Liver/Biliary Tract Wisdom

Question 0

What is the difference between conjugated (direct) and unconjugated (indirect) bilirubin?

Answer 0

The main biochemical difference boils down to how tightly is is bound to albumin, and whether or not it is water soluble.

Conjugated/direct bili is losely bound to albumin and is therefore WATER SOLUBLE. It is also non-toxic. Therefore, when it is present in excess, it can be/is excreted in the urine. THUS, dark urine is only seen with conjugated hyperbilirubinemia.

Unconjugated/indirect (think not conjugated, not direct) bili is TIGHTLY bound to albumin and is therefore NOT water soluble. Thus, it cannot be excreted in the urine even when serum levels are high. It is TOXIC, because its inbound form can cross the BBB and cause neurologic deficits.

Question 1

What is jaundice? What are three major causes of jaundice?

Answer 1

Yellow coloration of the skin, mucous membranes, and sclerae due to OVERPRODUCTION or UNCLEARANCE of BILIRUBIN.

It becomes evident when total bilirubin is >= 2mg/dL

The three major causes of jaundice can be summarized to:

• Hemolysis
• Liver disease
• Biliary obstruction

Question 2

Bilirubin metabolism:
What are the sources of bilirubin in the body?
Which comes first, unconjugated or conjugated bilirubin?
Where does the conversion from one form to another occur?

Answer 2

80% of bilirubin is derived from hemoglobin, from red blood cell breakdown. The rest comes from myoglobin and liver enzymes.

Hemoglobin is converted to (unconjugated) bilirubin in the SPLEEN. This unconjugated (indirect) bilirubin circulates in the plasma bound to albumin. This bilirubin-albumin complex is not water soluble, and is therefore not excreted in the urine.

In the LIVER, unconjugated bili dissociates from albumin, and the bilirubin is conjugated with glucuronic acid by the hepatic enzyme uridine diphosphate glucoronyltransferase. It is then excreted into the intestine through the biliary tract.

Question 3

Bilirubin metabolism, part 2:

Describe enterohepatic circulation, i.e. how bilirubin is secreted into and is recycled by the intestines.

Answer 3

In the liver, bilirubin is conjugated with glucuronic acid by the enzyme glucuronyltransferase, making it soluble in water. Much of it goes into the bile and thus out into the small intestine. However, 95% of the secreted bilirubin is reabsorbed by the intestines (TERMINAL ILEUM) and reaches the liver by portal circulation and then resecreted by the liver into the small intestine. This process is known as enterohepatic circulation.

About half of the conjugated bilirubin remaining in the large intestine (about 5% of what was originally secreted) is metabolised by colonic bacteria to form UROBILINOGEN, which may be further oxidized to UROBILIN and STERCOBILIN. Urobilin, stercobilin and their degradation products give feces its brown color.

However, just like bile, some of the urobilinogen is reabsorbed and 95% of what is reabsorbed is resecreted in the bile which is also part of enterohepatic circulation. A small amount of the reabsorbed urobilinogen (about 5%) is excreted in the urine following further oxidation to urobilin which gives urine its characteristic yellow color. This whole process results in only 1–20% of secreted bile being lost in the feces. The amount lost depends on the secretion rate of bile.

Question 4

Laboratory levels of which substances reflect the liver’s SYNTHETIC function?

Answer 4

• Serum proteins (albumin, fibrinogen)
• Clotting factors, as determined by a coagulation test
• Cholesterol (recall,
• Blood glucose (recall, the liver is a main site of glycogen stores and gluconeogenesis)

Question 5

Where is the defect that causes unconjugated hyperbilirubinemia (urine negative for bilirubin)?

Answer 5

Defect BEFORE hepatic uptake. Namely, excess production, reduced hepatic uptake, or impaired conjugation of bili. A

A. Excess production of bilirubin, as in hemolytic anemias
B. Reduced hepatic uptake of bilirubin or impaired conjugation
- Diffuse liver disease (hepatitis, cirrhosis)
- Drugs (sulfonamides, penicillin, rifampin, radiocontrast)
- Crigler-Najjar syndrome, types I and II
- Physiologic jaundice of newborn (immaturity of conjugating system)
- Gilbert’s syndrome (autosomal dominant condition in which there is decreased activity of the hepatic uridine diphosphate glucoronyltransferase activity)

Question 6

Where is the defect that causes conjugated hyperbilirubinemia (urine positive for bilirubin)?

Answer 6

Defect AFTER hepatic uptake. Mainly, decreased extrahepatic excretion of bili or extrahepatic biliary obstruction.

A. Decreased intrahepatic excretion of bilirubin

• Hepatocellular disease (viral or alcoholic hepatitis, cirrhosis)
• Inherited disorders
• Drug-induced (OCPs)
• Primary biliary cirrhosis (PBS)
• Primary sclerosing cholangitis

B. Extrahepatic biliary OBSTRUCTION

• Gallstones (cholelithiasis, choledocholithiasis)
• Carcinoma of head of pancrease
• Cholangiocarcinoma
• Periampullary tumors
• Extrahepatic biliary atresia

Question 7

List the benign tumors of the liver

Answer 7

• Hemangioma (most common)
• Hepatocellular adenoma
• Focal nodular hyperplasia (FNH)
• Infantile hemangioendothelioma

Question 8

What is the major risk of a hepatocellular adenoma?

Answer 8

Spontaneous rupture and hemorrhage into the peritoneal cavity.

Question 9

Laboratory levels of which substances reflect the liver’s CLEARANCE function (of the hepatocytes)?

Answer 9

Ammonia
Indirect bilirubin (taken up from blood by hepatocytes)

Question 10

Which liver tumors are associated with oral contraceptive use?

Answer 10

Hepatocellular adenoma (strong) and focal nodular hyperplasia (weak).

Hepatocellular adenoma is also associated with the use of anabolic steroids.

Question 12

The symptoms and physical findings of hepatocellular adenoma and focal nodular hyperplasia, if present, are similar (palpable abdominal mass or abdominal pain). What are the major differences?

Answer 12

While the presenting symptoms are similar, FNH is usually asymptomatic and is discovered as an incidental finding.

Also, the risk of sponatenous rupture in FNH is rare.

Histologically, FNH contain all hepatic elements and are composed of hyperplastic hepatocytes with inflammatory (KUPFER) cells, also have bile duct epithelium. In contrast, hepatocellular adenoma contains only normal hepatocytes.

Question 12

Which imaging test is a good adjunct for distinguishing between hepatocellular adenoma and FNH?

Answer 12

Since the Kupfer cells take up the sulfur-colloid in a sufur-colloid scan, on this scan FNH appears as normal liver parenchyma whereas hepatocellular adenoma would appear as a filling defect (because it contains no Kupfer cells). Therefor, this is a useful test distinguish between these two tumors that present in the same patient population.

Question 13

If a patient has hyperbilirubinemia with NORMAL LFTs otherwise, what is on the differential?

Answer 13

Unconjugated hyperbilirubinemia

• Hemolysis
• Gilbert’s syndrome
• Crigler-Najjar
• Physiologic jaundice of newborn

Conjugated hyperbilirubinemia

• Dubin-Johnson syndrome (genetic deficit in excretion of conjugated bili from hepatocytes into biliary tract)
• Rotor’s syndrome

NOTE: the main theme is that these are either hemolysis, or a genetic (or maturity) defect in the conjugation system or in the excretion system for bilirubin. .

Question 14

If a patient has hyperbilirubinemia with abnormal LFTs, what are the things on the DDx?

Answer 14

• Suspected intrahepatic disease (hepatitis, cirrhosis, PBC, PSC)
• Suspected extrahepatic obstruction - use US or CT to assess biliary tract for obstruction.

If it’s a conjugated hyperbilirubinemia, the pattern of LFTs may point to the cause.

Question 15

What does ERCP stand for? HINT: diagnostic imaging test

Answer 15

Endoscopic retrograde cholagiopancratoaphy

Question 16

What does PTC stand for? HINT: diagnostic imaging test

Answer 16

Percutaneous transhepatic cholangiogram

Question 17

Laboratory levels of which substances reflect the EXCRETORY function of hepatocytes and the patency of the biliary tree?

Answer 17

1. Direct (conjugated) bilirubin

2. Enzyme levels - alkaline phosphatase (alk-P) and gamma glutamyl transferase (GGT)

Question 18

Laboratory serum levels of which substances reflect the EXTENT OF INJURY to the hepatocytes?

Answer 18

Alanine transaminase (ALT) 
Aspartate transaminase (AST) 

ALT is more sensitive and specific than AST for liver damage, since the former is primarily found in the liver, whereas the latter is found in many tissues.

Question 19

Elevated ALT/AST suggest a HEPATIDIC pattern of diseae. What is on the DDx, and what are some tests that could help nail the diagnosis?

HINT: for the top 5 things, think bugs, drugs (and alcohol), gluttony, and pride

Answer 19

1. Fatty liver/steatosis - get US
2. Viral hepatitis - HAV, HBV, HCV, HEV (if immunocompromised, also CMV, HSV, and EBV) - get serologies (antibodies, PCR viral RNA)
3. Alcoholic hepatitis (AST > ALT, AST:ALT ~2-3:1) - “scotch&tonic”
4. DILI (drug-induced liver injury)
5. Autoimmune hepatitis (AIH) - get tests for ANA, ASMA, AntiLKM, increased IgG levels

Lower on the differential you have:

6. Hemochromatosis (check ferritin %sat, iron levels)
7. Rhabdomyolisis
8. Wilson’s disease (check ceuloplasm, copper levels)
9. Glycogen storage diseases

Question 20

Elevated Tbili/AlkPhos/GGT (and possibly mildly elevated ALT/AST) suggest a CHOLESTATIC pattern of diseae. What is on the DDx, and what are some tests that could help nail the diagnosis?

Answer 20

1. PBC (primary biliary cirrhosis) - check AMA antibodies
2. PSC (primary sclerosing cholangitis) - check pANCA, MRCP, will see “beads on string” bile ducts on MRI
3. Cholangiocarcinoma
4. Pancreatic carcinoma (esp. of head)
5. Gallstones - check US
6. Cystic Fibrosis - sequence the CFTR gene
7. Biliary atresia

Question 21

What would a liver biopsy reveal for the following causes of liver disease?

• Fatty liver disease
• Hemochromatosis
• AIH

Answer 21

• Fatty liver disease -> fat deposits
• Hemochromatosis -> iron deposits
• AIH -> lymphoplastic infiltrate

Question 22

Let’s look at LFTs! The normal levels of ALT and AST are 6-40 (for both, how convenient!). What causes mildly elevated ALT/AST ( low hundreds)?

Answer 22

Chronic viral hepatitis
Acute alcoholic hepatitis
—> NOTE: in alcoholic hepatitis, the AST level is almost never > 500, and the ALT level is almost never > 300. The AST:ALT ratio may be >2:1. The higher the AST:ALT ratio, the greater the likelihood that alcohol is contributing to the abnormal LFTs.

Question 23

Let’s look at LFTs! The normal levels of ALT and AST are 6-40 (for both, how convenient!). What causes moderately elevated ALT/AST ( high hundreds to thousands)?

Answer 23

Acute viral hepatitis. Think HAV, HBV.

Question 24

Another DDx of elevated ALT/AST question! Use the mnemonic ABCDEFGHI to list causes of elevations in these two lab values in ASYMPTOMATIC patients:

Answer 24

Autoimmune hepatitis
hepatitis B
hepatitis C
Drugs or toxins
Ethanol (alcohol)
Fatty liver (steatosis, triglyceridemia)
Growths (tumors)
Hemodynamic disorders (CHF, portal HTN)
Iron (hemochromatosis), copper (Wilson's disease) or AAT deficiency

Question 25

Let’s look at LFTs! The normal levels of ALT and AST are 6-40 (for both, how convenient!). What causes severely elevated ALT/AST (>10,000)?

Answer 25

This denotes EXTENSIVE HEPATIC NECROSIS.

Typical causes include:

• Ischemia, shock liver (prolonged hypotension or circulatory collapse)
• Acetaminophen toxicity
• Severe viral hepatitis

Question 26

Alk-phos is not specific to the liver - it is also found in bone, gut, and placenta. It is elevated when there is cholestasis in any part of the biliary tree - normal levels make cholestasis unlikely. If the levels are VERY high (10x increase above the normal range of 30-120), think of extrahepatic obstruction or intrahepatic cholestasis (PBC, drug-induced cirrhosis). However, how should you interpret alk-Phos levels if they are merely elevated?

Answer 26

You need to measure the GGT (gamma glutamyl transferase) levels as well, to make sure that the elvation is hepatic in origin (rather than none or intestinal).

If the GGT is also elevated above its normal range of 0-42, this strongly suggests that the elevation is Alk-Phos is of hepatic origin.

If GGT is normal but alk-phos is elevated, consider pregnancy or bone disease.

Question 27

What is the purpose of ordering a GGT level?

Answer 27

To confirm whether a moderate elevation of alk-phos is of hepatic or extrahepatic (bone, placenta) origin.

Both GGT and Alk-phos are elevated if the elevation in Alk-phos if of hepatic origin.

Question 28

When are albumin levels decreased (hypoalbuminemia)?

Answer 28

Chronic liver disease (albumin is synthesized by hepatocytes)
Malnutrition (decreased synthesis)
Nephrotic syndrome (increased excretion in urine)
Inflammatory states (burnd, sepsis, traums)

Discussion: Albumin is synthesized in and catabolized by the liver. The normal range for serum albumin is 3.5-5 g/dL. Levels of this visceral protein may decline in the setting of acute injury and illness as the liver reprioritizes protein synthesis from visceral proteins to acute-phase reactant proteins. Synthesis also declines with hepatic insufficiency or failure. Renal losses of albumin can occur with nephrotic syndrome; enteropathies can result in losses via the GI tract. Systemic inflammation not only reduces albumin synthesis but can increase its degradation and promote transcapillary leakage of albumin. Fluid overload dilutes serum albumin, whereas dehydration or intravenous albumin infusion can temporarily raise levels.

Question 29

Which of the coagulation time assays gives you information about the synthetic function of the kidney?

Answer 29

PT and INR, which tell you about the extrinsic coagulation pathway, which is affected by coumadin. The liver-synthesized, vitK dependent clotting factors are in this pathway. NOTE: PT is not prolonged until most of the liver’s synthetic capacity is lost, which corresponds to advanced live disease.

PTT/aPTT and activated clotting time you about the intrinsic pathway, which is affected by heparin, lovenox (LMWH).

Question 30

Which are the clotting factors synthesized by the liver?

Answer 30

Clotting factors I, II, V, VII, IX, X, XII, and XIII. Essentially all of them, except vWF. Their function is reflected by the prothrombin time (PT).

Of note, the synthesis of factors II, VII, IX and X (a well as protein C and S) is vitK dependent (because VitK is needed for post-translational modification, namely, gamma carboxylation) and is inhibited by comadin/warfarin, a vitK antagonist.

Question 31

What are the sources of vitaminK? What are causes of vitK deficiency?

Also, fun fact: vitK was discovered by a german in the 1920s who ended up making chickens vitK definicent and coagulopathic. The name vitamin K comes from “Koagulationsvitamin,” because it was first published in a German journal:)

Answer 31

Sources of vitaminK are diet (green leafy vegetables) and synthesis by intestinal bacterial flora. It is a FAT-soluble vitamin (along with ADEK), which is ironically considering that it is obtained from leafy greens.

Indeed, the gut microbiome very important for normal vitamin K levels, and vitK levels are often decreased in patients whose gut microbiome has been suppressed by broad-spectrum abx.

Causes of vitK deficiency include:

• Broad-spectrum abx (suppression of gut flora) in patients who are NPO (and thus inadequate dietary intake)
• Patients on TPN (unless vitK is added)
• Malabsorption of fat-soluble vitamins (small bowel disease, inflammatory bowel disease, obstructive jaundice (bile is necessary for fat emulsification and absorption)
• Coumadin, a vitK antagonist (causes production of inactive clotting factors)