ICL 10.2: Chronic Liver Diseases

Question 1

describe the gross anatomy of the liver?

Answer 1

he liver is a large, reddish, lobed structure located in the right upper abdominal quadrant just beneath the diaphragm

it is the largest gland in the body (1.5 kg)

1. right and left lobes
2. the porta hepatis (hilum) is the site for the entry or exit of hepatic portal vein, hepatic artery, bile duct, lymphatic vessels and nodes, and autonomic nerves
3. the surface is covered by a thin connective tissue capsule = Glisson’s capsule

Question 2

what is the functional unit of the liver?

Answer 2

hexagonally arranged lobules with a central vein in the center

surrounded by portal triads composed of portal vein, hepatic artery, bile ducts, and lymphatics

Question 3

what are the 4 main cells of the liver?

Answer 3

1. hepatocytes
2. Kupffer cells
3. hepatic stellate (Ito) cells
4. sinusoidal endothelial cells

Question 4

what are hepatocytes?

Answer 4

main parenchymal cells of liver;

apical surface faces bile canaliculi draining bile to ductule and basolateral surface faces sinusoids that drain blood to central vein (in opposite direction from blood flow)

Question 5

what are Kupffer cells?

Answer 5

specialized macrophages located in sinusoids

they function in red blood cell cycling and immune surveillance of portal blood

Question 6

what are hepatic stellate cells?

Answer 6

when quiescent, store Vitamin A

when activated, produce extracellular matrix

they can also differentiate into myofibroblasts upon injury and cause fibrosis

Question 7

what are sinusoidal endothelial cells?

Answer 7

lack a basement membrane

they’re in the sinusoids

Question 8

what are the zones of the liver?

Answer 8

ZONE 1
periportal zone; located closest to the portal veins and hepatic artery

they’re affected first by viral hepatitis and ingested toxins; Ex: cocaine, hemosiderin deposition in hemochromatosis

ZONE 2
intermediate zone; affected in yellow fever

ZONE 3
centrilobular zone

located closest to central vein; affected first by ischemia and metabolic toxins like alcohol, drugs

highest concentration of cytochrome P450 located here

site of alcoholic hepatitis

Question 9

what is the blood supply of the liver?

Answer 9

the liver is a highly perfused organ, receiving about 25% of the total cardiac output.

1. portal vein (75% of hepatic blood supply)

oxygen-poor blood but it’s rich in:
- digestive products from the intestines (but not chylomicrons which bypass the liver via intestinal lymphatics!) via the Superior Mesenteric Vein

-emoglobin breakdown products from the spleen via the Splenic Vein

• endocrine hormones from the venous blood in the pancreatic vein
  Divides into left and right hepatic branches that enter the hepatic sinusoids.

2. hepatic artery

supplies about 25% of the hepatic blood supply = oxygen-rich blood from aorta

3. hepatic vein aka central vein

most of the hepatic venous blood drains to the three major hepatic veins – the right, middle and left. Each has short extrahepatic segment before joining the inferior vena cava

Question 10

what is the biliary system?

Answer 10

the liver produces bile continuously (600-1200ml per day) that is carried by the biliary tract system to the duodenum

cell membranes of the hepatocyte are indented to form small channels called bile canaliculi between hepatocytes with tight junctions to produce impermeable seals

the intralobular bile canaliculi carry bile to the periphery of the lobule

at the periphery of the lobule the canaliculi converge to form canals of Hering which enter small terminal ductules lined by cuboidal epithelium

the ductules enter larger ducts in the interlobular septum

this duct system follows the segmental anatomy of the vascular supply (in the reverse direction) to enter the bile ducts in the portal triad, then to larger ducts which supply the gallbladder

gallbladder stores bile until needed for digestion

Question 11

what is the function of bile?

Answer 11

bile salts are secreted into the intestine emulsify dietary fats in the intestines and facilitate digestion

Question 12

what is bile made of?

Answer 12

metabolic products (e.g. the hemoglobin breakdown product called bilirubin which gives bile a yellow color) and excess cholesterol

Question 13

what do liver function tests measure?

Answer 13

hepatic function

Question 14

which liver tests reflect hepatic synthetic function?

Answer 14

1. prothrombin time (INR)

this measures level of available clotting factors; this is the most sensitive measure with normal = 1.0 and elevated is >1.5.

2. serum albumin

albumin is made exclusively in the liver and has a normal half-life of 21 days, but will decrease significantly faster in liver disease; this is used as a secondary test

Question 15

which liver chemistries are the biochemical measure of hepatic injury?

Answer 15

1. AST

not specific to the liver, it can be present in skeletal muscle, heart, kidney, brain, pancreas, lungs, WBCs

2. ALT

made exclusively in the liver, therefore much more sensitive to liver damage

3. alkaline phosphatase

not specific to liver; when it comes from the liver, it is useful in determining different pathologies

Question 16

what does gamma glutamyl transferase tell you about the liver?

Answer 16

not a true reflection of injury but goes up alongside alkaline phosphatase and indicates an obstructive pattern of injury

can be induced by many diseases and drugs (alcohol)

Question 17

what does total and direct serum bilirubin tell you about the liver?

Answer 17

defines jaundice (>3.54mg total bilirubin)

normal total bilirubin =1mg/dL (0.3mg direct)

increased bilirubin is caused by overproduction, impaired uptake, conjugation or excretion

direct bilirubin = conjugated bilirubin

indirect bilirubin = unconjugated bilirubin

Question 18

which labs are indicative of loss of synthetic function of the liver?

Answer 18

1. serum albumin
2. bilirubin
3. prothrombin time

these are all indicators of liver synthetic function

Question 19

what do the transminiase levels tell you about the type of liver disease?

Answer 19

ALT > AST in most causes of liver damage

AST > ALT in alcoholic liver disease

transaminase level interpretation:

1. in hundreds → indicates chronic disease
2. in thousands → indicates acute liver disease/injury

Question 20

what are the patterns of liver injury?

Answer 20

1. hepatocellular
2. cholestatic
3. mixed

Question 21

what is hepatocellular liver injury?

Answer 21

injury within hepatocytes

increased ALT and AST with normal alkaline phosphatase

ex: Alcoholic Liver Disease, acute viral hepatitis

Question 22

what is cholestatic liver injury?

Answer 22

injury to gallbladder or bile ducts

high alkaline phosphatase, normal ALT and AST

ex: Primary Biliary Cholangitis

Question 23

what is mixed liver injury?

Answer 23

both bile ducts and liver are injured

ALT and alkaline phosphatase elevated

ex. gallstones, drugs

Question 24

what are the primary causes of chronic liver disease?

Answer 24

1. hepatitis
2. alcohol
3. hepatitis C and alcohol
4. hepatitis B

fatty liver disease is on the rise; especially in women over 50 – it’s now the #1 cause of liver transplant

Question 25

what are the pediatric causes of chronic liver disease?

Answer 25

1. biliary atresia

2. hereditary hyperbilirubinemia

Question 26

what is biliary atresia?

Answer 26

one or more bile ducts are narrowed, blocked, or absent

congenital or acquired

initial symptoms same as neonatal jaundice

liver is unable to excrete bilirubin through bile ducts, causing cholestasis → bilirubin accumulates in blood → jaundice, itchiness, pale stools with dark urine, abdominal swelling

can lead to cirrhosis with portal hypertension and liver failure → does not cause kernicterus because in this case, bilirubin is mostly conjugated

Question 27

how do you treat biliary atresia?

Answer 27

liver transplantation or Kasai procedure (bypass procedure)

both allow for drainage of bile

Question 28

what are the hereditary hyperbilirubinemia syndromes?

Answer 28

1. Gilbert syndrome
2. Crigler-Najjar syndrome type I
3. Dubin-Johnson
4. Rotor syndrome

Question 29

what is Gilbert syndrome?

Answer 29

a hereditary hyperbilirubinemia syndrome; AR

due to mildly low levels of UGT (glucorunosyltransferase enzyme)

jaundice during stress, but not usually clinically significant

high levels of unconjugated bilirubin

usually benign and not clinically significant

ex. medical student doesn’t sleep/eat for a few days and looks yellow

Question 30

what is Crigler Najjar syndrome type I?

Answer 30

a hereditary hyperbilirubinemia syndrome

due to absence of UGT = bilirubin cannot be conjugated

results in kernicterus = accumulation of unconjugated bilirubin in the brain which leads to bilirubin-induced brain dysfunction; usually fatal

Question 31

what is Dubin-Johnson syndrome?

Answer 31

a hereditary hyperbilirubinemia syndrome; AR

deficiency of bilirubin canalicular transport protein = build-up of bilirubin in liver

liver is dark, but not clinically significant

Question 32

what is Rotor syndrome?

Answer 32

a hereditary hyperbilirubinemia syndrome; AD

syndrome (autosomal dominant)

deficiency of bilirubin canalicular transport protein = build-up of bilirubin in liver

it’s like Dubin-Johnson, but liver is not dark

Question 33

what are the signs and symptoms of chronic liver disease?

Answer 33

1. jaundice
2. coagulopathy and thrombocytopenia → liver production of clotting factors and thrombopoietin decreases, causing decrease in platelets and increase in prothrombin time
3. excess estrogen because liver isn’t metabolizing estrogen properly = gynecomastia, spider angiomata, palmar erythema
4. portal HTN
5. hyperammonemia
6. hepatorenal syndrome

Question 34

what is portal HTN? what causes it?

Answer 34

portalhypertensionis an increase in theblood pressurewithin a system of veins called the portal venous system

it occurs due to 2 mechanisms:

1. increased intrahepatic resistance to the passage of blood flow through the liver due to fibrosis
2. increased splanchnic blood flow due to vasodilation in the splanchnic bed

Question 35

what is the hepatic venous pressure gradient?

Answer 35

1. the hepatic venous pressure gradient is the difference between the wedge hepatic vein pressure and the hepatic vein pressure

a HVPG of more than 5 defines portal hypertension

if the HVPG above 10 is threshold for formation of varices

Question 36

what are the clinical signs of portal hypertension?

Answer 36

1. volume overload: ascites and LE edema
2. splenomegaly
3. varices
4. hepatorenal syndrome
5. caput medusae
6. ascites

Question 37

what is portal hypertensive gastropathy?

Answer 37

engorging of the stomach mucosa due to high pressures; can lead to chronic bleeding

looks like snake skin

Question 38

how do you treat esophageal varicose?

Answer 38

Pharmacological treatment:
1. octreotide

2. beta blockers

Surgical:
1. sclerotherapy

2. ligation
3. Sengstaken -Blakemore tube(emergencies only)
4. trans jugular intrahepatic portosystemic shunt (TIPS)

Question 39

what is transjugular intrahepatic portosystemic shunt?

Answer 39

do when they failed sclerotherapy and banding or there’s a bleed despite therapy

they try to connect the portal venous system to the hepatic vein and redirect blood from the portal system to the systemic system to help lower hepatic venous pressure

Question 40

what is capet medusae?

Answer 40

giant veins in the stomach due to portal HTN

Question 41

what is ascites?

Answer 41

accumulation of fluid in the peritoneal cavity

usually caused by hypoalbuminemia due to low albumin production from damaged liver

Question 42

what is hypoalbuminemia?

Answer 42

low albumin levels

may cause low oncotic pressure (explain capillary fluid shifts - capillary hydrostatic pressure, capillary oncotic pressure)

contributes to ascites, edema

Question 43

what is spontaneous bacterial peritonitis? how do you diagnose and treat?

Answer 43

any patient with ascites from chronic liver disease is at risk to having that fluid become infected

caused by aerobic Gram negative organisms or Gram positive Streptococcus (less commonly) leading to infection of ascitic fluid

common, can be fatal

symptoms: fever, chills, abdominal pain/tenderness, encephalopathy, asymptomatic
diagnosis: paracentesis of ascitic fluid; absolute neutrophil count > 250 cells/mm3
treatment: third generation cephalosporin

Question 44

what are the causes of hyperammonemia?

Answer 44

portosystemic shunts decrease the metabolism of ammonium by directing it to the IVC, away from the liver

depatocytes are unable to metabolize the ammonium that makes it to the liver

leads to a build-up of ammonium in the bloodstream

Question 45

what are the symptoms of hyperammonemia?

Answer 45

1. asterixis - a flapping tremor of the hand when wrist is extended
2. hepatic encephalopathy - reversible neuropsychiatric dysfunction
3. ammonia crosses the blood-brain barrier and is metabolized by astrocytes
4. confusion, somnolence, speech slurring, cerebral edema, blurred vision, coma

Question 46

how do you treat hyperammonemia?

Answer 46

1. lactulose - acidifies the GI tract, trapping ammonia as ammonium which is excreted in stool
2. rifaximin (antibiotic): kills intestinal bacteria which produce ammonia

Question 47

what is hepatorenal syndrome?

Answer 47

progressive renal failure in advanced liver disease; secondary to renal hypoperfusion resulting from vasoconstriction of renal vessels due to decreased effective circulating volume

functional renal failure
1. kidneys are normal in terms of morphology

2. no specific causes of renal dysfunction are evident
3. condition does not respond to volume expansion

clinical features:
1. azotemia

2. oliguria
3. hyponatremia
4. hypotension
5. low urine sodium (<10 mEq/L)

idicates end-stage liver disease; in general, prognosis is poor

Question 48

what is cirrhosis?

Answer 48

irreversible; End Stage Liver Disease

normal liver parenchyma is replaced by scars

Question 49

what are the histological findings of cirrhosis?

Answer 49

1. nodules of regenerative hepatocytes

2. fibrosis

Question 50

what are the risks of hepatocellular carcinoma?

Answer 50

Hepatocellular Carcinoma (HCC)

1. cirrhosis from any cause can lead to HCC
2. can also be associated with Chronic Hepatitis B infection and aflatoxins from Aspergillus

spreads hematogenously

Question 51

how do you diagnose hepatocellular carcinoma?

Answer 51

1. increased alpha-fetoprotein (not all patients have this though so do imaging)
2. ultrasound or contrast CT/MRI
3. biopsy shows nuclear atypia, prominent nucleoli, increased hepatocytes with invasion into blood vessels

Question 52

what is hepatopulmonary syndrome?

Answer 52

severe pulmonary vascular complication of liver disease characterized by arterial oxygenation defects induced by intrapulmonary vascular dilations

casodilatation assumed to result from excessive vascular production of vasodilators, especially nitric oxide and carbon monoxide, due to liver dysfunction

patients usually present with nonspecific symptoms such as dyspnea at rest

clubbing of the digits in a patient with liver disease suggests HPS – cyanosis of nail beds indicates advanced disease

Question 53

what is portopulmonary HTN?

Answer 53

characterized by pulmonary vasoconstriction and vascular remodeling coexisting with portal hypertension

may lead to right heart failure and death

pathologically indistinguishable from idiopathic pulmonary arterial hypertension

pathogenesis unknown but factors proposed to play a role in development include dysregulated signaling in inflammatory and vasoactive pathways

patients often present with dyspnea

diagnosis is confirmed by right heart catheterization