Jaundice: Pathology review
Case Study0:00–1:08
Christine, a 20-hour-old female infant presented with neonatal jaundice. She was born at term following an uncomplicated pregnancy.
Laboratory studies reveal high total bilirubin of 25mg/dL, normal liver function tests, and no evidence of hemolysis. On the other hand, a 17-year-old boy named Steven comes to his primary care physician because his sister has been telling him that periodically, he look a little yellow.
Medical history is noncontributory, physical examination shows no abnormalities, but Steven mentions that he has recently started working out and dieting to prepare for prom.
Laboratory studies show elevated total bilirubin concentration. A week later, his bilirubin concentration is normal.
Now, both Christine and Steven have jaundice, but the underlying cause of their problem is different. Jaundice, also called icterus, is the abnormal yellowish pigmentation of the skin, mucous membranes, and sclera due to the deposition of the bilirubin.
Pathology1:08–2:11
The reference range for total bilirubin is 0.2 - 1.2 mg/dl; while jaundice typically occurs when total bilirubin levels exceed 2mg/dl.
Now for your exam, it’s crucial to know the metabolism of bilirubin! When old red blood cells pass through the spleen, macrophages eat them up and break down the hemoglobin to heme and globin.
Heme is then converted into biliverdin by an enzyme heme oxygenase. Biliverdin is further converted into unconjugated or indirect bilirubin by an enzyme biliverdin reductase.
Unconj. Hyperbilirubinem2:11–6:26
Instead, the unconjugated bilirubin undergoes hepatic metabolism of bilirubin, which consists of 3 main phases. The first phase is carrier-mediated uptake of bilirubin at the sinusoidal membrane of the hepatocyte.
In the second phase two molecules of glucuronic acid are attached to bilirubin by an enzyme UDP glucuronyl transferase. The final product is bilirubin diglucuronide, which is also known as conjugated or direct bilirubin.
In contrast to unconjugated bilirubin, conjugated bilirubin is water-soluble. So this form is secreted into the bile canaliculi, further drains into the bile ducts and eventually into the gallbladder.
Now, after a fatty meal, cholecystokinin causes contraction of the gallbladder which squeezes out the bile into the biliary duct system and further through the Ampulla of Vater into the duodenum.
It’s important to note that most of the bilirubin found in bile is in the form of conjugated bilirubin, but a small portion consists of unconjugated bilirubin!
In the gut, intestinal microbes convert conjugated bilirubin to urobilinogen, or UBG. 80% of the urobilinogen is converted to stercobilinogen which is further oxidized into stercobilin which is responsible for the brown color of feces.
On the flip side, 20% of urobilinogen gets reabsorbed into the blood and spontaneously oxidizes into urobilin. 90% of the urobilin is sent back to the liver and 10% of it is excreted by the kidneys and it is responsible for the yellow color of urine.
Now, if there is a problem with bilirubin metabolism, bilirubin accumulates and hyperbilirubinemia occurs; and based on the form of the bilirubin that is elevated, hyperbilirubinemia can be predominantly unconjugated, conjugated, or mixed.
Unconjugated, or indirect hyperbilirubinemia, is caused by an increased breakdown of hemoglobin, impaired hepatic bilirubin uptake, or defective conjugation of bilirubin.
Increased breakdown of hemoglobin is commonly seen in intravascular hemolytic conditions, such as hemolytic disease of the newborn, sickle cell anemia, and glucose-6-phosphate deficiency.
Increased destruction of red blood cells, results in an increased breakdown of hemoglobin, and eventual unconjugated hyperbilirubinemia.
On the other hand, impaired hepatic bilirubin uptake can be caused by congestive heart failure or some medications such as rifampicin and probenecid.
Finally, defective conjugation of bilirubin can be physiologic, which is also referred to as physiologic jaundice of the newborn; or pathologic, which is commonly seen in hereditary conditions such as Gilbert syndrome and Crigler-Najjar syndrome.
Now, as mentioned before, unconjugated bilirubin is lipid-soluble, meaning it can deposit in many organs of the body, including the brain.
Deposition of unconjugated bilirubin in basal ganglia can cause bilirubin encephalopathy, also known as kernicterus, which is a potentially fatal condition characterized by jaundice and neurological problems.
In addition, these individuals can have an increased concentration of unconjugated bilirubin in bile and this can result in the formation of numerous, small, black pigmented gallstones.
Now, physiologic jaundice of the newborn is extremely common and this is especially the case for preterm infants. A high yield fact to remember is that it typically manifests within the first 2 days to 1 week of life.
PJoN6:26–8:05
It’s important to note that physiologic jaundice of the newborn is more commonly seen in Asian newborns! At birth, newborns have a high hematocrit, but their red blood cells have a shorter life.
As a result, when that large number of red blood cells turn over, a lot of unconjugated bilirubin gets released. To make this problem worse, newborn livers have immature UDP glucuronyl transferase, therefore they are inefficient at conjugating this bilirubin and this eventually leads to unconjugated hyperbilirubinemia.
It’s important to note that sulfonamides and ceftriaxone should not be given to neonates and infants due to their ability to take up bilirubin binding sites on albumin, thereby exacerbating or facilitating jaundice.
Usually, this is a totally benign condition, but kernicterus can occur when large amounts of unconjugated bilirubin starts to deposit within the brain, causing brain damage.
Even though the physiologic jaundice of the newborn typically resolves without treatment in 1-2 weeks, babies that require therapy are usually treated with non-UV phototherapy, which isomerizes unconjugated bilirubin to water-soluble form that can be excreted by the body.Another type of jaundice that can be seen in healthy newborns is breast milk jaundice or BMJ.
Breast Milk Jaundice8:05–8:55
The gut flora is established one to two years after birth, so, when born, babies do not have enough bacteria to convert conjugated bilirubin to urobilinogen, and eventually to stercobilin.
With breast milk jaundice, high levels of glucuronidase in breast milk actually deconjugate conjugated intestinal bilirubin, thereby increasing enterohepatic circulation of unconjugated bilirubin, eventually causing unconjugated hyperbilirubinemia and jaundice!
For your exam, you should know that breast milk jaundice develops after the first 5 to 7 days of life and it peaks after 2 weeks.
Now it’s important to differentiate breast milk jaundice from breastfeeding failure jaundice, or BFJ, which is also known as starvation jaundice!
BFJ8:55–10:01
Breastfeeding failure jaundice typically occurs during the first week of life and it is typically caused by decreased or poor intake of breast milk.
As a result, these babies have inadequate stooling and decreased elimination of bilirubin by stool. Eventually, this leads to increased enterohepatic circulation, which is further followed by unconjugated hyperbilirubinemia, and jaundice.
Also, it’s important to mention that breastfeeding failure jaundice is associated with clinical features such as suboptimal breastfeeding, mild dehydration, and weight loss in the first few days of life.
Finally, the treatment of breastfeeding jaundice includes prevention of dehydration and increased frequency and duration of feeds, which promote excretion of bilirubin.Alright, now moving on to autosomal recessive conditions, Gilbert syndrome and Crigler-Najjar syndrome.
Gilbert Syndrome10:01–11:07
Gilbert syndrome is a relatively common, benign, genetic condition that is associated with an impaired hepatic bilirubin uptake and reduced production of enzyme UDP glucuronyl transferase.
In other words, these hepatocytes are less effective at conjugating bilirubin and this can result in unconjugated hyperbilirubinemia.
A high yield fact is that individuals with Gilbert syndrome are typically asymptomatic; but they can also present with mild jaundice.
This usually occurs in response to one of the classic triggers, which include fasting, febrile illness, fatigue, stress, physical exertion, all of which induce mild hemolysis.
Therefore, you should think of Gilbert syndrome in a person who presents with mild jaundice, no apparent liver disease, and normal liver function tests.
On the other hand, Crigler-Najjar syndrome type 1 is characterized by the absence of UDP glucuronyl transferase; therefore individuals with this syndrome can’t conjugate bilirubin at all!
Crigler-Najjar Syndrome11:07–13:01
Ultimately, this leads to unconjugated hyperbilirubinemia with a very high total bilirubin that can range from 20 mg/dl up to 50 mg/dl.
For your exam, you have to know that symptoms typically occur soon after birth and these infants present with persistent neonatal jaundice and even kernicterus.
On rare occasions, they can even develop neurological problems later in life. As far as the treatment goes, individuals with Crigler-Najjar syndrome type 1 are treated with plasmapheresis and phototherapy.
It’s important to note that phototherapy does not conjugate bilirubin molecules, instead, it works by increasing polarity and water solubility of unconjugated bilirubin.
But since this condition is associated with a fatal outcome, the only curative treatment for individuals with this type of Crigler-Najjar syndrome is liver transplantation.
On the flip side, Crigler-Najjar syndrome type 2 is the less severe form and it is associated with reduced activity of the UDP glucuronyl transferase enzyme.
As a result, these individuals develop unconjugated hyperbilirubinemia with total bilirubin that is usually below 20mg/dl.
Prognosis is good since people with this type have a good response to treatment with phenobarbital, which induces the synthesis of liver enzymes.
Now, let’s move on to conjugated, or direct hyperbilirubinemia, which is commonly associated with pruritus, or itchiness.
Con. Hyperbilirubinemia13:01–13:41
Furthermore, you have to know that pruritus occurs due to increased plasma bile acids that builds up in tissues. Now, conjugated hyperbilirubinemia can be caused by decreased excretion of bilirubin, some biliary tract conditions, and biliary tract obstructions.
Decreased excretion of bilirubin is commonly seen in hereditary conditions such as Dubin-Johnson syndrome and Rotor syndrome.
Dubin-Johnson syndrome is a benign, rare, genetic condition that is characterized by the absence of a biliary transport protein found on the canalicular membrane of the hepatocyte.
Dubin-Johnson Syndrome13:41–15:43
This transport protein is called multidrug resistance protein 2, or short MRP2. As a result less conjugated bilirubin is transported out of the hepatocyte into bile canaliculi.
Eventually, this leads to conjugated hyperbilirubinemia with total bilirubin levels between 2 and 5 mg/dl. But, it’s important to note that these individuals can also present with normal or extremely elevated levels of bilirubin that can range between 20 and 25 mg/dl.
For your exam, you have to know that most individuals are asymptomatic, while some have nonspecific symptoms such as fatigue, abdominal pain, and weakness.
In some cases, individuals present with mild jaundice, that’s usually noted during illnesses, pregnancy or after using certain medications, like oral contraceptives.
You should think of this syndrome in individuals who have elevated total bilirubin with a conjugated bilirubin fraction of at least 50%; and normal liver function tests.
The diagnosis is confirmed by detecting abnormally high levels of coproporphyrin I in the urine. Histopathology reveals normal hepatocytes with a dense pigment composed of epinephrine metabolites within the lysosomes of hepatocytes.
A frequently tested concept is that individuals with Dubin-Johnson syndrome have strikingly black liver. Since individuals with Dubin-Johnson syndrome have good prognosis, no treatment is necessary.Next, we have Rotor syndrome, which is another benign condition that is associated with numerous defects in proteins that enable normal hepatic uptake and excretion of bilirubin.
Rotor Syndrome15:43–16:30
The defective proteins lead to an accumulation of conjugated bilirubin and conjugated hyperbilirubinemia. Individuals with Rotor syndrome have total bilirubin levels below 5 mg/dl and they can be asymptomatic or they can present with mild jaundice.
In contrast to Dubin-Johnson syndrome, the urinary excretion of coproporphyrin I is normal and the liver has regular color.
Finally, no specific treatment is required since these individuals enjoy normal life expectancies. Conjugated hyperbilirubinemia is also associated with biliary tract conditions, such as primary sclerosing cholangitis and primary biliary cholangitis.
Primary Sclerosing Chola16:30–17:17
Primary sclerosing cholangitis, or PSC, is a progressive liver disease characterized by inflammation, fibrosis, and strictures of both intra- and extra- hepatic parts of the biliary tree.
This is classically described as “onion- skin” fibrosis, because on histology, it looks a bit like an onion skin, with concentric rings of fibrosis around the bile duct.
It’s classically seen in middle-aged males with inflammatory bowel disease. It’s also linked to cholangiocarcinoma and cancer of the gallbladder.
On the other hand, primary biliary cholangitis, or PBC, is associated with the gradual destruction of the epithelial cells lining the intrahepatic biliary ducts by granulomatous inflammation.
Primary Biliary Cholangi17:17–18:26
The cause is unknown but it’s possibly autoimmune in nature since it’s typically seen in middle-aged females with another autoimmune condition, like autoimmune thyroiditis or rheumatoid arthritis.
Symptoms of primary biliary cholangitis develop gradually, first with pruritus, especially at night, and fatigue. As the condition progresses, these individuals present with signs of cholestasis, such as jaundice, pale stools, and dark urine.
And since the liver plays a major role in cholesterol metabolism, PBC can lead to hypercholesterolemia, which can manifest as xanthelasmas.
Xanthelasmas are a type of xanthomas which are cholesterol deposits that present as well-demarcated yellowish papules or plaques.
Xanthelasmas typically occur on or around the eyelids. Finally, conjugated hyperbilirubinemia and jaundice can be caused by biliary tract obstruction.
BTO18:26–20:00
Also, don’t forget that obstruction of the normal bile flow also leads to pale stools and dark urine. This is because there’s less conjugated bilirubin in the intestines so there's less urobilinogen and stercobilin, and this results in pale stools.
On the other hand, increased levels of conjugated bilirubin in the blood lead to dark urine. Since there’s less bile secreted into the intestines, individuals with biliary tract obstruction are commonly associated with hypercholesterolemia and malabsorption of the fat soluble vitamins; A, D, E, and K vitamins.
As far as laboratory findings go, individuals with biliary tract obstruction typically present with elevated alkaline phosphatase and gamma-glutamyl transpeptidase.
Now, biliary tract obstructions are usually caused by gallstones and this happens with choledocholithiasis, which is the presence of a gallstone in the common bile duct; and acute cholangitis, which is an infection behind the blockage.
For your exam, you absolutely have to know that the Charcot triad of cholangitis includes jaundice, fever, and right upper quadrant pain.
Another cause is cholangiocarcinoma, which is a tumor of bile ducts that can be either intrahepatic or extrahepatic. In addition, the normal flow of bile can be compromised by tumors outside of the biliary tree, such as liver or pancreatic cancer.
Pancreatic Cancer20:00–22:57
Pancreatic cancer that is associated with jaundice is typically located in the pancreatic head or neck. Now, the most common pancreatic cancer is pancreatic adenocarcinoma, which arises from the epithelial cells lining the pancreatic ducts.
This is a very aggressive tumor and its histopathology features include disorganized glandular and ductal structures with cellular infiltration.
Important risk factors include smoking; high alcohol consumption; chronic pancreatitis, especially if it lasts more than 20 years.
Also, it’s important to note that individuals older than 50 years of age, and Jewish or African-American males have a higher risk of developing pancreatic adenocarcinoma.
Common clinical features include mid epigastric pain that radiates to the mid- or lower-back; weight loss, due to malabsorption and anorexia; Trousseau sign, also called migratory thrombophlebitis, which is when blood clots, appear unexpectedly in superficial veins, and then over time, migrate to different locations.
Another high yield point is that Trousseau sign presents with swelling, erythema, and tenderness on the extremities. Also, these individuals can present with Courvoisier sign, which is an enlarged, palpable, and nontender gallbladder along with jaundice.
It’s important to note that at the time of presentation, these individuals typically have metastasis, therefore their average survival rate is 1 year after diagnosis.
A frequently tested fact is that tumor markers associated with pancreatic adenocarcinoma are: carbohydrate antigen 19-9, which is used for diagnosis and monitoring of pancreatic adenocarcinoma; and carcinoembryonic antigen, which is less specific since it is also seen in individuals with colorectal, breast, lung, and thyroid cancers.
Finally, the treatment of pancreatic adenocarcinoma includes the Whipple procedure, also known as pancreaticoduodenectomy; chemotherapy; and radiation therapy.
But, don’t forget that individuals with lung cancer can have liver metastasis, therefore they can present with jaundice, just like the ones with liver or pancreatic cancer.
Finally, for your exam, you have to know that clonorchis sinensis is a liver fluke that is associated with obstructive jaundice.Similar to biliary tract obstruction, there is also biliary atresia which occurs in infants.
Biliary Atresia22:57–24:36
This is a childhood disorder where the gallbladder fails to form or there’s early fibro-obliterative destruction of the extrahepatic biliary tree.
It can be caused by inflammation of the biliary tract, typically due to viral infection or toxins; and by the end of the third week after birth, there is a total obstruction of the biliary tree.
For your exam, it’s important to remember that neonates with biliary atresia have normal birth weight and weight gain. But you should suspect biliary atresia in neonates that present with persistent jaundice after 2 weeks of life, dark urine, acholic stools, and hepatomegaly.
Physical examination shows firm and enlarged liver, while laboratory findings reveal increased levels of conjugated bilirubin, alkaline phosphatase, and gamma-glutamyl transferase.
It’s important to note that the method of choice for the diagnosis is a liver biopsy, which shows intrahepatic bile duct proliferation; fibrosis and edema of the portal tract; and parenchymal cholestasis.
Biliary atresia is the most frequent cause of early childhood death related to liver disease, therefore it requires surgical intervention to prevent progression to biliary cirrhosis.
Finally, biliary atresia is the most common reason for pediatric liver transplantation! Now, a frequently tested concept on your exam is to differentiate unconjugated and conjugated hyperbilirubinemia, and an easy way to do this is by using urinalysis.
Urinalysis24:36–25:43
In unconjugated hyperbilirubinemia, there’s no problem with liver metabolism so there’s an increased production of conjugated bilirubin.
This means that individuals with unconjugated hyperbilirubinemia have more urobilinogen in the intestines. More urobilinogen means more reabsorption and excretion by the kidneys, therefore these individuals have increased levels of urobilinogen in urine.
But, it's important to note that unconjugated bilirubin is not increased, since it’s not water-soluble, therefore it cannot be excreted in the urine.
On the other hand, in conjugated hyperbilirubinemia, low amounts of conjugated bilirubin reach the intestines, therefore there is less urobilinogen.
Less urobilinogen in the intestines means less reabsorption and excretion by the kidneys, so the amount of urobilinogen in the urine is low.
Last, but not least, mixed unconjugated and conjugated hyperbilirubinemia is typically caused by hepatocellular problems due to impaired bilirubin conjugation and canalicular excretion.
Mixed Hyperbilirubinemia25:43–26:03
This type of hyperbilirubinemia is commonly seen in individuals with hepatitis and cirrhosis. All right, as a quick recap.
Review26:03–28:27
Jaundice is the abnormal yellowish pigmentation of the skin, mucous membranes, and sclera due to the deposition of bilirubin.
It typically occurs when total bilirubin levels exceed 2mg/dl and can be caused by an increased breakdown of hemoglobin, impaired hepatic bilirubin uptake, and defective conjugation of bilirubin.
Unconjugated or indirect hyperbilirubinemia can be physiologic or pathologic. In severe cases, unconjugated bilirubin can accumulate in the brain, causing bilirubin encephalopathy, which is also known as kernicterus.
Physiologic defective conjugation of bilirubin is also known as physiologic jaundice of the newborn and it’s due to an immature UDP glucuronyl transferase.
On the other hand, pathologic defective conjugation of bilirubin is commonly seen in Gilbert syndrome, which is associated with impaired hepatic bilirubin uptake and reduced production of enzyme UDP glucuronyl transferase; and Crigler-Najjar syndrome, which is characterized by the absence or reduced activity of UDP glucuronyl transferase.
Conjugated, or direct hyperbilirubinemia, is caused by decreased excretion of bilirubin, which is commonly seen in Dubin-Johnson syndrome which is characterized by the absence of a biliary transport protein found on the canalicular membrane of the hepatocyte; and Rotor syndrome which is associated with defects in the proteins that enable normal hepatic uptake and excretion of bilirubin.
Other causes of conjugated, or direct hyperbilirubinemia include biliary tract conditions such as primary sclerosing cholangitis and primary biliary cholangitis; but also biliary tract obstruction, which can be caused by gallstones, cholangiocarcinoma, liver flukes, liver and pancreatic cancer, and biliary atresia.
Christine is a 20-hour-old female infant with neonatal jaundice but without organomegaly. Laboratory studies revealed a total bilirubin of 25 mg/dl, normal liver function tests, and no evidence of hemolysis.
Summary28:27–30:18
There are many potential causes for neonatal jaundice like breast milk jaundice or physiological jaundice. The key clue here is the extremely elevated total bilirubin level, which is more common in Crigler-Najjar syndrome type 1 where there’s a complete absence of functional UDP glucuronyl transferase, so these individuals can’t conjugate bilirubin at all.
Also, they are at risk of developing kernicterus, so they must be treated timely with plasmapheresis and phototherapy. Remember that phenobarbital does not treat this disorder since it works by inducing the production of liver enzymes.
On the other hand, Steven is a 17-year-old boy who came to his primary care physician because his sister had been telling him that he looks “a little yellow” sometimes.
Medical history was noncontributory; physical examination showed no abnormalities; liver function tests were normal. One of the laboratory studies revealed elevated bilirubin concentration, but a week later, his bilirubin was back within normal range.
Steven most likely has Gilbert syndrome where there’s an impaired hepatic bilirubin uptake and reduced production of enzyme UDP glucuronyl transferase.
No treatment was needed but Steven was advised to
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