Hepatobiliary - liver injury and repair

Question 1

metabolic liver disease

Answer 1

• P: Nonalcoholic fatty liver disease (NAFLD)
• S: Amyloidosis
  P=primary (in), S=secondary (out)

Question 2

toxic liver disease

Answer 2

• P: Alcoholic liver disease (ALD)

- S: Drug-induced liver injury (DILI)

Question 3

infectious liver disease

Answer 3

• P: Viral hepatitis

- S: Extrahepatic/systemic infections (viruses, bacteria, fungi)

Question 4

immune-mediated liver disease

Answer 4

• P: Autoimmune hepatitis (AIH)
• P: Primary biliary cholangitis (PBC)
• P: Primary sclerosing cholangitis (PSC)
• S: Systemic lupus erythematosus (SLE)

Question 5

obstructive liver disease

Answer 5

• P: Small intrahepatic biliary disorders (congenital/ acquired)
• S: Extrahepatic obstructive lesions

Question 6

vascular liver disease

Answer 6

• P: Veno-occlusive disease (VOD)/ sinusoidal obstruction syndrome (SOS)
• S: Heart failure

Question 7

neoplasms

Answer 7

• P: Hepatocellular carcinoma (HCC)

- S: Metastatic cancer

Question 8

investigative tests to test hepatocyte function (3)

Answer 8

Serum aspartate aminotransferase (AST)
Serum alanine aminotransferase (ALT)
Serum lactate dehydrogenase (LDH)

Question 9

investigative tests to test biliary excretory function (2 ways - 5 tests)

Answer 9

1. level of substances normally secreted in bile:
   - Serum bilirubin – Total, unconjugated (indirect) and conjugated (direct)
   - Urine bilirubin
   - Serum bile acids
2. Plasma membrane enzyme (produced when there is damage to bile canaliculus - high levels = bad)
   - Serum alkaline phosphatase (ALP)
   - Serum γ-glutamyl transpeptidase (GGT)

Question 10

investigative tests to test hepatocytes synthetic function - based on serum protein levels

Answer 10

• Serum albumin
  +ve = good
• Coagulation factors: prothrombin (PT) and partial thromboplastin (PTT) times (fibrinogen, prothrombin, factors V, VII, IX, X)

Question 11

investigative tests to test hepatocyte metab

Answer 11

• Serum ammonia
• Aminopyrine breath test (test for hepatic demethylation)
  +ve = good

Question 12

investigative tests to test for infections (3)

Answer 12

• Serology: IgM/IgG to HAV, anti-HBs
• Microbiology: CMV/EBV PCR, cultures
• Radiology (for suspected abscess): ultrasound HBS, CT abdomen, MRI liver

Question 13

investigative tests to test for autoimmune diseases

Answer 13

• Serology: anti-nuclear antibodies (ANA), smooth muscle antibodies (SMA)

Question 14

investigative tests to test for bile duct obstruction (2)

Answer 14

• Endoscopy: Endoscopic retrograde cholangiopancreatography
  (ERCP)/
  brushing cytology/
  biopsy
• Radiology:
  Magnetic resonance cholangiopancreatography (MRCP)
  CT abdomen

Question 15

mechanisms of liver injury and repair (3 steps)

Answer 15

1. hepatocyte and parenchymal response
2. scar formation and regression
3. inflammation/ immunity

Question 16

1. hepatocyte and parenchymal response

- 3 possible types of responses

Answer 16

• regeneration:
  Mitotic replication of hepatocytes/
  Activation of primary stem cell niche (canals of Hering)
  -> hepatocytes reach replicative senescence and there is stem cell activation (seen as ‘ductular reaction’)
• Irreversible injury and cell death
  cell necrosis and apoptosis
• Degenerative but potentially reversible changes
  Cellular swelling (ballooning degeneration)
  Steatosis (accumulation of fat)
  Cholestasis (accumulation of bilirubin)

Question 17

2. scar formation and regression

Answer 17

1. parenchymal transforming into dense fibrous tissue
   • Hepatic stellate cells activated and converted into highly fibrogenic myofibroblasts
2. cirrhosis
   PORTAL/ periportal fibrosis
   -> portal-central and portal-portal bridging fibrosis / septa
   -> cirrhosis
3. CELLULAR: Pericellular / perisinusoidal fibrosis
4. Reversal of fibrosis / cirrhosis regression

Question 18

3. inflammation/ immunity

- histo features

Answer 18

esp for hepatitis - eliminate infected hepatocytes

• Lymphocytes, plasma cells, neutrophils, eosinophils, histiocytes / macrophages
• Lymphoid aggregates
• Granulomas
• Microabscesses

Question 19

causes of ACUTE liver failure

Answer 19

caused by sudden massive injury
- Drugs/ toxins
- Acute Hepatitis A/B/E (autoimmune hepatitis)
[chronic liver failure: B/C - chronic and persistent]

Question 20

acute liver failure

gross + histo appearance

Answer 20

shrunken liver with wrinkled liver capsule

• Massive necrosis - RBC extravasation
• death of hepatocytes
• Diffuse injury without obvious cell death - diffuse microvesicular steatosis (in fatty liver of pregnancy/ drug reaction)

Question 21

acute liver failure

complications

Answer 21

high mortality rate (80%) w/o transplant (cause of major loss in hepatic fn)

impact on liver:

• coagulopathy: impaired hepatic synthetic fn
• hepatic encephalopathy: impaired hepatic metabolism - liver cannot remove toxins -> brain damage
• cholestasis: impaired bile excretion

impact on renal:
- Hepatorenal, hepatopulmonary syndrome
cause of vasodilation of vessels in the lungs -> shortness of breath

portal system:

• Ascites
• Portosystemic venous shunts
• Congestive splenomegaly
• hepatic encephalopathy

Question 22

causes of chronic liver failure (4)

Answer 22

• Hep B/C infection
• NAFLD (non-alcoholic fatty liver disease)
• alcoholic liver disease, (cryptogenic)
• liver cirrhosis

Question 23

liver cirrhosis**

Answer 23

transformation of liver into regenerative parenchymal nodules

• fibrous bands - from scarring of liver
• disturbed vascular architecture: vascular shunting

Question 24

liver cirrhosis **

• clinical features
• complications

Answer 24

• anorexia, weight loss, weakness
• Hepatic encephalopathy
• Bleeding from oesophageal varices
• Bacterial infections / sepsis

Question 25

chronic liver disease | - clinical presentation (4)

Answer 25

- Cholestasis: buildup of bilirubin Jaundice -> pruritus (itch) Scleral icterus ``` - Hyperoestrogenemia Palmar erythema Spider angiomas Hypogonadism Gynaecomastia ``` - Coagulopathy - easy bruising ``` - Portal hypertension Ascites Portosystemic venous shunts: Splenomegaly Hepatic encephalopathy: asterixis ‘hepatic flap’ ```

Question 26

portal hypertension | causes

Answer 26

- increased flow - increased resistance - prehepatic: Obstructive thrombosis or narrowing Massive splenomegaly with increased splenic vein blood flow - intrahepatic Cirrhosis Diffuse infiltrative processes (granulomatous inflammation, amyloid, malignancy) non-cirrhotic (Nodular regenerative hyperplasia) - post-hepatic Hepatic vein outflow obstruction Heart problems: right heart failure, constrictive pericarditis

Question 27

ascites definition

Answer 27

ascites = Accumulation of excess fluid in the peritoneal cavity

Question 28

hepatic encephalopathy pathogenesis from liver failure

Answer 28

liver failure: increased ammonia increase metabolism of ammonia -> glutamine in CNS

Question 29

splenomegaly pathogenesis from liver failure

Answer 29

LF: increase venous pressure -> congestion | -> Retention of leukocytes, erythrocytes and platelets in the spleen

Question 30

main consequences of liver failure

Answer 30

ABCDE - ammonia -> hepatic encephalopathy - bile retention - coagulopathy - distension (ascites) - esophageal varices

Question 31

chronic ingestion of alcohol pathogenesis (3)**

Answer 31

alcohol forms acetaldehyde ``` - hepatic steatosis: alcohol increase NADH/NAD+ ratio -> inhibit gluconeogenesis -> promotes lipogenesis causes intracellular lipid accumulation ``` - alcoholic hepatitis: acetaldehyde can cause liver cell oxidative injury - alcoholic cirrhosis

Question 32

liver cirrhosis ** | - gross and histo features

Answer 32

``` gross: Enlarged early, shrunken late stage Nodular surface colour base on what causes it: yellow = fatty change grey = viral hep green = jaundice brown = Fe ``` histo: - Bridging fibrous septa - Regenerative liver nodules - Inflammatory infiltrate - Ductular proliferation in septa - Cholestasis fibrous - hepatocytes undergoing apoptosis - chronic: groundglass appearance (flat hazy and uniformly dull cytoplasm)