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HMS Homeostasis II > Acute Liver Disease > Flashcards

Acute Liver Disease Flashcards

1
Q

Unlike most organs, the liver an truly ___.

A

Unlike most organs, the liver an truly regenerate.

If you surgically remove some liver, more will grow to replace it!

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2
Q

Couinaud system

A

Anatomic classification system where the liver is broken down into segments. There is an imaginary transverse plane through the birufcation of the main portal vein. Functional lobes are then divided into eight segments

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3
Q

Enteric blood circulation diagram

A
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4
Q

Basic liver embryology

A
  • The liver and gallbladder begin as ventral buds off the endodermal tube
  • Cells that form liver parenchyma and bile duct lining are all of endodermal origin
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5
Q

Liver lobule

A
  • The basic the anatomical and histologic unit of the liver at the microscopic level.
  • The lobule is hexagonal in cross-section with interlobular portal triads (portal vein, hepatic artery, and bile duct) forming the angles of the hexagon.
  • The central vein (which drains into the hepatic vein) sits at the center of the lobule. Hepatocytes are arranged as single-cell plates radiating from the central to the portal region
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6
Q

Duct and vaculature arrangement within the liver

A
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7
Q

Liver lobule structure

A
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8
Q

Liver plate ultrastructure diagram

A
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9
Q

Cannaliculi

A
  • Boundaries formed by apical membranes of hepatocytes and tight-junctions between hepatocytes.
  • Lined by microfillaments within hepatocytes
  • Canaliculi form a continuous network that drains eventually into progressively larger bile ducts
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10
Q

Disse’s space

A

The space between basal surface of endothelium and plates of hepatocytes

The exchange of substances between liver and blood occurs here.

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11
Q

Stellate cells

A

Fat-storing cells of the liver

Smaller cells that reside in-between hepatocytes and have a cone shape with a much broader swath of membrane touching the space of Disse.

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12
Q

Schematic of a liver capillary

A
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13
Q

Liver acinus model of microscopic liver anatomy

A
  • In this model, the portal triad comprises the center of the acinus, and the hepatic venules (central veins) lie at the periphery
  • Functional distinctions have zone 1 hepatocytes performing more energy-intensive functions (urea cycle, gluconeogenesis) while zone 3 is the predominant site of biotransformation and glucose storage
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14
Q

Stellate cell ultrastructure

A

Note that the main features of stellate cells are:

  1. One or multiple large fat globules
  2. Scant periglobular mitochondria
  3. Small but euchromatic nuclei

Stellates are frequently found bordering two heptatocytes and a kupfer cell

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15
Q

Portal triad histology

A
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16
Q

Liver zones 1, 2, and 3 on H and E

A
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17
Q

Stellate cell function

A
  • They store a variety of lipids, most notably vitamin A
  • Cells are contractile and help regulate sinusoid diameter
  • Activate in response to pro-inflammatory stimuli, mobilizing vitamin A stores and producing matrix proteins like collagen
    • This collagen contributes to the liver fibrosis seen in cirrhosis
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18
Q

ceruloplasmin

A

Copper transporter

Also synthesized by the liver

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19
Q

“True” measures of liver function

A
  • Serum albumin
  • PT
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20
Q

Ammonia detoxification

A
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21
Q

Phase I vs Phase II reactions

A

Phase I: Hydroxylation - detoxifies compounds (usually - acetaminophen is a big exception)

Phase II: Conjugation - makes compounds excretable in urine

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22
Q

Hepatic metabolism of acetominophen

A

At low doses, almost all acetominophen is conjugated and excreted.

At high doses, a significant portion undergoes hyrdoxylation to form NAPQI, a highly electrophilic metabolite. This intermediate is detoxified by cell glutathione stores, but once these stores run out it will react with sulfhydryl groups within the cell and cause cellular damage.

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23
Q

Why is bile yellow?

A

Bilirubin!

NOT bile salts

Though, the two often travel together.

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24
Q

Bile salt overview

A
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25
Q

BSEP

A

Bile Salt Export Pump

Present in the canalicular membrane on the apical side of hepatocytes and cholangiocytes. Pumps conjugated bile salts into the canaliculi against their concentration gradient.

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26
Q

Various bile transport proteins present on the apical side of hepatocytes

A
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27
Q

Mechanisms of bile flow

A
  • Active adjustment: The hepatocytes pump substrates into the lumen of the canaliculus against their concentration gradient, creating a transiently hyperosmotic lumen. Cations follow to maintain electrical neutrality, further increasing the osmotic pressure.
  • Passive adjustment: This osmotic pressure results in the flow of water into the canaliculus through the permeable tight junctions to balance this potential.
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28
Q

Heme catabolism

A
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29
Q

How does bilirubin travel in serum?

A

Bound to albumin

It is highly water insoluble

30
Q

Organic Anion Transport Protein

A

Protein that facilitates diffusion of bilirubin (among other substrates) into hepatocytes from the portal blood via the basolateral membrane.

31
Q

cMOAT

A

canalicular Multispecific Organic Anion Transporter

Transports glucuronide-conjugated bilirubin out of the apical membrane of the hepatocyte into the canalicular lumen.

This is the rate-limiting step of bilirubin excretion and is highly susceptible to damage from a variety of liver diseases.

32
Q

The fate of intestinal bilirubin

A

Once in the intestinal lumen, conjugated bilirubin cannot re-enter the body. It travels down the GI tract to the colon where much of it is metabolized by bacteria into a series of colorless tetrapyrroles, termed urobilinogens.

A small amount of these urobilinogens are passively reabsorbed, and must be re-secreted by the liver as conjugated bilirubin. A small fraction is also excreted in urine, where it is oxidized to produce urobilin, the compound that gives urine its yellow color.

33
Q

Bilirubin excretion summary image

A
34
Q

Stercobilin

A

A urobilinogen that gives feces its characteristic brown color.

35
Q

Bilirubin vs bile acid summary

A
36
Q

Flow of bilirubin vs bile acid

A
37
Q

5 categories of liver screening tests

A
38
Q

AST and ALT. Which is more specific for the liver?

A

ALT

39
Q

If AST is elevated but ALT is normal . . .

A

. . . search for evidence of hemolysis, acute rhabdomyolysis, myopathic process, myocardial disease, recent vigorous activity (weight lifting, long distance running). Additional testing (haptoglobin, LDH, creatine phosphokinase, aldolase) may be helpful.

40
Q

Downtrending AST/ALT is not always reassuring, as it may indicate. . .

A

. . . loss of hepatocytes entirely

41
Q

AST/ALT in alcoholic liver disease

A

AST: ALT ratio of at least 2:1 is common, with values of AST or ALT generally 300 IU/l or less .

42
Q

Low serum AP may indicate. . .

A

. . . Zinc deficiency!

Because Zinc is a cofactor for AP, so the measured activity of AP will be low in low zinc states

43
Q

Gamma-Glutamyl Transferase

A

Exists in liver microsomes and T catalyzes the transfer of gamma glutamyl from peptides (like glutathione).

In adults, an elevated GGT has been described in chronic alcoholism, exocrine pancreatic disease, myocardial infarction, renal failure, and diabetes, so it is not a very specific test.

44
Q

GGT and AP

A

While neither of these tests is specific alone, when elevated together they often indicate liver injury.

However, even together these cannot distinguish between intrinsic liver injury vs extrahepatic disease, such as cholecystitis.

45
Q

___ is often the last of hepatic functions to deteriorate before the patient presents with full-on liver failure.

A

Coagulation is often the last of hepatic functions to deteriorate before the patient presents with full-on liver failure.

46
Q

Managing an asymptomatic elevation in AST/ALT

A
  1. Check Hx: Is this new or has this been seen before in patient’s history?
  2. Try to pinpoint inciting trigger in Hx
  3. Consider Hep Viridae (in many cases elevated enzymes is the only sign of indolent infection)
  4. Monitor trajectory of enzyme levels
47
Q

Risk factors for NAFLD

A
  • HTN
  • Dyslipidemia
  • DM
  • Obesity
48
Q

Indications of hepatocellular injury

A
  • Disproportionate elevation in AST/ALT relative to AP
  • Largely nonspecific symptoms, but may present w/ jaundice
  • Intrinsic-hepatic causes below
49
Q

Cholestatic injury

A
  • Decrease in bile flow
  • Histologic presence of bile pigment in hepatocytes/bile ducts
  • Accumulation of substances usually excreted in bile (bilirubin, bile acids, and cholesterol)
  • Greater increase in GGP and AP relative to ALT/AST
  • Patients with cholestatic injuries often are jaundiced, have dark urine, and pale stools
  • Other possible symptoms: Xanthomas, fat-soluble vitamin deficiency, pruritis
50
Q

Extrahepatic causes of hepatocellular disease

A
51
Q

The presence of bilirubin in the urine is suggestive of ___

A

The presence of bilirubin in the urine is suggestive of cholestasis

52
Q

Alagille syndrome

A
  • Caused by paucity of intrahepatic bile ducts
  • Characteristic facial dysmorphisms, absence of the interlobular bile ducts, extrahepatic findings (eye abnormalities, butterfly vertebrae, renal tubular acidosis, vascular disease), severe pruritus
53
Q

Dubin Johnson Syndrome

A
  • Problem w/ excretion of conjugated bilirubin into the bile duct
  • Results in conjugated hyperbilirubinemia without hemolysis
54
Q

Management strategies for indirect hyperbilirubinemia

A
  • Avoid medications that bind to albumin and displace bilirubin (e.g.- sulfonamides, Ceftriaxone, ibuprofen)
  • Phototherapy: Blue light converts bilirubin circulating through the skin into more soluble forms that are less tightly bound to albumin, and hence can be excreted in the urine
  • Pharmacologic therapy: give inducers of UGT (e.g.-phenobarbital)
  • Exchange transfusion: (severe cases)
55
Q

Acute liver failure

A
  • Entails disruption of synthetic liver function as well, not just elevated enzymes as in other forms of liver injury
  • Entails encephalopathy, coagulopathy (INR > 1.5) in a patient without cirrhosis or pre-existing liver disease
  • Life threatening - true medical emergency
  • Can present with mental status changes, jaundice, or right upper quadrant pain, but may also present with less specific symptoms, such as nausea, vomiting, malaise.
56
Q

Evaluating children for pediatric acute liver failure

A
  • No evidence of chronic liver disease
  • Biochemical evidence of acute liver injury
  • Coagulopathy not corrected by Vitamin K (INR >1.5 if patient is encephalopathic, INR >2 without encephalopathy)
57
Q

Causes of acute liver failure around the world

A
58
Q

Manifestations of liver failure in various organs

A
59
Q

Etiology of acute liver failure in US kids vs US adults

A
60
Q

What is going on in this liver biopsy?

A

Cholestasis

The yellow/orangish material in the swolen canaliculi and in hepatocytes is bile!

You would expect this patient to have elevated conjugated and unconjugated bilirubin.

61
Q

What is going on in this liver biopsy?

A

Alagille syndrome

There is no bile duct!

Just one of these might be a fluke, but if two or three portal triads are lacking ducts, this is pretty definitive. You can be extra sure by staining for epcam or another epithelial marker to see if there is any non-endothelial epithelium here.

62
Q

Progression of NAFLD

A
63
Q

What is going on in this liver biopsy?

A

Budd Chiari syndrome OR Heart failure

You can tell by the dilated sinusoids, indicating increased sinusoidal pressure.

In Budd Chiari, this is due to obstruction to hepatic venous outflow by a thrombus, a cancer, a congenital abnormality, or inflammation. Clinically, this will present with hepatomegaly and elevated liver enzymes as well, but JVD will be absent. Caput medusae and other signs of portal hypertension will also be present.

In CHF, this is due to lack of motive pressure differential to move the fluid up towards the right heart. This will present with hepatomegaly in the presence of JVD. Signs of portal hypertension will not usually be present.

64
Q

Phenobarbital

A

Induces UGT expression in the liver, enabling the liver to conjugate more bilirubin IF the liver has any functional enzyme at all (this drug obviously won’t help if the patient is a true knockout for the gene)

65
Q

Kernicterus

A
  • Deposits of cerebral unconjugated bilirubin that has crossed the blood brain barrier
  • Shows a characteristic yellow staining of the basal ganglia and hippocampus, along with some other structures, on gross pathology
  • Has devastating, irreversable neurological sequelae
  • THIS is why neonatal jaundice is taken so seriously
66
Q

Biliary Atresia

A
67
Q

Kasai procedure

A
  • Used to treat biliary atresia
  • Not a cure, but buys infants time before a liver donor can be found
68
Q

Major symptom of vitamin A deficiency

A

Night blindness

69
Q

If someone presents with apparent bile obstruction or loss of stool coloration, you should worry about dietary. . .

A

. . . fat soluble vitamins.

Remember that AquaDek and medium chain fatty acids are absorbable even in patients who don’t have any bile salts at all.

70
Q

ABCs of Hepatitis Viridae

A
71
Q

Cure for tylenol overdose

A

N-acetyl cysteine

HMS Homeostasis II (35 decks)

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