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GI Week 4 > ICL 6.1: Hyperbilirubinemia > Flashcards

ICL 6.1: Hyperbilirubinemia Flashcards

1
Q

what is the overview of the heme to bile pathway?

A

heme moiety –> tetrapyrrole biliverdin + Fe via heme oxygenate

then tetrapyrrole iliverdine –> bilirubin via billiverdine reductase

bilirubin is insoluble so it has to form a complex with albumin to travel through the blood to get to the liver

once it gets to the liver, they dissociate and bilirubin is picked up by OATP and goes to the cytosol where it’s glycerolized:

unconjugated bilirubin + UDP-glucuronic acid–> bilirubin monoglucuronides (BMG) via UDP-glucuronosyl-transferase

BMG 00> bilirubin diglucuronides (BDG)

then BMG and BDG go to tile in the bile canalicculi in the gallbladder via MRP-2 protein to make bile which is turned into urobilinogen which is then reabsorbed via portal circulation where it re-enters the liver and enters the secretory cycle again –> some urobilingoen stays in the large intestine where it is oxidized into stercobilin that makes our poop brown!!

other urobilinogen since it’s water soluble and goes to the kidney and turns pee yellow!

some of the BMG and BDG is regurgitated back in the blood sinusoid but ultimately most of it ends up back in the liver

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2
Q

what is jaundice?

A

a yellow discoloration of the skin, mucous membranes and sclera

jaundice is the clinical manifestation of increased bilirubin in the plasma, hyperbilirubinemia above 3-4mg/dL

hyperbilirubinemia below 3mg/dL may not be detected clinically

jaundice is the most common clinical manifestation of liver diseases

jaundice is usually, but not always, associated with pruritis (itching)

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3
Q

what are the dynamics of bilirubin binding to albumin in hyperbilirubinemic states?

A

bilirubin at concentration of 25mg/100 ml or below binds to albumin at the high affinity binding sites – so there’s plenty of albumin to carry all the bilirubin

bilirubin at concentration higher than 25mg/100 ml binds to albumin at the low affinity binding sites which is a weak bond and can be easily displaced by:
1. sulfonamides

  1. some analgesics
  2. ethacrynic acid
  3. furosemide

these are also carried by albumin to the liver and they displace bilirubin in hyperbilirubinemia and can manifest jaundice

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4
Q

what are the etiological types of jaundice?

A
  1. hemolytic hyperbilirubinemia (prehepatic)
  2. hepatocellular hyperbilirubinemia (Hepatic)
  3. obstructive or cholestatic hyperbilirubinemia (post-hepatic)
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5
Q

how do you classify jaundice based on the fraction of bilirubin is elevated?

A
  1. unconjugated hyperbilirubinemia
  2. conjugated hyperbilirubinemia
  3. mixed hyperbilirubinemia
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6
Q

what are the mechanistic types of jaundice?

A
  1. increased bilirubin production
  2. decreased bilirubin disposition (hepatocellular dysfunction)
  3. decreased bile flow (cholestasis)
    - intrahepatic
    - extrahepatic
  4. inherited or acquired defects in specific aspects of hepatic bilirubin disposition
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7
Q

what is the mechanism of increased bilirubin production?

A

increased hemolysis = an accelerated destruction of transfused erythrocytes that leads to an increase in bilirubin production that is more than the liver can handle

in normal liver, bilirubin detoxification system is highly efficient in handling mild to moderate hemolysis and the hyperbilirubinemia is mild and rarely exceeds the 4mg/dL

so for hemolysis alone to manifest as jaundice, it has to be severe hemolysis (hemolytic crisis)

ex. massive blood transfusion, absorption of a hematoma, favism

prolonged hemolysis may lead to the formation of bilirubin gallstones, which may be complicated by obstructive jaundice

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8
Q

what conditions could cause increased rates of bilirubin production?

A
  1. resorption of hematomas
  2. ineffective erythropoiesis owing to lead poisoning
  3. membrane abnormalities (spherocytosis and elliptocytosis)
  4. hemoglobin abnormalities (Thalassemia and sickle cell anemia)
  5. megaloblastic anemias related to deficiency of either folic acid or vitamin B12, sideroblastic anemia
  6. infections, sepsis
  7. congenital erythropoietic porphyria
  8. myeloproliferative or Myelodysplastic diseases.
  9. RBC enzyme deficiency (G-6-PD Deficiency)
  10. autoimmune
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9
Q

when does mild or moderate hemolysis manifest as jaundice?

A

it normally doesn’t, you just have signs of anemia

for mild hemolysis to manifest as jaundice you have to have a compound problem like

  1. an associated liver dysfunction
  2. taking medications that will displace bilirubin from its binding sites on albumin = sulfonamide, analgesics, ethacrynic acid, furosemia
  3. selected drugs can interfere with hepatocellular uptake of bilirubin = rifampin and the immunosuppressive agent cyclosporine
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10
Q

what conditions can cause decreased hepatic disposition of bilirubin/hepatocellular dysfunction?

A
  1. infections
  2. toxic
    ex. isoniazid, alpha-methyldopa, acetaminophen
  3. metabolic diseases
  4. vascular
  5. inflammation of intrahepatic bile ductules
    ex. chlorpromazine, erythromycin
  6. granulomatous disease
  7. neoplasm
  8. miscellaneous
    ex. contraceptive jaundice, estrogen,s anabolic steroids
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11
Q

what are the intrahepatic cholestasis causes of decreased bile flow?

A
  1. familial colestatic disorders
  2. diffuse infiltrative disorders
  3. inflammation of intrahepatic bile ductules and/or portal tracts
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12
Q

what are the extrahepatic cholestasis causes of decreased bile flow?

A
  1. choledocolithiasis
  2. bile duct disease
  3. inflammation, infection
  4. neoplasm: cholangiocarcinoma
  5. extrinsic compression: [ancreatic carcinoma, metastatic lymphadenopathy, hepatocellular carcinoma, ampullary adenoma/carcinoma, lymphoma
  6. pancreatitis
  7. vascular enlargement: aneurysm, cavernous transformation of the portal vein (portal cavernoma)
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13
Q

what are the inerheited or acquired defects in specific aspects of hepatic bilirubin disposition/isolated disorders of bilirubin metabolism?

A
  1. hepatocellular bilirubin uptake involves both facilitated transport (OATP1B1) and simple diffusion components.
    disease: Gilbert Syndrome: secondary mechanism effecting bilirubin conjugation
  2. drugs: several drugs competitively inhibit the transporter protein OATP1B1
    - rifampin
    - novobiocin
    - immunosuppressive cyclosporin
    - cholecystographic contrast agents
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14
Q

what conditions can cause decreased conjugation of bilirubin?

A
  1. Gilbert syndrome
  2. Crigler-Najjar syndromes
  3. physiologic jaundice of the newborn
  4. drugs (HIV protease inhibitors, e.g., indinavir, atazanavir)
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15
Q

how is bilirubin conjugated? which diseases effect this?

A

bilirubin conjugation with glucuronic acid is catalyzed principally by a specific UDP-GlucuronosylTransferase, which is designated UGT1A1 and encoded by theUGT1gene complex

three autosomally inherited disorders of unconjugated hyperbilirubinemia are due to impaired bilirubin conjugation:

  1. Gilbert Syndrome
  2. Crigler-Najjar Syndrome type 1
  3. Crigler-Najjar Syndrome type 2
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16
Q

what is Gilbert syndrome?

A

Gilbert syndrome is a hereditary (autosomal recessive) form of unconjugated hyperbilirubinemia and has a prevalence of approximately 7-10% in white populations.

the molecular basis of Gilbert syndrome has been linked to missense mutations in the promoter region and, less commonly, in the coding region.

patients with Gilbert syndrome have 10 to 33% of normal enzymatic activity, leading to bilirubin 1.5 to 3 mg/dL

Gilbert syndrome is generally benign condition and requires no treatment.

clinical jaundice is uncommon and the patient is asymptomatic and the isolated hyperbilirubinemia is incidentally discovered in routine blood work

serum bilirubin levels may rise 2- to 3-fold with fasting or dehydration but are generally below 4 mg/dL.

patient with Gilbert syndrome has increased risks for:

  1. gallstones
  2. toxicity of selected drugs like irinotecan that require glucuronidation for metabolic disposal

on the other hand, patients with Gilbert syndrome may be at decreased risk for cardiovascular disease and certain neoplasms (bilirubin is antioxidation regulatory molecule)

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17
Q

what is Crigler -Nahhar syndrome type 1?

A

Crigler-Najjar type 1 is characterized by striking unconjugated hyperbilirubinemia that appears in the neonatal period and persists throughout the patient life.

the majority of patients (type 1A) exhibit defects in the glucuronide conjugation of a spectrum of substrates in addition to bilirubin as the result of mutations in one of the common exons (2 to 5) of theUGT1complex.

almost 60 genotypes are reported for UGT1A1mutations that can cause Crigler-Najjar type 1; their common feature is that all encoded proteins are absent or, at most, traces of enzymatic activity

in a smaller subset (type 1B), a mutation in the bilirubin-specific exon A1 limits the defect to bilirubin conjugation

in Crigler-Najjar type 1, essentially no functional enzyme activity is present leading to bilirubin concentrations of 18 to 45 mg/dL

before the availability of phototherapy, most patients with Crigler-Najjar type 1 died of bilirubin encephalopathy (kernicterus) in infancy or early childhood

Crigler-Najjar type 1 is unresponsive to phenobarbital therapy.!!

18
Q

what is Crigler -Nahhar syndrome type 2?

A

almost 50 different genotypes (mutations) ofUGT1A1have been associated with Crigler-Najjar type 2; all encode a bilirubin-UDP-glucuronosyltransferase with markedly reduced but detectable enzymatic activity

Crigler-Najjar type 2 have up to 10% of normal enzymatic activity, leading to bilirubin concentrations of 6 to 25 mg/dL.

bilirubin concentrations are typically lower in Crigler-Najjar type 2, and plasma bilirubin levels can be reduced to 3 to 5 mg/dL by phenobarbital.

phenobarbital therapy is often recommended; a single bedtime dose usually maintains clinically safe plasma bilirubin concentrations –> only exon 1 is involved which is bilirubin specific and the rest of the stuff is still fine!

19
Q

what condition leads to decreased secretion of bilirubin?

A
  1. Dubin-Johnson syndrome
  2. Rotor’s syndrome

they are autosomally inherited disorders

the two conditions are phenotypically similar (total serum bilirubin 2-5mg/dL), but mechanistically distinct inherited disorders

both syndromes carry a benign prognosis without specific therapy

20
Q

what is Dubin-Johnson syndrome?

A

Dubin-Johnson syndrome results from any of several mutations in the ABCC2 gene encoding the ATP-dependent canalicular organic anion transporter MRP2/cMOAT

in absence of expression or altered trafficking of MRP2 impairs secretion of conjugated bilirubin into the bile canaliculus

compensatory up-regulation of the sinusoidal export protein MRP3 may prevent hepatocellular overload by potentially toxic organic anions that are normally secreted by MRP2, and this can contribute to the degree of hyperbilirubinemia in the disorder

21
Q

what is Rotor’s syndrome?

A

individuals with Rotor syndrome exhibit the simultaneous disruption of two genes that code for the organic anion transporting polypeptides OATP1B1 and OATP1B3 that rey-take regurgitated conjugated bilirubin

despite the conjugated hyperbilirubinemia, patients with Rotor syndrome are not cholestatic like those with Dubin-Johnson

22
Q

what is postoperative jaundice?

A

some patients suffer from hyperbilirubinemia after surgery –> this is a complex syndrome where multiple mechanisms could be at play in causing hyperbilirubinemia (jaundice).

  1. increased bilirubin production

this could be due to breakdown of transfused erythrocytes, resorption of hematomas or sepsis

  1. decreased hepatic bilirubin clearance

this could be due to bacteremia, endotoxemia, viral hepatitis, poor parenteral nutrition, anesthetic injury, preoperative hypoxia

  1. biochemical features
    - hyperbilirubinemia
    - several-fold increase in alkaline phosphatase and GGT
    - aminotransferases are minimally elevated.
    - synthetic function of the liver is typically normal (Albumin and PT).
23
Q

what is jaundice in pregnancy?

A
  1. liver diseases associated with and unique to pregnancy often occurs in patient with hyperemesis gravidarum in the first trimester. It is generally modest and self-limited elevation of the aminotransferase and bilirubin levels
  2. intrahepatic cholestasis of pregnancy (Obstetric Cholestasis): occurs during the second and third trimesters, is associated with intrauterine fetal death and resolves spontaneously after delivery. Mutations in genes encoding biliary transporters, especiallyABCB4,have been reported in some but not all cases
  3. acute fatty liver syndrome of pregnancy: acute fatty liver may resemble fulminant hepatic failure, with early delivery a prerequisite to maternal recovery
24
Q

what is HELLP?

A

this condition occurs in association with preeclampsia in the third trimester.

Hemolysis,

ElevatedLiver enzymes

LowPlatelets

25
Q

how common is jaundice in neonates?

A

newborn babies are more prone to jaundice than adults.

  1. they are cute and adorable
  2. increased rate of bilirubin production than adult due to faster destruction of fetal RBC and fetal hemoglobin and gradually switching to adult RBC and adult hemoglobin
  3. immature liver and delayed expression of UDP-Glucuronosyltransferase (UGT) enzyme
  4. less bulky meal and slow movement of the intestine and delayed defecation of meconium
  5. birth injuries that may leave hematomas.
26
Q

what is the physiologic jaundice of newborns?

A

this is a quite common condition in neonate (60%-80%) .

most neonates develop mild unconjugated hyperbilirubinemia between days 2 and 5 after birth because:

  1. hepatic immaturity and
  2. delayed developmental expression of UGT1A1 gene which conjugates bilirubin

the peak bilirubin levels are typically less than 5 to 10 mg/dL

it generally resolves rapidly in the neonatal period (within two weeks)

a brief course of phototherapy (see later) may be required to prevent kernicterus

27
Q

what is breast milk jaundice?

A

the breast milk in some mother contains:
1
. 3α,2β-pregnanediol, a progestational steroid (progesterone metabolite)

  1. certain fatty acids

these two products in the breast milk inhibit bilirubin conjugation and can cause excessive neonatal hyperbilirubinemia(breast milk jaundice)

28
Q

what is breast feeding jaundice?

A

inadequate milk intake leads to less bulky stool and slow the passage of stool which leads to increased chance of reabsorption of bilirubin back to the circulation, increasing the load of bilirubin in blood

this further complicated by the fact that neonatal gut is less populated with bacterial flora that oxidize conjugated bilirubin into urobilinogen, increasing the chance of reabsorption of conjugated bilirubin back into the blood

29
Q

what is kernicterus?

A

a form of irreversible brain damage due to high bilirubin level which cross blood brain barrier and bind to brain tissues

when a baby with high bilirubin level start to be:

  1. lethargic
  2. sleepy and hard to awake
  3. high-pitched cry
  4. become hypotonic (floppy baby).

these signs are indicative of early brain damage (bilirubin encephalopathy).

bilirubin
encephalopathy should be treated as a medical emergency before the brain damage becomes irreversible with phototherapy or blood exchange transfusion

30
Q

what is the diagnostic approach to patients with jaundice/hyperbillirubinemia?

A
  1. How many pounds of carrots did you eat today? or how many gallons of carrot juice did you drink today?

2 anorexia, nausea, vomiting

  1. stool and urine color
  2. pruritis
  3. joint pain
  4. history of surgery
  5. medications
  6. blood transfusion
    Intravenous drug use
  7. alcohol use
  8. sexual history
  9. symptoms of anemia (easy fatigue, shortness of breath, tachycardia or palpitation, and lack of concentration)
  10. abdominal pain
  11. recent travel
  12. recent contact with farm animals
31
Q

what should you do in a PE for someone with jaundice?

A
  1. general condition
  2. skin
    - the tone of yellow (olive green yellow vs orange yellow)
    - scratch marks
    - vascular lesion we call spider nevi (spider telangiectasia)
  3. abdominal tenderness
  4. enlarged liver or spleen
  5. signs of portal hypertension (caput medusa)
  6. abdominal masses
  7. signs of anemia
  8. surgical scars
  9. ascites
  10. lower limb edema
  11. asterixis (flapping tremor)
  12. mental confusion
  13. fetor hepaticus
32
Q

what are the blood, urine and stool findings in hemolytic jaundice?

A

BLOOD
unconjugated bilirubin = increased

conjugated bilirubin = normal

ALT and AST = nromal

ALP and GGT and 5-NT = normal

URINE
unconjugated bilirubin = null

conjugated bilirubin = null

urobilinogen = increased

color = deep yellow

STOOL
dark brown color

33
Q

what are the blood, urine and stool findings in hepatocelluar jaundice?

A

BLOOD
unconjugated bilirubin = increased

conjugated bilirubin = increased

ALT and AST = markedly elevated

ALP and GGT and 5-NT = normal/slightly elevated

URINE
unconjugated bilirubin = null

conjugated bilirubin = bilirubinuria

urobilinogen = decreased/increased

color = dark brown like tea

STOOL
pale

34
Q

what are the blood, urine and stool findings in obstructive jaundice?

A

BLOOD
unconjugated bilirubin = normal/increased

conjugated bilirubin = increased

ALT and AST = normal/slightly elevated

ALP and GGT and 5-NT = markedly elevated

URINE
unconjugated bilirubin = null

conjugated bilirubin = bilirubinuria

urobilinogen = decreased/null

color = dark brown like tea

STOOL
clay colored

35
Q

why is it important to identify which type of jaundice it is?

A

obstructive jaundice is a medical emergency that required immediate surgical intervention

36
Q

what are the signs of obstructive jaundice?

A
  1. history and physical
  2. history of recurrent pain in the right upper quadrant
  3. history of abdominal surgery
  4. abdominal scar on inspection
  5. pale stool and dark urine
  6. itching & itching marks
  7. live green complexion
  8. ab
    ALP, GGT and 5-NT are markedly elevated.

ALT and AST are minimally elevated or normal

provisional diagnosis is obstructive jaundice; confirm with maging studies to make definitive diagnosis

37
Q

what are the signs of hemolytic anemia?

A
  1. fatigue
  2. pale skin and mucous membrane
  3. palpitation
  4. shortness of breath
  5. dizziness or lightheadedness
  6. lack of concentration
  7. headaches

Lab:
1. high bilirubin (unconjugated)

  1. low RBC count
  2. low Hgb
  3. low hematocrit
  4. normal liver enzymes
38
Q

what are the signs of hepatocellular jaundice?

A
  1. nausea, vomiting, loss of appetite
  2. weight loss
  3. fatigue
  4. abdominal pain or swelling
  5. low grade fever
  6. loint pain
  7. history of blood transfusion or IV drug use, alcohol use
  8. travel abroad
  9. recent contact with farm animals

Lab:
1. ALT and AST are markedly elevated

  1. ALP, GGT, 5’-NT are normal or slightly elevated
  2. prothrombin time or albumin concentration normal or elevated

confirm with more lab (serology) and many imaging modalities or a liver biopsy

39
Q

what are the signs of an isolated disorder of bilirubin metabolism aka hereditary hyperbilirubinemia?

A

the patient is asymptomatic (except for the jaundice)

normal liver function tests (except high bilirubin)

normal blood profile

40
Q

what are benign conditions of yellow discoloring of the skin?

A
  1. carotenosis

aka carotenemia, carotenoderma, anthemia from eating too many carots

  1. quinacrine-induced medication yellow discoloration of the skin used to treat malaria or resistant giardia

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