (breast milk or lactose containing formulas) lactose breaks down into glucose + galactose
- Acidic stols with reducing sugars, osmotic diarrhoea
- Diarrhoea ceases immediately with removal of offending sugars
Rx: fructose based formula
Congenital secretory diarrhoeas
Congenital chloride diarrhoea
- Life threatening secretary diarrhoea in 1st week of life
- Metabolic alkalosis, hypochloremia, hypokalemia, hyponatremia (profuse loss of all electrolytes in stool)
- Faecal chloride concentrations >90
Congenital sodium diarrhoea
- Massive secretory diarrhoea and severe metabolic acidosis
- Alkaline stools
- Hyponatremia, with fecal Na >70 mmol/L
Urine secretion of sodium low-normal
Microvillous inclusion disease
- MYO5B
- Presents at birth with profuse watery secretory diarrhoea –> dehydration + FTT
- Microscopy- diffuse thinning or mucosa with hypoplastic villous atrophy , than/absent brush border with intracellular inclusions
- Hallmark= presence of microvilli within the involutions of apical membrane
- No real treatment, most die in childhood
- TPN
Tufting enteropathy
- Presents first weeks of life with persistent watery secretory diarrhoea
- Biopsy- focal epithelial tufts in epithelial surface
- TPN dependant
Distal intestinal obstruction syndrome
GI manifestation of CF- 15% of CF
Common in teens and adults
Most also have hx mec ileus
Cramping RLQ pain, palpable mass, reduced stool frequency
Management- same as constipation; surgery if refractory to medical management
Other GI manifestation of CF- rectal prolapse (20%)
exocrine pancreatic insufficiency unrelated to CF
Shwachman diamond syndrome
AR
Pancreatic insufficiency + BM dysfunction (neutropenia most common, other call lines can also be affected) + skeletal abnormalities (dysplasias) + SS
Pearson syndrome
Mitochondrial mutation
Presents in infancy with severe bone marrow failure - severe macrocytic anemia + variable thrombodytopenia + neutropenia
Pancreatic fibrosis –> pancreatic insufficiency
Liver: hepatomegaly, steatosis, cirrhosis
Renal tubular disease
No skeletal abnormalities
Johanson-Blizzard syndrome
Hypoplasia of nasal alae
exocrine pancreatic insufficiency
congenital deafness
HLH
Acute liver failure in neonate
Overwhelming activation of normal T lymphocytes and histocytes
Can be genetic (primary) or secondary
Secondary - EBV most common trigger
Diagnostic criteria- gene identified OR
5 out of 9- fever, splenomegaly, 2 cell lines cytopenia, increased triglyceride, low fibrinogen, high ferritin (in thousands), low NK activity, haemophagocytosis on biopsy, elevated CD25
Gastro associated mutations
PSINK- familial pancreatitis
NOTCH2/JAG1- Alagille syndrome (JAG1 more common)
SERPINA1- A1AT deficiency (PiZZ)
STK11- Peutz Jager
RET- Hirschprungs
ATP7B- Wilsons disease
UGTP81 Gilberts syndrome
SBDS Schwachman- Diamond Syndrome
IPEX
Immune dysregulation polyadenopathy enteropathy x linked syndrome
Early onset insulin dependant DM
Enteropathy = Severe watery diarrhoea
Dermatitis
Ix: mutation in FOXP3 gene
Rx: HSCT
HLA DQ2 homozygote
which HLA has highest risk coeliac disease
which deficiency gives glossitis and chelitis
B2 (riboflavin)
B1 deficiency
- Deficiency= beriberi(peripheral neuritis, reduced tendon reflexes, cramping leg muscles, heart failure, psychological disturbances), weakness, oedema, wernikes encephalopathy
Pellagra is caused by which deficinecy
B3 (niacin)
which carbohydrates are absorbed by SGLT1
glucose + galactose
what is GLUT5 for
fructose transport
what is GLUT2 for
glucose transport
normal urinary chloride /24 hours
110-250 mmol
normal urinary sodium
75-300 mmol
normal urinary potassium
40-100 mmol
mechanism of paracetamol toxicity
The main toxicity following paracetamol poisoning is acute liver injury which results from the formation of a toxic metabolite of paracetamol, N-acetyl-p-benzoquinone imine (NAPQI). In adults taking therapeutic doses, paracetamol is metabolised into two major non-toxic metabolites – sulphate and glucuronide conjugates – which account for 30% and 55% of paracetamol metabolism. NAPQI, is formed in small amounts following a therapeutic dose of paracetamol. It is a highly reactive toxic metabolite formed by cytochrome P450 2E1 and is responsible for the hepatocellular injury that occurs with paracetamol toxicity. The small amounts of NAPQI produced after therapeutic doses are detoxified by irreversible glutathione-dependent conjugation reactions to two non-toxic metabolites. In overdose, the increased formation of NAPQI depletes glutathione and once glutathione is depleted by more than two-thirds it covalently binds to critical cellular proteins. It is hypothesised that this results in loss of activity of critical proteins and eventually hepatic cell death.
To summarise, NAPQI is bad, in therapeutic doses glutathione can make in non-toxic. In overdose the glutathione mechanism is overwhelmed. Hence NAC works as a glutathione donor preventing NAPQI accumulation
what kind of renal stones occur with malabsorptive syndromes
Oxalate
key facts about biliary atresia babies presentation
look well , well grown
feeding well
mild jaundice (conjugated)
acholic stools
dark urine
elevated AST and GGT
A1AT deficiency mutations
MM- normal
ZZ- liver and lung disease
SS- liver and lung disease
null/null - lung disease only
M/other- normal ish
**A1AT level is an acute phase reactant and is normal when sick, so need to do a genotype/phenotype **
what does elevated e antigen signify in hepatitis
active viral replication
what is the first serological marker of hep b
Hep B surface antigen
E antigen becomes positive slightly later
what does surface antibody imply
immunity
either vaccination or post infection
what does core antibody imply
recent (IgM) or past (IgG) exposure to hep B virus ie infection
this is a non protective antibody - doesnt indicate recovery (only exposure)
can mean past or present exposure
what does surface antigen imply
current infection
what do D cells of stomach secrete
somatostatin
Ibd early onset gene
NOD2 (CARD15)
What ANCA is usually positive in Ibd
CD- ASCA positive
UC- pANACA positive- this also predisposes to PSC
