Genetics of GI Disorders Flashcards
Jaundice in the setting of elevated AST/ALT would indicate what type of etiology?
Hepatocellular, such as with acute viral hepatitis
Jaundice in the setting of elevated ALP would indicate what type of etiology?
Cholestasis, like with common duct stone
Bilirubin is considered indirect/unconjugated prior to UDP glucoronyl transferase activity in the liver, what acts as the carrier for unconjugated bili in the bloodstream?
Albumin
Enzyme deficiency of criglar-najjar syndrome
UDP glucuronyl transferase
Is criglar najjar associated with indirect or direct bili?
All indirect/unconjugated bili
What is a complication of the more severe type 1 criglar najjar, characterized by encephalopathy?
Kernicturus
When does type 1 criglar najjar manifest? What are some treatments?
Infancy
Tx = transfusions, phototherapy, heme oxygenase inhibitors, oral calcium phosphate and carbonate, liver transplant
How does type 2 criglar najjar differ from type 1?
Benign form resulting from mutation that causes partial deficiency of gene
Presents in childhood/adolesence (vs infancy in type 1)
Can be tx with phenobarbitol (while type 1 cannot)
Inheritance of dubin johnson syndrome
Autosomal recessive
Is dubin johnson syndrome associated with direct or indirect bili?
Direct/conjugated
Defect in dubin johnson syndrome
What does it lead to?
Defect in canalicular multiple organic anion transporter Mrp2
Leads to accumulation of conjugated bili because it can no longer be exported from hepatocytes into bile
Dubin johnson is normally asymptomatic and benign, but it may manifest in _______ or when _______ drugs are taken (which are contraindicated)
Pregnancy; oral contraceptive
Inheritance of rotor syndrome
Autosomal recessive
What syndrome is rotor syndrome very similar to?
Dubin johnson; both involve impaired biliary excretion of conjugated organic anions and bilirubin, usually asymptomatic other than possible jaundice
How is rotor syndrome different from DJ syndrome?
Slow BSP elimination kinetics without secondary rise (DJ has secondary rise)
Age of onset is adolecence/early adulthood while DJ can arise earlier in childhood
Does gilberts disease have to do with conjugated or unconjugated bili?
Unconjugated
Is gilberts disease severe?
No, it is a relatively common benign disorder where serum total bili is below 6, but it may increase in the setting of lifestyle factors like alcohol use
Why is phenobarbitol an effective tx for gilberts disease and criglar najjar type 2?
The unconjugated bili that is accumulating is hydrophobic, as is the drug phenobarbitol
Phenobarbitol increases the mRNA synthesis and expression of UTG1A1, the enzyme that is affected in these two conditions
When does gillbert’s usually present?
In early adulthood, often first recognized with fasting. Mild hemolysis may be seen in some patients
What is the most common porphyria in the US?
Porphyria cutanea tarda (PCT)
What enzyme is defective in PCT? What effect does this have?
Uroporphyrinogen decarboxylase
Leads to accumulation of uroporphyrinogen III, which converts to uroporphyrinogen I and its uroporphyrin oxidation products
Is PCT erythropoeitic, hepatic, or both?
What are the symptoms?
It is hepatoerythropoeitic, resulting in photosensitivity in vesicles and bullae on skin of exposed areas; wine colored urine
Inheritance of PCT
Autosomal dominant
Defective enzyme in acute intermittent porphyria
What does deficiency lead to?
Porphobilinogen (PBG) deaminase
Deficiency leads to excessive production of ALA and PBG
Is acute intermittent porphyria erythropoietic, hepatic, or both?
Hepatic, PBG deaminase is found in the liver
Inheritance of acute intermittent porphyria
Autosomal dominant
Symptoms of acute intermittent porphyria
Periodic attacks of abdominal pain and neuro dysfunction
Tx for acute intermittent porphyria
Hemin = an iron-containing porphyrin consisting of protoporphyrin IX containing ferric (Fe3) bound by chloride ligand
Beneficial bc it inhibits ALA synthase to prevent buildup of ALA
What disease is associated with a buildup of copper in the liver?
Wilson’s disease
Inheritance of wilsons disease
Autosomal recessive
Symptoms of wilson’s disease
Liver disease, copper deposits in eye (Kayser Fleischer rings), dementia, movement disorders
Inheritance of hemochromatosis
Autosomal recessive; mutations in HFE gene
Age of onset of hemachromatosis
Usually in 6th decade
Describe hemochromatosis
Unregulated iron absorption d/t low levels of hepcidin, which would normally negatively regulate ferroportin in iron absorption
This results in accumulation of iron in liver, heart, pancreas, and skin
Normal iron vs. someone with hemochromatosis
Normal = 3-5g
Hemochromatosis = 15g
Symptoms of hemochromatosis
Cirrhosis, heart failure, DM, bronzed skin, malabsorption
What lab technique is used to diagnose hemochromatosis?
PCT
Inheritance of galactosemia
Autosomal recessive
When do symptoms of classic galactosemia typically manifest?
When infant drinks milk
Enzyme deficiency in classic vs. mild galactosemia
Classic = galactose I phosphate uridyltransferase (GALT) - catalyzes RL step in galactose metabolism
Mild form = galactokinase or UDP-galactose epimerase
Symptoms of classic galactosemia
Cataracts within first few weeks of life, hepatomegaly, jaundice, FTT
Symptoms of mild form of galactosemia
Galactose accumulation in blood and urine
Hereditary fructose intolerance may result in _____ _____, or fructose in the urine
Essential fructosuria
Inheritance of hereditary fructose intolerance
Autosomal recessive
Enzyme deficiency in hereditary fructose intolerance and the effect this has
Aldolase B - typically responsible for cleaving fructose 1P into glyceraldehyde and DHAP
Results in accumulation of F1P, which sequester’s much of a cell’s phosphate, thus inhibiting glycogen phosphorylase (and thus glycogenolysis)
VIRTUALLY STOPS ATP SYNTH IN THE LIVER
Patient presentation in hereditary fructose intolerance
Hypophosphatemia
Hypoglycemia
Low tolerance to foods with fructose and sucrose
Signs/symptoms manifest when infant is weaned off milk and given foods containing fructose and sucrose
May have essential fructosuria
PEPCK deficiency inheritance and symptoms
Auto recessive, mutation in PEPCK1/2 that results in defective gluconeogenesis and hypoglycemia, FTT, loss of muscle tone, hepatomegaly
Normal action of PEPCK
Catalyzes conversion of OAA to PEP in gluconeogenesis
Inheritance of von gierke disease
Autosomal recessive
Enzyme deficiency in von gierke Ia; what does this lead to
Deficient glucose 6 phosphatase - normally necessary for release of free glucose into blood by liver
Patients exhibit marked fasting hypoglycemia d/t inability to utilize glycogenolysis or gluconeogenesis
Also lactic acidosis, hepatomegaly, elevated serum TAGs, retarded growth, buildup of lactate, alanine, and glycerol
If von gierke Ia is caused by G6Pase deficiency (catalytic unit), what causes types Ib and c?
Mutations in transporter part of G6Pase enzyme complex in ER membrane
Irinotecan is a medication that should be avoided in those with which of the following?
A. Criglar Najjar B. Gilbert’s Syndrome C. Dubin-Johnson/Rotor’s Syndrome D. Wilson’s disease E. PEPCK deficiency F. Von Gierke’s disease
B. Gilbert’s syndrome
Which of the following is associated with a grossly black liver due to impaired excretion of epinephrine metabolites?
A. Criglar Najjar B. Gilbert’s Syndrome C. Dubin-Johnson syndrome D. Wilson’s disease E. PEPCK deficiency F. Von Gierke’s disease
C. Dubin-Johnson syndrome
You are evaluating a patient for possible metabolic disease and lab work shows direct hyperbilirubinemia, decreased coproporphyrin III:corproporphyrin I ratio, and elevated total urine coproporphyrin levels. What is the likely diagnosis?
A. Criglar Najjar B. Gilbert’s Syndrome C. Dubin-Johnson Syndrome D. Rotor’s Syndrome E. Wilson’s disease
D. Rotor’s syndrome
[same presentation as DJS, but would not get elevated urine coproporphyrin levels in DJS]
Wilson’s disease is associated with a mutation in what gene?
ATP7B - encodes a transmembrane P-type ATPase used to pump copper into bile and plasma
Inheritance of Gilbert’s disease
Can be AD or AR
Inheritance of criglar najjar type 1 vs. type 2
Type 1 is AR
Type 2 is AD
Both are mutations in UTG1A1, as is Gilbert’s disease
[UGT1A1 is an enzyme that sticks a sugar on things to make them soluble so that they can be excreted]
Wilson’s disease results in free copper accumulation due to mutation in ATP7B. This leads to failure of copper to enter circulation bound to ________, which is the transport protein for copper. Free copper generates free radicals that damage tissues
Ceruloplasmin
Both Wilson’s disease and primary biliary cirrhosis, as well as several other conditions, may result in increased copper accumulation. How would you differentiate Wilson’s disease from things like primary biliary cirrhosis?
Presence of Kayser-Fleischer rings - which are RARELY seen in conditions other than Wilson’s disease
