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!
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
3
Q
Enteric blood circulation diagram
A
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
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
6
Q
Duct and vaculature arrangement within the liver
A
7
Q
Liver lobule structure
A
8
Q
Liver plate ultrastructure diagram
A
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
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.
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.
12
Q
Schematic of a liver capillary
A
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
14
Q
Stellate cell ultrastructure
A
Note that the main features of stellate cells are:
- One or multiple large fat globules
- Scant periglobular mitochondria
- Small but euchromatic nuclei
Stellates are frequently found bordering two heptatocytes and a kupfer cell
15
Q
Portal triad histology
A
16
Q
Liver zones 1, 2, and 3 on H and E
A
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
18
Q
ceruloplasmin
A
Copper transporter
Also synthesized by the liver
19
Q
“True” measures of liver function
A
- Serum albumin
- PT
20
Q
Ammonia detoxification
A
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
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.
23
Q
Why is bile yellow?
A
Bilirubin!
NOT bile salts
Though, the two often travel together.
24
Q
Bile salt overview
A
25
BSEP
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.
26
Various bile transport proteins present on the apical side of hepatocytes
27
Mechanisms of bile flow
* 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.
28
Heme catabolism
29
How does bilirubin travel in serum?
Bound to albumin
It is highly water insoluble
30
Organic Anion Transport Protein
Protein that facilitates diffusion of bilirubin (among other substrates) into hepatocytes from the portal blood via the basolateral membrane.
31
cMOAT
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
The fate of intestinal bilirubin
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
Bilirubin excretion summary image
34
Stercobilin
A urobilinogen that gives feces its characteristic brown color.
35
Bilirubin vs bile acid summary
36
Flow of bilirubin vs bile acid
37
5 categories of liver screening tests
38
AST and ALT. Which is more specific for the liver?
ALT
39
If AST is elevated but ALT is normal . . .
. . . 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
Downtrending AST/ALT is not always reassuring, as it may indicate. . .
. . . loss of hepatocytes entirely
41
AST/ALT in alcoholic liver disease
AST: ALT ratio of at least 2:1 is common, with values of AST or ALT generally 300 IU/l or less .
42
Low serum AP may indicate. . .
. . . Zinc deficiency!
Because Zinc is a cofactor for AP, so the measured activity of AP will be low in low zinc states
43
Gamma-Glutamyl Transferase
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
GGT and AP
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
\_\_\_ is often the last of hepatic functions to deteriorate before the patient presents with full-on liver failure.
**Coagulation** is often the last of hepatic functions to deteriorate before the patient presents with full-on liver failure.
46
Managing an asymptomatic elevation in AST/ALT
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
Risk factors for NAFLD
* HTN
* Dyslipidemia
* DM
* Obesity
48
Indications of hepatocellular injury
* Disproportionate elevation in AST/ALT relative to AP
* Largely nonspecific symptoms, but may present w/ jaundice
* Intrinsic-hepatic causes below
49
Cholestatic injury
* **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
Extrahepatic causes of hepatocellular disease
51
The presence of bilirubin in the urine is suggestive of \_\_\_
The presence of bilirubin in the urine is suggestive of **cholestasis**
52
Alagille syndrome
* 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
Dubin Johnson Syndrome
* Problem w/ excretion of conjugated bilirubin into the bile duct
* Results in **conjugated** **hyperbilirubinemia without hemolysis**
54
Management strategies for indirect hyperbilirubinemia
* **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
Acute liver failure
* 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
Evaluating children for pediatric acute liver failure
* 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
Causes of acute liver failure around the world
58
Manifestations of liver failure in various organs
59
Etiology of acute liver failure in US kids vs US adults
60
What is going on in this liver biopsy?
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
What is going on in this liver biopsy?
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
Progression of NAFLD
63
What is going on in this liver biopsy?
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
Phenobarbital
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
Kernicterus
* 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
Biliary Atresia
67
Kasai procedure
* Used to treat biliary atresia
* Not a cure, but buys infants time before a liver donor can be found
68
Major symptom of vitamin A deficiency
Night blindness
69
If someone presents with apparent bile obstruction or loss of stool coloration, you should worry about dietary. . .
. . . **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
ABCs of Hepatitis Viridae
71
Cure for tylenol overdose
N-acetyl cysteine
