Genetics of GI Disorders

Question 1

How is Crigler Najjar inherited and what does it affect?

Answer 1

• Autossomal Recessive
• Affects metabolism of bilirubin resulting in:
  
  • Brain damage in infants
  • Non hemolytic jaundice
  • High levels of unconjugated bilirubin

Question 2

How could a vignette for Crigler Najjar present?

Answer 2

An infant with parents concerned about yellowing of the skin and behaviour changes. Also concerns about the infant seeming more tired and weak than normal with his arms flopping down and not reaching for toys. Parents are first cousins, this is importanat bc this disorder is AR.

Question 3

When does Crigler Najjar present?

Answer 3

• Presents early in life resulting in brain damage in infancy
• Hereditary unconjugated hyperbilirubinemia

Question 4

Differentiate type one and two Crigler Najjar.

Answer 4

Hereditary unconjugated hyperbilirubinemia

Type 1:

• Severe jaundice and kernicterus, bililruubin induced brain dysfunction
• UGT1A1 enzyme activity is totally absent or not expressed

Type 2:

• less severe (Arias syndrome)
• Mutation in UGT1A1 coding region rendering the enzyme less active than normal

Question 5

Patient presentation with Crigler Najjar?

Answer 5

Sx:

• Neonatal jaundice
• Sepsis
• Hypotonia
• Kernicterus- deafness and poor mental development

PE will include jaundice and oculomotor palsy

Question 6

What is Kernicterus?

Answer 6

Bilirubin deposition in the brain resulting in poor mental development. This can result in death w/n a few years if severe

Question 7

How do you treat Crigler Najjar?

Answer 7

• Plasmapheresis
• Phototherapy
• Phenobarbital-UGT1A1 inducer, only used for type II resulting in increased UDP-hlucoronyl transferase mRNA synthesis and UGT activity
• possible liver transplant

Question 8

What is Gilbert’s syndrome?

Answer 8

• Hereditary unconjugated hyperbilirubinemia due to a defect in the gene promotor for UGT1A1, resulting in mild decrease of UDP-glucuronyl transferase activity due to lower expression of the wild type enzyme. There is also a mild decrease in bilirubin uptake.
• Can be AD or AR inheritance and is very common

Question 9

What key aspects in a vignette could lead you towards Gilbert’s syndrome?

Answer 9

• yellow eyes
• fasting
• stress
• alcohol intake

Question 10

How does Gilbert’s present?

Answer 10

• Mostoly asymptomatic but sometimes recurrent mild jaundice occurs
• This is associated with fasting, stress, and alcohol

Question 11

What is the mechanism for gilbert’s being associated with fasting?

Answer 11

• fasting state increases hepatic uptake of non esterified fatty acids interfering with hepatic clearance of bilirubin contributing to the unconjugated hypyerbilirubinemia seen with fasting.

Question 12

How do you diagnose Gilbert’s syndrome?

Answer 12

• Genetic testing
• Isolated unconjugated hyperbilirubinemia w/o evidence of hepatitis or hemolysis
• Rifampin test, with fasting for 12 to 24 hrs an absolute increase of bilirubin to greater than 1.9 2 to 6 hrs after administration of 900 mg of rifampin will differentiate patients with gilberts and without

Question 13

What medication should be avoided with gilbert’s syndrome?

Answer 13

Irinotecan

Question 14

What causes dubin johnson syndrome, what is it, and how does it present?

Answer 14

• Mutations in the MRP2 gene which is responsible for moving bile acids from hepatocytes to the bile
• Hereditary conjugated hyperbilirubinemia, decreassed excretion of conjugated bilirubin
• Black liver due to deposition of pigments and impaired excretion of epinephrine metabolites
• It is benign and inherited in AR manner

Question 15

What causes Rotor’s syndrome & how does it present, how is it inherited?

Answer 15

• Mutations in OATP1B1 and OATP1B3, these are part of a family of influx transporters and are expressed on sinusoidal mem. of hepatocytes and facilitate liver uptake of their substrate drugs
• Mutations in these transporters results in impaired secretion/storage of bilirubin in the liver
• Usually asymptomatic but may have jaundice and 50%+ of serum bilirubin is conjugated in labs and bilirubinuria is present
• Inherited AR, milder than dubin johnson, does NOT caue black liver
• Normal life expectancy and no treatment needed

Question 16

What can exacerbate Rotor’s syndrome?

Answer 16

• Patients who are pregnant, fatigued, or on birth control may become jaundiced or icteric due to a reduction in hepatic excretory functions

Question 17

How will labs look for patients with Dubin Johnson and Rotor’s Syndrome?

Answer 17

• May show 2-5mg/dL conjugated hyperbilirubinemia
• Coproporphyrin III: Coproporphyrin I ration ranges from 1:3 to 1:4, opposite of normal

In Rotors:

• Total urine coproporphyrin levels are elevated

In DJS:

• Total urine coproporphyrin levels are are normal
• Liver is black
• Increased total bilirubin

Question 18

What makes up the hepatic portal system, what does it allow for, what is the relationship to prodrugs? (pg 4 green box)

Answer 18

• Consists of portal vein and the splenic,superior mesenteric and inferior mesenteric veins.
• It connects the GI to the liver and allows for transport of nutrients and drugs to the liver first.
• This allows for porodrugs to be converted to active forms in the liver.

Question 19

What are prehepatic causes of portal htn?

Answer 19

Portail vein thrombosis

Question 20

What are intrahepatic causes of portal htn?

Answer 20

• Liver cirrhosis and fibrosis due to hemochromatosis and wilson disease

Question 21

What are the posthepatic causes of portal htn?

Answer 21

• Thromnbosis in hepatic vein and IVC

Question 22

What is the significance of htn in the portal system?

Answer 22

It can lead to ascites, splenomegaly, and hepatic encephalopathy due to blood being forced into the systemic venous system.

Question 23

How are macrophages and iron related? (pg. 19 orange box)

Answer 23

• Macrophages engluf and digest old RBC’s. This allows for extraction of iron from the degraded hemoglobin and iron is then loaded onto transferrin for transport

Question 24

Pg 72 Q40:

24 yr old man had jaundice 5 yrs ago, and it cleared after a few weeks. Since then he has had increasing difficulty with walking, getting up, or raising his arms, as well as increasing pain in his legs. He is bed ridden and analgesics are not effective. No muscle weakness is present. X rays show demineralization of bones somewhat improved with Ca and Vit. D administration. Labs: hemoglobin,WBC, cholessterol,BUN, bilirubin and alkaline phosphatase were normal. AST and ALT were elevated, ceruloplasmin is low. 24 hr urine excretion of Ca and HPO^2-₄ is elevated. Slit lamp exam shows Kayser Fleischer rings and pt is diagnosed with Wilson disease. What should he be treated with?

• Cu supplementation
• Zn supplemeentation
• Penicillamine (Cu chelation therapy)
• Deferoxamine (iron poisoning treatment)
• Multivitamin

Answer 24

Penicillamine (Cu chelation therapy)

Question 25

33 yr old female referred to neurologist by PCP for unsteady gate, forgetfulness, turret like spells where she flings one arm out and above her head unprovoked. On PE neurologist notes her irises are multicoolored wit hconcentric rings around periphery. Neurologist is concerned for what disease? What should this patient not eat?

Answer 25

• Concerned for Wilson’s diease
• Pt should avoid chocolate, organ meats, dried beans, peas, whole wheat, and shellfish as these foods are high in copper
• She also needs to be wary of her drinking water as some can be high in Cu

Question 26

What is Wilson’s disease?

Answer 26

• Free Cu accumulation in many tissues such as brain liver cornea and joints
• It is aka Hepato-lenticular degeneration
• There is a mutation in ATP7B which causes inadequate Cu excretion by the liver into bile and Cu doesn’t enter blood bound to Ceruloplasmin

Question 27

How is wilsons inherited?

Answer 27

AR inheritance

Question 28

Describe wilson’s disease sx and PE.

Answer 28

• Parkinsons like sx secondary to Cu deposits in the putamen
• Hemiballismus secondary to Cu deposits in the subthalamic nucleus
• Dementia secondary to Cu deposits in the cerebral cortex
• Cirrhosis & corneal deposits on slit lamp exam–>Kayser Fleischer rings

Question 29

How will the labs of a wilsons patient present?

Answer 29

• Decreased total serum copper due to a decresed ceruloplasmin
• Increased serum non ceruloplasmin bouond Cu
• Increased urine serum free Cu
• hemolytic anemia
• If liver biopsy is done it will show increased hepatic Cu

Question 30

How do you treat wilsons?

Answer 30

• Ammonium tetrathiomolybdate facilitates urinary excretion of Cu
• Penicillamine is a Cu chelating agent
• Trientine Cu chelating agent
• Zinc, competes with Cu for absorption in the gut via ATPB7
• Could do liver transplant if clincial condition deteriorates

Question 31

Wilson’s disease puts patients at a higher risk for what diseases? (4)

Answer 31

• Hepatitis
• Cirrhosis
• Hepatocellular carcinoma
• Fanconi’s (disease of prox. tubules)

Question 32

Staudinger Question:

Impaired UDP-Glucoronosyl Transferase activity is observed in all of the following except ___.

• Breast Milk Jaundice
• Physiological Jaundice of the newborn
• Crigler Najjar Syndrome
• Dubin-Johnson Syndrome

Answer 32

• Breast Milk JaundiceRare, may be linked to a substance in the breast milk that prevents certain proteins in the infant’s liver from breaking down bilirubin inhibition of UGT activity??? Not too clear.
• Physiological Jaundice of the newborn Underdeveloped UGT activity, UGT increases immediately after birth.
• Crigler Najjar Syndrome Mutant UGT
• Dubin-Johnson Syndrome•Mutant conj-bilirubin transporter  MRP2 (liver into bile)

Question 33

Staudinger Question:

A 4 day old female child with yellow skin and eyes . The baby was born at term by a normal vaginal delivery. Pregnancy was uncomplicated; there were no risk factors for sepsis and no history of maternal alcohol or drug use. The baby is breast fed and has been nursing every 2 hours, about 10 minutes at each breast. The bilirubin level is 15 mg (unconjugated) , the hematocrit is 45% and the combs test is negative. Which of the following is the most likely diagnosis?

A. Congenital biliary atresia

B. Isoimmune hemolytic disease

C. Crigler-Najjar syndrome

D. Breast milk jaundice

E. Breast feeding jaundice

Answer 33

Breast feeding jaundice

• Congenital biliary atresia : infants usually have icterus by 2-6 weeks of age and have HIGH CONJUGATED BILIRUBIN, dark urine and acholic stools so A is not the answer
• B. Isoimmune hemolitic disease (B) is not the answer because indirect Coombs test will be positive in mother and Coombs test weakly positive is infant and ANEMIA is usually present.
• C. Crigler-Najjar syndrome is autosomal recessive with marked Unconjugated Hyperbilirubinemia in otherwise asymptomatic child so C is not the answer.
• D. Breast milk jaundice is not the answer because it presents in SECOND WEEK OF LIFE and this child is 4 days old. It can increase by the 7th day of life at the earliest and concentrations are up to 30 mg/dl, so D is not the answer
• E. is the answer. Breast Feeding Jaundice is correct because it appears in 2-4 days of life. Just because the infant is fed every 2 hours does not mean the baby is successfully getting enough milk. https://en.wikipedia.org/wiki/Coombs_testRationale:

Question 34

Staudinger Question:

A 14-year-old Caucasian male patient found to have low serum copper, high urine copper, and low serum ceruloplasmin is placed on penicillamine for management of his genetic disorder. Which of the following is LEAST consistent with this patient’s clinical picture?

A.Kinky, easily breakable hair

B.Cirrhosis

C.Hemiballismus

D.Corneal deposits

E.Parkinson-like symptoms

Answer 34

A.Kinky, easily breakable hair

Kinky, easily breakable hair is a feature of Menke’s disease, another copper transport disorder associated with growth failure, seizures, and developmental delay. The genetic mutation responsible for Wilson disease impairs copper-trafficking within hepatocytes. This leads to copper accumulation within hepatocytes since the main routes of copper export (via bile and into the bloodstream bound with ceruloplasmin) are impaired. Eventually, this excess copper accumulates and causes tissue damage. Penicillamine, a copper chelating agent, functions by removing excess loosely-bound serum copper Incorrect Answers: Answer B: Cirrhosis develops in Wilson disease due to hepatic damage from copper-generated free radicals. Answer C: Hemiballismus develops in Wilson disease as a result of copper deposits in the subthalamic nucleus. Answer D: Copper deposits in the cornea result in Kayser-Fleischer rings, a pathognomonic physical finding of Wilson disease. Answer E: Parkinson-like symptoms result in WIlson disease due to copper deposits in the putamen.

Question 35

Staudinger question:

An infant who was healthy at birth is brought to your office for her first office visit at the age of 6 weeks. You notice that the infant is jaundiced and that there is bilirubin staining of the wet diaper. Which one of the following diagnoses is most consistent with these findings?

a. Physiologic jaundice of the newborn
b. Hemolysis secondary to Rh incompatibility
c. Crigler-Najjar syndromed.
d. Gilbert’s syndromee.
e. Biliary atresia

Answer 35

Biliary atresia