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*GIGU I > Lecture 25: The Genetics of GI Disorders > Flashcards

Lecture 25: The Genetics of GI Disorders Flashcards

1
Q

What is Crigler Najjar Type I vs. Type II?

A
  • Hereditary unconjugated hyperbilirubinemia

Type I: severe due to absent levels of hepatic bilirubin-UGT activity (UGT1A1)

Type II: less severe (Arias syndrome), only partly deficient in gene

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2
Q

What function does UGT1A1 have on SN-38

A
  • SN-38 is a toxic antineoplastic drug metabolized by UGTA1
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3
Q

Treatment for Crigler-Najjar?

A
  • Plasmapheresis
  • Phototherapy (blue lights)
  • Phenobarbital-UGT1A1 inducer: only for Type II - results in increased UDP-glucuronyl transferase mRNA synthesis and UGT activity
  • Liver transplant
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4
Q

What is Gilbert’s Syndrome; genetic issue; and what will be decreased?

A
  • Hereditary unconjugated hyperbilirubinemia due to defect in promotor gene for UGT1A1
  • Mild decrease in UDP-glucuronyl trasnferase activity
  • Mild decrease in bilirubin uptake
  • Autosomal dominant or recessive inheritance (very common)
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5
Q

Symptoms of Gilbert’s syndrome?

A
  • Largely asymptomatic, but occasional recurrent mild jaundice
  • Associated w/ fasting, stress, and EtOH intake
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6
Q

What testing is available to diagnose Gilbet’s Syndrome?

A
  • Genetic testing
  • Fasting test: unconjugated bilirubin will rise after a day of fasting w/ low lipid, 400kcal diet (more specific test for Gilbert’s)
  • Rifampin test: unconjugated bilirubin rises after a dose of Rifampin, induces cytochrome P-450 and competes for excretory pathways in liver (less specific to Gilbert’s as levels can rise in those w/ chronic liver disease
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7
Q

Treatment for Gilbert’s syndrome; avoid what med?

A
  • No treatment needed!
  • Avoid certain medications (irinotecan)
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8
Q

What are the 2 types of hereditary conjugated hyperbilirubinemia?

A

1) Dubin-Johnson syndrome - benign and AR
2) Rotor’s syndrome - AR and milder than DJS

*Both associated w/ decreased hepatic excretion of conjugated bilirubin

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9
Q

What is one of the common gross pathologies of DJS that differentiates it from Rotors?

A

Grossly black liver due to impaired excretion of epinephrine metabolites in DJS

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10
Q

Patients w/ DJS or Rotor’s syndrome may present with jaundice or icteric when?

A

During pregnancy or w/ oral contraceptives

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11
Q

What is the molecular basis for DJS?

A

Defect in the canalicular multiple organic anion transporter (cMOAT, MRP2, ABCC2) and leads to the accumulation of conjugated (direct) bilirubin, which can no longer be excreted from hepatocytes into the bile

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12
Q

What labs are significant in DJS?

A
  • Direct hyperbilirubinemia (usually 2-5 mg/dL) and resulting increased total bilirubin in DJS
  • Coproporphyrin III:coproporphyrin I ratio is 1:3-4 (opposite of normal)
  • Normal total urine coproporphyrin levels
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13
Q

What labs are significant in Rotor’s syndrome?

A
  • Coproporphyrin III:coproporphyrin I ratio is 1:3-4 (opposite of normal)
  • Elevated total urine coproporphyrin levels
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14
Q

Treatment for DJS and Rotor’s syndrome; what medication is contradindicated in these patients?

A
  • No treatment is needed
  • Oral contraceptives are contraindicated in these patients
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15
Q

What are intrahepatic causes of portal HTN?

A

Liver cirrhosis and fibrosis due to disorders such a hemochromatosis and Wilson disease

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16
Q

Explain the relationship between macrophages and iron?

A

Macrophages engulf and digest aged erythrocytes, which allows for the extraction of iron from degraded hemoglobin.

17
Q

What is Wilson’s disease; caused by; genetic inheritance pattern?

A
  • Free copper accumulation in many tissues (liver, brain, cornea, joints)
  • Mutation in ATP7B results in: inadequate copper excretion by liver into bile and failure of copper to enter circulation bound to ceruloplasmin
  • AR inheritance
18
Q

What normally represents the largest fraction of copper in the body and why is free/unbound copper dangerous?

A
  • Copper bound to ceruloplasmin
  • Free copper generates free radicals that damage tissues
19
Q

What type of protein is the one affected by Wilson disease?

A

Transmembrane P-type ATPase encoded by ATP7B that uses ATP–>ADP to pump copper into bile and plasma

20
Q

What are some common presentations associated w/ Wilson’s disease?

A
  • Proximal renal tubular dysfunction
  • Kayser Fleischer rings
  • Hepatomegaly, jaundice, acute hepatitis, portal HTN, cirrhosis
  • Arthritis and Rickets
  • Neuro defects
21
Q

What are some of the neurological symptoms caused by Wilson’s disease and what causes them?

A
  • Parkinson-like symptoms: copper deposits in putamen

- Hemiballismus: flailing, ballistic, undesired movements of the limbs caused by copper deposits in subthalamic nucleus

- Dementia: copper deposits in cerebral cortex

22
Q

What are the relevant labs for Wilson’s disease?

A
  • Decreased total serum copper due to decreased ceruloplasmin
  • Increased serum non-ceruloplasmin bound copper
  • Increased urine/serum free copper
  • Hemolytic anemia
23
Q

What are the treatment options for Wilson’s disease?

A
  • Ammonia tetrathiomolybdate –> facilitates urinary excretionn of Cu
  • Penicillamine –> Copper chelating agent
  • Trientine –> Copper chelating agent
  • Zinc –> competes w/ copper for absorption in the gut via ATPB7
24
Q

People with Wilson’s disease are at risk for several liver disease, what are they?

A
  • Hepatitis
  • Cirrhosis
  • Hepatocellular carcinoma (HCC)

*Also at risk for Fanconi’s disease of the proximal tubules

25
Q

What is hemochromatosis; genetic cause; inheritance pattern?

A
  • Autosomal recessive disorder caused by mutations in HFE gene, which regulates hepcidin.
  • Disease characterized by unregulated duodenal reabsorption of iron due to low hepcidin levels
26
Q

What is Acute intermittent porphyria?

A
  • Autosomal dominant disorder caused by mutation in the PBG deaminase gene
  • Buildup of Porphobilinogen rings which are able absorb large amounts of energy and can lead to photosensitivity as these molcules buildup in the skin and brain
27
Q

What is Porphyria cutanea tarda?

A
  • Autosomal dominant disorder caused by deficiency in uroporphyrinogen decarboxylase

- Disease can be initiated after exposure to organic solvents

28
Q

What is Hemin and what is it used to treat?

A
  • Iron-containing porphyrin consisting of protoporphyrin IX containing Fe3+ ion bound by a Cl- ligand
  • Beneficial in treating acute intermittent porphyria, since Hemin inhibits ALA synthase to prevent the buildup of ALA (precursor to porphobilinogen)
29
Q

What causes classical Galactosemia; common symptoms?

A
  • Galactose 1-phosphate uridyltransferase (GALT) is deficient
  • Infants present w/ cataracts, hepatomegaly, jaundice, and failure to thrive
30
Q

What is the milder forms of galactosemia caused by; common issues?

A
  • Deficiency in galactokinase or in UDP-galactose epimerase
  • Galactose accumulates in blood and urine, particularly when galactos-containing foods are consumed (i.e., milk)
31
Q

What leads to the cataracts seen in patients with galactosemia?

A

Galactitol deposition in the eye

32
Q

Essential fructosuria is what type of disorder?

A

Asymptomatic AR disorder marked by hepatic deficiency in fructokinase, causing fructose accumulation and excretion

33
Q

What is hereditary fructose intolerance; often leads to?

A
  • Destructive AR disorder caused by a deficiency in hepatic aldolase B
  • Fructose 1-phosphate accumulates and sequesters cellular phosphorous, patients present w/ low blood levels of phosphorus
  • Leads to kidney disease/failure
34
Q

What is Von Gierke disease caused by and common symptoms?

A
  • Type Ia glycogen storage disease that is AR
  • Deficiency in glucose 6-phosphatase
  • Pt’s have marked fasting hypoglycemia, lactic acidosis, and hepatomegaly
  • Due to mutation in catalytic unit of glucose 6-phosphatase complex in the ER
35
Q

What are glycogen storage disease Ib and how is it treated?

A
  • Defect of the transport protein that moves glucose 6-phosphate from the cytosol into the lumen of the ER of hepatocytes
  • Liver transplant or surgical transposition of the portal vein (redirecting nutrient-rich blood from the intestine into the peripheral circulation)
36
Q

What is PEPCK deficiency and common symptoms?

A
  • Rare AR disorder of PEPCK, which is not able to convert oxaloacetate into phosphoenolpyruvate
  • Symptoms include increased amounts of acid in the blood (acidemia), hypoglycemia, loss of muscle tone, hepatomegaly, and failure to thrive
37
Q

What is the significance of PEP production in the mitochondria?

A
  • PEP made in mitochondria is converted to glucose via gluconeogenesis.
  • Occurs when lactate levels are elevated
38
Q

Accumulation of glycogen in the lysosomes indicates a defect in?

A

Acid maltase enzyme, which is known as Pompe disease

39
Q

If the patient has an isolated unconjugated hyperbilirubinemia w/o evidence of hepatitis or hemolysis, what is the likely pathology?

A

Gilbert’s Syndrome

*GIGU I (67 decks)

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