5.01 Approach to Px w/ Jaundice, Abdominal Swelling, and Ascites Flashcards
What is jaundice?
Jaundice is the accumulation of bilirubin which is a yellow pigment which may be due to excess production or decrease in metabolism.
3 main steps in bilirubin metabolism
Uptake, Conjugation, and Excretion
Normal level of serum bilirubin?
When is jaundice clinically apparent?
How do you check for it via PE?
Normal lvl:
x < 1 mg/dL (x < 17 umol/L)
It is clinically apparent when the serum levels exceed:
- Old units: 3 mg/dL or 3 mg%
- New unit: 51 umol/L
Look for it in the sclerae.
-So although it is abn when it is beyond 1 mg%, at that lvl can’t detect it clinically. You can only see it in the sclerae once it exceeds 3 mg%. Now, this accum of bilirubin called jaundice is easily detectable in the sclerae. Simply bc the sclerae is white and bilirubin has a high affinity to the elastin w/c is present in the sclerae.
How do you distinguish jaundice from the ff:
a. Carotenoderma
b. Quinacrine usage
a. Carotenoderma
Now, you have to distinguish jaundice from carotenoderma w/c is v common esp among health buffs. Those who like drink carrot juice and those who consume significant amt of yellow colored food stuff like papaya or oranges. Anything that’s colored yellow. But carotenoderma is not a disease. It is just the accum of carotene in the skin.
> Ans: Now, to distinguish it from jaundice, in carotenoderma, the sclerae is not discolored unlike in jaundice<
b. Quinacrine usage
More importantly, however, we have to distinguish also jaundice from the accum of yellow pigment due to the intake of quinacrine. Quinacrine is an old drug that was used before for the tx of malaria, giardiasis, and sometimes even for SLE. Those px taking quinacrine abt 4–37% will have discoloration of the skin and also of the sclerae. Now in px who are v dark like those w/ black colored skin, if you can’t see it v well on the skin and the sclerae is dirty so you cannot distinguish dirty sclerae fr jaundice
> the 2nd place to examine in the body to detect jaundice is under the tongue
Where does bilirubin come from?
80% come from metabolism of Hgb coming from old or senescent RBCs
20% if produced from ineffective erythropoiesis, sometimes also from degradation of hepatic cytochromes, ms myoglobin, and other heme-containing enzymes
Bilirubin production
Degradation of RBCs -> Release of Hgb -> Globin part metabolized (easy bc mainly, protein) while heme undergoes several processes particularly:
Heme —heme oxygenase —> Biliverdin (green pigment) —biliverdin reductase —> Unconjugated Bilirubin which is released into the bloodstream attached to albumin and transported to the liver —Uridine Diphosphate Glucoronosyl Transferase *transfering 1-2 moieties of glucoronide) —> Conjugated Bilirubin w/c is excreted into the bile ducts and exit into the duodenum and in the small and large intestine —Bacterial beta-glucoronidase (reducing it to)—> Urobilinogen —> Hepatic uptake while some excreted into the urine) —via oxidation—> Urobilin
T or F. Unconjugated and conjugated bilirubin are water-soluble and can exist alone in the serum e.g. during transport.
F F F!! Unconjugated bilirubin is NOT water-soluble. It is lipid-soluble, it cannot exist in soln so the way it will be transported from the reticuloendothelial system like the spleen to the liver is through binding to albumin.
Conjugated bilirubin on the other hand is water soluble thus can exist in soln in the serum.
Irreversible binding of conjugated bilirubin to albumin? When does this occur? Significance?
Now when a px has deep jaundice for a long time, this conjugated bilirubin can irreversibly bind to albumin and this is called delta bilirubin whose importance is that its T1/2 follows the T1/2 of serum albumin w/c is abt 12-14 days. In contradistinction to the T1/2 of conjugated bilirubin in the serum w/c is only abt 4 hrs so therefore if you look at the serum of pxs who have direct hyperbilirubinemia and then you relieve the obstruction, if you check the color of the serum, sometimes days after it is still color yellow but this is not bc of the persistence of serum bilirubin in the serum, persistence of conjugated bilirubin. The persistence of the yellow color is bc of the delta bilirubin, bc the serum T1/2 of serum bilirubin follows that of the T1/2 of serum albumin.
Metabolism of bilirubin
W/c is the most sensitive and RLS?
Heme —UPTAKE—> Unconjugated bilirubin (attached to albumin then transported to the liver —> In the liver attached to ligandin (aka glutathione-S-transferase beta) w/c prevents UB from refluxing back into the plasma —> UB undergoes CONJUGATION by UDP-glucoronosyl transferase —> CB —EXCRETION —> Bile
RLS: EXCRETION
-Curiously enough, the most sensitive and the RLS in hepatic metabolism of bilirubin is excretion. Many students would think that it’s conjugation but not. It is impt to understand this bc in px w/ hepatic dysfxn let’s say bc of acute viral hepatitis, it will affect the metabolism of bilirubin but since excretion is the most impt step and the RLS, if you dec the excretion, what will accumulate in the serum is conjugated bilirubin and NOT unconj bil. If you look at this slide, if it was conjugation w/c is the RLS and affected, then what should accum would be unconj bil. BUT NOT. Since what’s affected mostly is excretion, what will accum will be the conjugated bilirubin in px w/ hepatic parenchymal dysfxns be it due to viral hepatitis or even px w/ cirrhosis.
B1 vs B2 in terms of:
- Polarity
- Renal excretion
- van den Bergh test
- Oxidation to biliverdin?
- Polarity
-B1: Non-polar
-B2: Polar
Explanation: There are differences between the unconj bil and the conj bil. Unconj bil is also called B1 while conj bil is also called B2. As I mentioned earlier B1 is not water soluble bc it is basically non-polar. It is lipid soluble and bc it is non polar, it will not dissolve in water media like the serum and for it to exist in the serum, it has to be attached to serum albumin. Now when you add 1 or 2 moeities of glucoronide to B1 it is now conv to B2. Since the glucoronide are actually polar molecules, it converts the B1 into the water soluble or polar B2. - Renal excretion
-B1: No
-B2: Yes
Now bc B1 in the serum is attached to serum albumin and serum albumin is not filtered into the urine, then B1 is not excreted by the kidney into the urine. So therefore px w/ elevation of the serum B1 will not be associated with a tea-colored urine. On the other hand since B2 is water soluble, it is filtered into the urinary filtrate by the kidneys and so you will see it in the urine and this is the reason why px w/ conjugated hyperbilirubinemia will have an assoc tea-colored urine that is bc of the presence of B2 in the urine. - van den Bergh test
- B1: Indirect
- B2: Direct - Oxidized to biliverdin?
-B1: No
-B2: Yes
they noticed w/ the new technique is that part of the direct reacting bilirubin w/c is supposed to be the conjugated bilirubin, part of that are actually due to the delta bilirubin. What we said earlier, delta bilirubin is the bilirubin that is covalently bound to albumin in px w/ long standing jaundice.
Classification of hyperbilirubinemia
a. If more than 80% of the total is B1 = unconjugated hyperbilirubinemia
b. If more than 50% of the total is Be = conjugated hyperbilirubinemia
c. If they do not meet the criteria of a or b = indeterminate
- Meaning to say the bilirubin fractionation will not help you to guide you in making your differential diagnosis.
Jaundice may occur if there is an ___(inc/dec)___ in the ff:
- Production of bilirubin
- Hepatic uptake of B1
- Hepatic conjugation of B1
- Excretion of B2
Classify the 4 based on the classification of hyperbilirubinemia
- Overproduction
- Dec
- Dec
- Dec
If the jaundice is due to first 3, you’ll develop unconjugated hyperbilirubinemia but if it’s due to the last, you’ll dev conjugated hyperbilirubinemia
Overproduction of bilirubin are due to:
a. Hemolytic d/o (familial or acquired)
- sign
b. Ineffective erythropoietin
a. Hemolytic d/o
- Most of destruction of RBC occurs in the spleen
- Undergo extravascular hemolysis so RBCs are normal, taken up by RES in spleen, spleen would destroy RBCs to release heme w/c is conv to B1.
- Since extravascular hemolysis, will not release Hgb directly in the serum and can exit through the kidneys since water soluble. Thus, associated w/ passing out black colored urine. (Other cond assoc w/ hemoglobinuria: P. falciparum malaria)
b. Ineffective erythropoietin
- Like in cobalamin, folate, or severe iron deficiency
- There’s ineffective erythropoiesis in the BM -> Body tries to produce RBCs but bc of deficiencies, RBCs would never mature at stop at the stage before it does so it’ll be destroyed by the BM (aka “ineffective erythropoiesis”)
- In a VA or after being mold, px produce a lot of bruises w/c represent blood that escapes from the BVs and the blood in the bruises will have to be metabolized and when there’s significantly so much bruises, a few days later, px may be noticeably jaundiced
Px has TB and is jaundiced, what do you do?
Ask if taking rifampicin which will DECREASE HEPATIC UPTAKE leading to the development of UNCONJUGATED HYPERBILIRUBINEMIA in the liver.
This is the same for Probenecid, a drug used before combined w/ penicillin to dec the renal excretion of penicillin. This is so that they can reduce the dose of penicillin that they have to give. Ofc we don’t use it anymore nowadays. Can also lead to the development of dec hepatic uptake and then unconj hyperbilirubinemia.
Px w/ Crigler-Najjar type I or 2 or Gilbert’s syndrome can develop jaundice due to?
- Crigler-Najjar type I
- Complete absence of UDP glucoronosyl transferase -> v high lvls of B1 in the serum
- Since complete absence occurs after a child is born, B1 can enter the brain bc BBB is still immature and produce KERNICTERUS leading to death - Crigler-Najjar type II
-Partial absence of UDPGT, cond can be dec by inducing the enzyme through phenobarbital administration
-There is another form however that is transmitted as an autosomal dominant unlike in type I which is autosomal recessive. In CN type II, there’s only a partial absence of UDPGT and bc it is only partially absent, the lvl of B1 in the serum is not as high as that of the type I so depending on how much UDPGT is present, some of these px may survive into adulthood.
Now curiously, these UDPGT can be induced by certain drugs like phenobarbital so when phenobarbital is given to these px, the lvl of the jaundice can decrease but ofc we never use phenobarbital to tx this condition bc the induction of the UDPGT is only temporary and you cannot give the phenobarbital for a long time just bc of this. - Gilbert’s Syndrome
- Reduced UDPGT activity, jaundice induced by fasting
- 3-7% of the population, male predominance
- Problem of both HEPATIC UPTAKE and DEC HEPATIC CONJUGATION
- Now, there are a lot of px w/ Gilb syndrome but they do not know that they have it or they notice it only at certain times so they don’t really pay attention to it, these pxs w/ Gilb syndrome usually develop jaundice after fasting or after drinking ROH the whole night or not sleeping for the recommended 8 hrs. So when a px goes drinking and does not sleep well and then the next day they would notice that their sclerae is a little bit discolored but a day later it disappears so they don’t actually pay attention to it so these gilb syndrome is not actually a serious condition.
- It is just impt for you to realize what it is so you can reassure the px. But how do you document it? Firstly, these px w/ Gilbert’s syndrome, when you look at the serum bilirubin fractionation, the B1 is more than 80% of the total. They are classified actually as unconj hyperbil. Secondly, if you want to induce the development of jaundice, what we do sometimes is we admit them in the hospital and then we starve them then the next day we measure the serum bilirubin and if it would increase after starving the px or decreasing the amt of caloric intake, and then you have confirmed a diagnosis of Gilb syndrome. Now it is impt that when you are thinking of Gilb syndrome, you don’t need anymore sophisticated diagnostics like CT scan, ultrasound, liver biopsy. This can be done clinically.
Decreased Excretion
Familial
- Dubin Johnson syndrome
- Rotor syndrome
- Benign Recurrent Cholestasis
- Progressive Familial Intrahepatic Cholestasis
- Dubin Johnson syndrome
- Defect in excretion of B2 thus, if you take a liver biopsy, you would notice hepatocytes that appear black and before we do oral cholecystography (not done anymore), you will not visualize the GB - Rotor syndrome
- Defect in the storage of blirubin thus liver biopsy: normal; oral cholecy: GB visualized
NTK
To dx between the two: measure urinary coproporphyrin
-Dubin: N; Rotor: Inc
Look at serum:
-Dubin: Copro I > 80%; Rotor: < 70%
Bromsulphthalein test
-Dubin: Rise in plasma BSP at 90 mins; Rotor: No rise in BSP at 90 mins
- Benign Recurrent Cholestasis
- Will not lead to liver impairment - Progressive Familial Intrahepatic Cholestasis
- Will eventually lead to hepatocyte destruction
Note: in cholestasis whether the benign or progressive type is associated not just w/ accumulation of B2 in the serum but also of the rise of the serum bile acids bc cholestasis means that the bile is not flowing as well from the bile ducts into the intestines. And bile acids is also contained in the bile so when you have cholestasis, these bile acid can be reabsorbed back into the systemic circulation, accumulate just under the skin, and produce pruritus
