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Flashcards in Hepatobiliary Deck (202):

Liver Function Test Parameters

1) Parenchymal enzymes for cellular integrity
i) AST (aspartate transaminase)
- cytosolic and mitochondrial enzyme, found in liver, cardiac muscle, skeletal muscle, kidneys, pancreas 
- Shorter half life
ii) ALT (alanine transaminase)
- cytosolic enzyme, more specific to the liver
- rises more than AST in liver disease (except malignancy & alcoholic)

2) Ductal enzymes for excretory function
i) ALP (alkaline phosphatase)
- found in liver, bone (bone met), intestine
- liver ALP can be identified by electrophoresis or heat stable index
ii) GGT (gamma glutamyltransferase)
-  microsomal enzyme
- also a marker for alcoholic liver disease

3) Protein Synthesis function
i) Albumin (A:G ratio)
ii) Prothrombin time

4) Others:
i) Differential bilirubin level
ii) Arterial ammonia (to assess hepatic encephalopathy)


Interpretation of LFT

1) Markedly elevated AST & ALT
-> hepatocellular damage

2) Markedly elevated ALP & GGT
-> biliary obstruction

3) Degree of ALT elevation in descending order:
- Ischemic
- toxic injury
- Chronic viral cause
- Acute biliary obstruction
- Alcoholic cause

4) isolated GGT elevation with normal ALP 
- Drug: phenytoin, carbamazepine, barbituates
- Alcohol liver disease
- Fatty liver

5) isolated ALP elevation with normal GGT
- Bone disease (e.g. bone met, note the isoform is heat unstable)
- Puberty (due to active growth)

6) AST marked elevated with a relatively smaller increase in ALT
- i.e. if AST:ALT ratio is greater than 2
- suggests of alcoholic liver disease (esp with isolated GGT elevation)
- or other sources of AST e.g. hemoptysis in unconjugated hyperbilirubinemia, rhabdomyolysis, etc

7) In fulminant hepatitis, the AST & ALT will be falling as disease progress

8) AST and PT (factor VII) are quite sensitive and can be used assess acute derangement or recovery due to their short t1/2



Lab tests for hepatobiliary diseases

1) CBC
- leucocytosis if infection
- pancytopenia if hypersplenism in splenomegaly
- rule out hemolytic jaundice
- PBS if suspecting prehepatic jaundice

- bilirubin differential count
- PT, albumin, globulin
- arterial ammonia (for encephalopathy)
- Serum creatinine in important for MELD score

3) Hepatitis Viral panel
- When hepatitis suspected
- HBsAg, anti-HBc, HBeAg 
- Anti-HAV (IgM), Anti-HCV, Anti-HEV (IgM)

4) Autoimmune Ab (for autoimmune hepatitis)
- Anti-Sm Ab
- anti LKM-1
- AMA (if suspecting primary biliary cirrhosis) 

5) Toxicology screen
- Acetaminophen
- Drug

6) Serum tumour markers
- AFP is a tumour marker for HCC
- CEA, CA 19-9 for CA pancreas or CRC
- CA 15-3, CA 27-29 for CA breast

7) Wilson's disease
- ceruloplasmin
- ALP7B genetic screening

8) Iron profile (in caucasians)

- for haemochromatosis; transfusion patient for haemosiderosis

9) Pancreatitis (especially important in a ductal LFT pattern)
- Serum amylase
- Seum lipase
- Ca, BUN, glucose LDH etc for Ranson Criteria

10) Ascitic fluid analysis
- Serum-Ascites albumin Gradient (SAAG)
- Cell count (differential, WBC to screen for SBP)


Why might globulin increase in hepatic disease?

Portal systemic shunting, thus no liver detoxification

As a result, Ag rises 


Reversed A:G ratio DDx

1) Liver disease (A drops, G rises)

2) Malnutrition e.g. due to anorexia (A drops)

3) Nephrotic syndrome, lupus nephritis, etc (A drops by renal loss)

4) Multiple myeloma, MGUS (G rises)


Heme degradation & bilirubin metabolism

Heme in hemoglobin is converted to unconjucated bilirubin by the reticuloendothelial system in spleen

UC bilirubin is carried by blood via albumin

In liver, UDP gluconronyl transferase (UDPGT) conjugate the bilirubin

Conjucated bilirubin is excreted via bile after temporarily stored in gallbladder

Enterohepatic circulation: a small amount is reabsorbed from bowel, directed to liver or urine

Urobilin (yellow color) is excreted via urine

Stercobilin (brown color) is formed via bacteria and removed via faeces

A image thumb

Bilirubin panel in prehepatic, hepatic, and post hepatic pictures

(serum, urine, stool)

- Serum unconjugated hyperbilirubinaemia

- Dark urine (due to hemoglobin)
- High urine urobilinogen (will not cause dark urine)

- Normal stool (with stercobilinogen & stercobilin)

- Serum both conjugated and unconjugated hyperbilirubinaemia

- Normal urine color; normal urobilinogen

- Normal stool (normal stercobilinogen & stercobilin)

- Serum conjugated hyperbilirubinaemia

- Dark urine (due to bile; no urobilinogen in urine)

- Pale stool (no stercobilinogen or stercobilin in stool)


Features suggestive of Cholestasis (obstructive jaundice)

1) Jaundice with conjugated hyperbilirubinaemia

2) Ductal pattern of LFT (ALP & GGT)

3) Tea color urine with pale stool

4) Pruritus


Obstructive Jaundice DDx

Very Painful
1) Cholelithiasis (obstructs cystic duct)

2) Cholecystitis (calculous or acalculous)
+ Murphy's sign, fever

3) Choledocholithiasis

4) Cholangitis
+ fever, Chacot's triad, Reynold's pentad

5) Choledochal cyst

Not really painful
5) Primary biliary cirrhosis

6) Primary sclerosing colangitis (note IBD)

7) Bile duct stricture

8) Biliary dyskinesia

9) Malignant Biliary obstruction (note the presence of epigastric mass, and constitutional symptoms):
- CA gallbladder
- Cholangiosarcoma, cholangiocarcinoma, @ hilum (e.g. Klatskin tumour)
- Periampullary carcinoma
- CA Head of pancreas 
- duodenal carcinoma (GI bleeding, SBO)
- Lymphoma @ the hilar nodes
- Hepatocarcinoma (rarely; from direct infiltration, compression, tumor fragments in CBD)



Hepatobiliary ductal system

+ left and right hepatic duct

A image thumb

Normal size of gallbladder and CBD in US

Gallbladder wall 



Gallbladder wall edema (definition & DDx)

Thickened gallbladder wall (>3mm) as seen by RUQ Ultrasonography, with the following DDx:

- Cholecystis

- Mimicry by nearby inflammation (e.g. hepatitis, right pyelonephritis)


- hypoalbuminaemia

- tumour 



Possible radiological investigations for hepatobiliary system

- for initial screening
- look for gallstone, pancreatic calcifications
- Gas in gallbladder (cholecystoenteric fistula? emphysematous infection?)
- Pneumobilia (biliary-enteric fistula? incompetency of Sphincter of Oddi after sphincterectomy?)
- free gas under diaphragm (pneumoperitoneum? perforation?)
- soft tissue mass (abscess?)

2) Ultrasonography
- for initial screening
- note gallstones, dilated intrahepatic duct or other biliary duct


4) EUS (endoscopic US)
- detection of microlithiasis
- evaluation of the ampulla, periductal structures, & regional lymph nodes in neoplasm 

4) Cholangiography:
- for histology, biopsy or intervention

5) HIDA scan (Radionucleotide scan)
- HIDA scan for acute cholecystitis


Pneumobilia (causes & identification)

Pneumobilia refers to free gas in the CBD, and must be distinguished from Portal Venous Gas by its location:

Pneumobilia = more centrally intrahepatic (c=CBD)

Portal venous gas = more peripherally intrahepatic (p=portal vein)
Causes are:
1) biliary-enteric anastomosis

2) incompetent sphincter of Oddi (e.g. after ERCP sphincterectomy)

3) Spontaneous biliary-enteric fistula (due to gallstones erosion etc)


ERCP use and risk

1) Use small needle to puncture sphincter of Vater, use a wire to advance, and inject contrast to visualize biliary system

2) Allows intervention, such as:
- Sphincterotomy and stone extraction (basket or balloon extraction)
- Brushing for cytology, biopsy
- set up endoprosthesis (i.e. stenting an obstructed biliary tract)
- Biliary drainage

- perforation
- acute pancreatitis
- Bleeding 


What are the common choleliths?

i.e. gallstone types:

1) Mixed stone
- most common

2) Cholesterol stones (yellow/green)
associated with:
- obesity, DM, hyperlipidemia
- multiple pregnancy, COC
- Cirrhosis, irritable bowel diseases

3) Black Pigment Stone
associated with:
- hemolysis (e.g. thalassemia)
- alcoholic cirrhosis

4) Brown pigment stone
associated with biliary tract infection


Gallstones symptoms and complications

1) Mostly asymptomatic

2) Biliary colic
- caused by contraction of gallbladder against an obstructed cystic duct
- RUQ or epigastrium pain, usually at night or post-prandial
- Boas sign (right scapular pain)

3) Complications:
- Cholecystitis

- Choledocholithiasis

- Gallstone ileus (i.e. SBO caused by blockade of ileocecal valve by gallstone eroded outside via cholecystoenteric fistula)

- GB carcinoma


RUQ ultrasonography of cholelithiasis

- a dense echogenic spherical body

- "Comet tail sign" posterior acoustic shadowing

- Mobile gallstone in the gallbladder


Choledocholithiasis definition and etiology

Gallstone in the common bile duct

1) Secondary (95%)
- usually cholesterol or mixed stone originated in the gallbladder

1) Primary
- usually pigmented stones originating in CBD



Complications of choledocholithiasis

- Cholangitis

- Obstructive jaundice

- Acute biliary pancreatitis

- Biliary colic

- Biliary cirrhosis


Diagnositic imaging tests of choledocholithiasis

1) RUQ ultrasounds

2) CT, MRI
- esp MRCP (Prone to motion artefact thus need breath hold quite well, so not for elderly, people with reduced lung capacity, or children)

3) PTC (Percutaneous transhepatic cholangiography)
- Cholangiogram 
- can perform stenting




Acute cholecystitis symptoms and signs

- Low grade Fever

- Pain is located in RUQ or epigastrium; maybe radiation to right subscapular area (Boas Sign)

- Nausea and vomiting

- Fever, leucocytosis

- Murphy sign

- RUQ tenderness, guarding, rebound tenderness; hypoactive bowel sounds

x) usually no jaundice (consider cholangitis if jaundiced, fever, RUQ pain)




Pathogenesis and Aetiology of acute cholecystitis

Acute inflammation of the gallbladder often caused by obstruction of cystic duct due to gallstone (cholecystolithiasis).

Very rarely can be acalculous, usually idiopathic or associated with patients with severe underlying illness, e.g. dehydration, ischemia, burns, severe trauma, post-operation



Investigations in suspected cholecystitis

1) General Ix
- CBC (look for leucocytosis to rule out infection, sometimes DIC)
- Blood culture (rule out infection)
- LFT/RFT (cholestasis?)
- Clotting profile, Type & screen
- Urinanalysis (e.g. look for bile, urobilinogen)
- AXR (might see gallstone)

2) Diagnostic Ix for cholecystitis
i) RUQ Ultrasonography

ii) CT or MRI of the hepatobiliary system
- Gallstone might be missed on CT due to the same composition with bile
-> MRCP (Magnetic resonance cholangiopancreatography)

iii) Radionuclide scan (HIDA scan)
- use when ultrasound is inconclusive
- Positive HIDA scan (confirm cholecystitis) means the gallbladder is not visualised 4 hours after injection


Radiological findings (US) of acute cholecystitis

1) Gallstones (echogenic body, mobile, posterior acoustic shadows), sometimes even impacted (immobile)

2) Positive sonographic Murphy’s sign

3) Thickened Gallbladder wall >3mm (i.e. gallbladder wall oedema)

4) Gallbladder enlargement > 4x10cm 

5) Air-fluid level in gallbladder

6) Pericholecystic fluid



Complications of cholecystitis

1) Gangrenous cholecystitis, emphysematous cholecystitis, GB empyema

2) GB perforation

3) Cholecystoenteric fistula with gallstone ileus


Management of acute cholecystitis

1) Admitted with conservative measures:
- Hydration with IV fluid
- NPO (nil per oral)
- analgesics
- IV antibiotics

2) Cholecystectomy
- Early cholecystectomy is preferred to delayed cholecystectomy
- Choose between laparascopic approach or open surgery

3) Cholecystostomy 
- If cholectstectomy is not possible or prefered
- i.e. drainage of gallbladder


Pros and cons of laparascopic cholecystectomy

- less pain
- faster recovery and shorter hospital stay
- better cosmesis

- technically demanding
- higher conversion rate than open surgery
- more serious complications


Early or delay cholecystectomy in suspected cholecystitis? 

Give some advantage of each

Early cholecystectomy is preferred:

Pros of early (48-72 hours)
- avoid urgent operation
- avod recurrence
- avoid readmission
- shorter hospital stay

Pros of delay
- less septic complications (due to antibiotic regimen first)
- less serious consequences
- avoid misdiagnosis
- easy dissection

- Might cause urgent deterioration with severe complications e.g. perforation


Indications of cholecystostomy

For acute cholecystitis, as second line to cholecystectomy, when:

- there is high surgical risk

- haemodynamically unstable

- difficult cholecystectomy 


Cholangitis pathogenesis & etiology

Biliary tract obstruction, causing cholestasis, biliary stasis, and bacterial overgrowth. Ultimately the Biliary tract becomes infected and inflammed. Etiology is biliary tract obstruction, such as:

1) Choledocholithiasis (most common)

2) Benign bile duct strictures (e.g. post op), choledochal cysts 

3) Malignant biliary obstruction (e.g. cholangiosarcoma, cholangiocarcinoma etc)

4) iatrogenic e.g. ERCP, PTC

5) Parasite (clonorchis sinensis, ascaris lumbricoides)


Parasitic causes of cholestasis

Clonorchis Sinensis
- in Asian countries, Hong Kong
- Transmission by ingestin raw fish (i.e. congee)
- diagnosis by stool ova and parasites 
- Give praziquantel

Ascaris Lumbrocoidis
- intestinal roundworm
- parasitic infestation
- Give Mebendazole


Clinical presentation of acute cholangitis

1) Charcot triad: RUQ pain, jaundice, fever

2) Reynold's pentad: plus septic shock, CNS depression (e.g. coma, confusion, disorientation)

3) Abdominal tenderness, rebound tenderness, guarding

4) Cholestasis i.e. jaundice, tea color urine, pale stool, (pruritus)


Bacterial pathogen in acute cholangitis

1) Usually single organism, i.e.
- Gram negative rods, e.g. E coli, Klebsiella, enterobacteroides
- Enterococcus
- Anaerobes

2) Mixed -> suspect perforation



Cholangitis Investigations

1) General Ix
- Vitals, BP, temperature
- CBC (look for leucocytosis for infection, DIC of septic shock)
- Blood culture (infection)
- LFT/RFT (cholestactic picture, electrolytes)
- Clotting profile, Type & screen
- Urinanalysis (e.g. look for bile, urobilinogen)
- AXR (might see gallstone)
- Serum amylase (to rule out pancreatitis)

2) Diagnostic Ix
i) LFT of cholestatic pattern

ii) RUQ Ultrasonography

iii) Cholangiography (ERCP or PTC)
- definitive, but do not perform during the acute phase of illness
- with EUS (endoscopic ultrasonography)


Management of Cholangitis

1) Resuscitatoin
- IV fluid and electrolyte resuscitation
- close monitoring of hemodynamics, BP, fever, urine output

2) IV antibiotics
- Empirical e.g. piperacillin, Augmentin, ceftazidime, quinolones
- Guided by blood culture & antibiotic susceptibility test

3) Decompression of bile duct (after patient is stabilised i.e. afebrile for 48 hours; emergently if antibiotics is not working):

i) PTBD Drainage by PTC, longer period via Nasobiliary drainage (allows daily monitoring of drainage)
ii) Endoscopic Sphincterotomy by ERCP
if ERCP fails, then:
iii) Percutaneous cholecystostomy

OPERATIVE, when endoscopic fails:
iv) Surgical CBD exploration (laparotomy with T tube insertion)

4) Correction of obstruction depending on pathology
i) usually stone extraction

ii) Endoprosthesis, e.g. Endoscopic biliary stenting


Choledocholithiasis stone extraction

1) Endoscopic extraction
Performed by ERCP:
ia) Endoscopic Balloon sphincteroplasty
- sphincter is dilated, thus function is preserved
- cannot extract large stones

ib) Endoscopic sphincterectomy
- sphincter is destroyed, for larger stone extraction
- related to bleeding, perforation, and long term consequence e.g. cholecystitis
- cholecystectomy is recommended afterwards

ii) followed by Basket or Balloon endoscopic extraction 

2) Lithotripsy
i) Mechanical lithotripsy
- for gallstones too large, the stone is first fragmented before extraction
- cf. ESWL for renal stones

3) Surgical extraction


Primary sclerosing cholangitis

Chronic idiopathic progressive obstruction of BOTH extrahepatic and intrahepatic ducts, characterised by thickening of bile duct wall and narrowing lumens, leading to:

- cholestasis
- cirrhosis
- portal hypertension
- liver failure


Primary sclerosing cholangitis (clinical features & diagnosis & treatment)

Clinical features:
- Insidious and chronic onset of signs and symptoms

- Strong association with ulcerative colitis (less so with Crohn's disease), thus IBD symptoms

- Chronic cholestasis, i.e. jaundice, tea urine, pale stool, pruritus

- Cirrhosis and stigmata of chronic liver disease

- fatigue, malaise, weight loss

- "String of Beads" appearance, i.e. multiple areas of bead-like strictures and dilataion of intrahepatic & extrahepatic ducts

2) LFT
- cholestatic pattern (marked increase of ALP, GGT; conjugated hyperbilirubinaemia)

3) Ultrasound and CT
- might be cirrhosis

no treatment other than liver transplantation


Primary biliary cirrhosis pathogenesis

Chronic & progressive cholestatic liver disease due to:

- autoimmune destruction of INTRAHEPATIC ducts with portal inflammation and scarrings,

Ultimately causing cirrhosis


Primary biliary cirrhosis (epidemiology & clinical features)

- Female predominant (F:M = 9:1)
- Age of symptoms: 40-60

Clinical features:
- Asymptomatic
- Obstructive Jaundice (prutitus, pale stool, tea color urine)
- Cirrhosis (smaller liver, hard)
- Portal hypertension, splenomegaly etc
- fatigue 
- Associated with osteoporosis (hepatic osteodystrophy) as fat soluble Vit D cannot be effectively absorbed
- Xanthalesma and xanthoma (as fat is normally excreted via bile)
- Steatorrhoea (as fat absorption requires bile emusification)


PBC investigations

For diagnosis
- cholestatic pattern (elevated ALP, GGT)
- hyperbilirubinaemia depends on stage (originally conjugated, less so as it goes on)

2) Lipid profile
- Elevated cholesterol (as normally cholesterol is excreted via bile)

3) Autoantibody
- Positive Antimitochondrial antibodies (AMA)
- Increased IgM
- screen for other autoimmune diseases e.g. ANA, RF, anti-CCP antibody, TSH

4) Liver Biopsy
- quite insensitive due to diffuse nature of fibrosis
- confirm the diagnosis, rule out other causes

For ruling out other cause:
5) US, CT, MRI, Cholangiogram via ERCP, PTC
- to rule out other causes of biliary obstruction

6) Fibroscan (transient elastography)
- to rule out fatty liver
- confirms cirrhosis


Associated autoimmune conditions in PBC


Sjogren’s syndrome (dry eyes, mouth)

Arthropathy, e.g., RA


Renal tubular acidosis 


Management of PBC

Reduce Disease progression
1) Ursodeoxycholic acid (UDCA)
-¬†‚Üď pruritis &¬†fatigue & IgM
- Improvement of LFT
-¬†‚Üď the incidence of death or transplantation¬†
- AMA unchanged
- no side effects!

2) Liver transplant
- recurrence unlikely

Symptomatic Control
1) Pruritus management
- Ursodeoxycholic acid (UDCA)
- Cholestyramine 

2) Hepatic osteodystrophy
- Oral Ca & Vitamin D, bisphosphonates
- Medium chain triglycerides (MCT)

3) Malabsorption of fat-soluble vitamins (ADEK)
- Intramuscular Vitamin A, when night blindness begins (avoid in pregnancy due to teratogenic)
- intramuscular Vitamin K
- oral Ca & Vit D

4) Steatorrhoea
- low fat diet
- Medium chain triglycerides


What is the Courvoisier's Law? 

In (painless obstructive) jaundice, a palpable gallbladder would means it isn't gallstone:

DDx: indicates acalcuous extrahepatic obstruction, most likely a Malignant Biliary Obstruction (MBO):

1) Common bile duct obstruction
   - Cholangiosarcoma, Cholangiocarcinoma
   - CA head of pancreas
   - Biliary atresia (in infants)

2) Cystic Duct obstruction
   - mucocele, cholechal cyst

3) And many others (e.g. CA ampulla of vater, CA gallbladder, CA duodenum, rarely CA body pancreas, HCC)

*MOST UNLIKELY TO BE GALLSTONES (in which GB should be impalpable due to fibrosis as stone takes long time to develop)

1) recurrent pyogenic cholangitis in which gallbladder wall is dilatable due to lack of fibrosis (since primary pathology is not in gall bladder)

2) Double gall stones, one at the CBD (causing jaundice), the other at cystic duct (causing GB enlargement)


Causes of Malignant Biliary obstruction

Think about MBO when presented with painless obstructive jaundice, constitutional symptoms, Courvoisier's sign, and sometimes abdominal mass:

1) CA gallbladder (usually adenocarcinoma in elderly)
- cystic duct LN enlargement
- direct infiltration of CBD 
- tumour fragments

2) Cholangiosarcoma, cholangiocarcinoma, @ hilum (e.g. Klatskin tumour)

3) Periampullary carcinoma

4) CA Head of pancreas 

5) Duodenal carcinoma (note GI bleeding, SBO)

6) Lymphoma @ the hilar nodes

7) Hepatocarcinoma (rarely) 
- direct infiltration of ducts
- compression by mass effects
- tumor fragments in CBD)


Imaging modalities for suspected MBO 

1) Abdomen US
- look for stones
- look for dilated intrahepatic duct 

2) EUS (endoscopic US)
- to look for tiny stones
- identify mass in pancreas, bile duct, gall bladder
- assess depth, vascularity, LN involvement
- FNA of lesion

3) ERCP, with drainage

4) PTC with drainage (PTBD)

5) Computed tomography (CT)
- dilatation of pancreatic duct, intrahepatic duct etc

6) MRI with MRCP
- no irradiation

for disant metastasis, LN involvement
- staging


Risk factors of gallbladder adenocarcinoma

1) Gallstone (cholelithiasis)

2) Porcelain gallbladder
- Intramural calcification of gallbladder wall
- prophylactic cholecystectomy might be prudent


Sites of cholangiocarcinoma

1) Proximal third of common bile duct 
- most common
- aka Klatskin tumour

2) Distal extrahepatic
- best change of resectability

3) Intrahepatic
- least common


Risk factors of Cholangiocarcinoma

1) Clonorchus sinensis infestation

2) Choledochal cyst

3) Primary sclerosing cholangitis (esp associated with Ulcerative cholitis) 

4) Recurrent pyogenic cholangitis

5) Hepatitis B


Cholangiocarcinoma diagnosis and treatment

- Cholangiogram (ERCP, PTC) for diagnosis and assessment of resectability
- Carcinoembryonic antigen (CEA) may be elevated 
- FNAC, or Trucut core biopsy
- Cholstatic pattern in LFT

- Only 20% patient have resectable tumours
- Palliative biliary drain


Types of pancreatic tumours

Exocrine tumour
1) Pancreatic ductal adenocarcinoma (PDAC)
- most common
- most commonly head of pancreas

2) Intraductal papillary mucin neoplasm (IPMN)
- in old people
- note mucus that cause pancreatic ductal expansion

Endocrine tumour
note highly vascular nature of mass; also endocrine features:
1) Gastrinomas (Zollinger-Ellison Syndrome)
- severe peptic ulcer, UGIB
- head of pancreas
- most commonly found in MEN1

2) VIPomas
- watery diarrhoea and hypokalaemia achlorhydria (WDHA)
- tail of pancreas

3) Glucagonomas
- hyperglycaemia, anaemia
- tail of pancreas
- often found in MEN1

4) Insulinoma
- hypoglycaemia

5) Somatostatinomas
- very rare
- steatorrhoea and gallstones


Pancreatic adenocarcinoma sites

1) Pancreatic head (75%)

2) Pancreatic body (20%)

3) Pancreatic tail (5-10%)


Risk factors of pancreatic cancer

1) Cigarette smoking

2) Chronic pancreatitis

3) DM

4) Heavy alcoholism

5) Exposure to chemicals e.g. Benzidine (in dye industry)


Investigations for suspected CA pancreas

1) ERCP with EUS & biopsy
- most sensitive test for diagnosis of pancreatic cancer
- endoscopic ultrasound to differentiate structures

2) CT scan
- identify and characterise the lesion (adenocarcinoma or other tumour?)
- stage the tumour and note extra-pancreatic sites
- assess resectability

3) MRI with MRCP
- alternative
- "Double duct sign"
- Better detection of smaller lesions 

4) Tumour markers
- CA 19-9

- for staging

: Ultrasonography does not visualise head of pancreas well, because:
- US does not penetrate gas well, and head of pancreas is therefore obscured by C-loop of duodenum and possibly large bowel


Management of CA head of pancreas


1) If operable, perform Whipple Procedure
- i.e. pancreaticoduodenectomy
- a combination of antrectomy, cholecystectomy, duodenectomy, proximal jejunectomy, and removal of head of pancreas, plus:
- reconstruction by pancreaticojejunostomy, hepaticojejunostomy, gastrojejunostomy
- see pic

2) If operable, but found to be spread disease, then perform palliative Double Bypass:
- hepato/choledocho -jejunostomy
+ gastrojejunostomy 

3) If inoperable, just perform palliative biliary drainage by:
- PTC with PTBD
- endoprosthesis

A image thumb

Sometimes pancreatic body/tail tumour will lead to jaundice too. How does that happen?

Doesn’t normally lead to jaundice unless spread to surrounding LNs, which then causes bilairy tract obstruction


Pathology producing jaundice and epigastric mass 

- Hepatomegaly secondary to biliary obstruction

- Hepatomegaly due to metastases or HCC

- Lymph node metastases to the coeliac axis or porta hepatis

- Carcinoma of stomach with metastatic lymph node in the porta hepatis

- Distended stomach due to duodenal obstruction by tumor which obstruct the bile duct as well 


How to decide whether operate or not in MBO

Laparotomy only if general condition is fit, and tumour is confined (No promise of resection until laparotomy finding shows no spread):

General status assessment
1) Age
2) Comorbodities
3) Assess baseline functions:

- spirometry
- blood sugar

Tumour status assessment (inoperable if no longer confined to organ of origin)
1) Clinical examination
- liver met (hepatomegaly)?
- peritoneal met (ascites)?
- Virchow's, Irish's, Blumer's shelf, sister mary joseph nodule?

2) Radiological examination 
US, CT, MRI, PET/CT to find:
- SMA, SMV/PV encasement
- Lymph node met
- Liver met



MBO general flow of intervention

1) Biliary Drainage if unfit for surgery or non-confined tumour:
- PTC with PTBD
- endoprosthesis
- Percutaneous cholecystostomy

2) Laparotomy 
first, pre-op relief of biliary obstruction by ERCP, endoprosthesis, or PTBD (Target Serum bilirubin

- ony perform palliative bypass if spread is identified after laparotomy

- radical resection if tumour is confirmed to be confined

A image thumb

Bypass for MBO 

These are all palliative treatments for wide spread malignancy causing MBO:

Single bypass 
- roux-en-Y hepaticojejunostomy
- roux-en-Y choledochojejunostomy 

Double bypass
usu for pancreatic head tumour
- hepato/choledocho -jejunostomy
+ gastrojejunostomy 

Triple Bypass (obsolete)
used in the past for pain relief from distended pancreatic duct (made obsolete by better modern analgesics):
- hepato/choledocho -jejunostomy
+ gastrojejunostomy 
+ pancreaticojejunostomy

A image thumb

What is the definition of "Radical Resection"

Resection of:

- Tumour and part of organ of origin 

- Tumour-free resection margin 

- Regional lymph node


Why is malignant biliary obstruction so risky for operation? 

1) Cancer cachexia
 causing malnutrition and poor baseline function of patient

2) Impaired liver function
- Impaired protein synthesis (thus poor wound & anastomosis healing)
- Impaired clotting factor synthesis (thus bleeding tendency during surgery; also note bleeding gastric ulcers)
- Impaired gluconeogenesis & ketogenesis
- Renal failure from Hepatorenal syndrome

3) Superimposed biliary infection 
- reduced cell-mediated immunity 
- Endotoxemia
- without normal bile flow should flush out bacteria, thus higher risk of post-surgical infection


Measures to reduce complications related to surgery for MBO 

1) Nutritional support

2) IV Vitamin K

3) FFP infusion during surgery

4) Prophylactic Antibiotic

5) Mannitol, dopamine to prevent renal failure

6) H2 antagonist to prevent peptic ulcer


Different types of PTBD

Different forms of percutaneous transhepatic biliary drainage are:

1) Internal-external type PTBD
- with tip extended up to duodenum
- Pro: bile can be drained externally via the PTBD, or can be drained internally downwards to duodenum
- Con:¬†More prone to infection (when blocked ‚ÄĒ> cholangitis leading to septicaemia)

2) External type PTBD
- with tip only in biliary tract, thus only bile drainage externally via PTBD

3) Double PTBD 
- sometimes multiple PTBD are set up for segregated intrahepatic duct e.g. by tumour located in liver hilum 


Acute pancreatitis etiology

Most commonly chronic alcoholism, gallstone in Ampulla of Vater


Infection, usu viral (mumps, coxsackievirus), mycoplasma

Trauma, i.e. post-ERCP, blunt trauma (more commonly in children)

Hypercalcemia (e.g. in hyperparathyroidism)

Ulcer (posterior duodenal) perforation

Renal - uremia, post-transplant

Tumour - CA pancreas, CA ampulla of Vater

Strcutural anomaly - pancreas divisum, annular pancreas, duodenal diverticulum

Biliary obstruction at ampulla of Vater, usually gallstones

Alcohol (chronic, most common)

Drugs, that DEFEATS
- Didanosine (HIV)
- Estrogen
- Frusemide
- Erythromycin
- Azathioprine
- Tetracyclines, thiazide
- Sulphonamides

Lipids - hyperlipidemia

Y? i.e. idiopathic


Clinical features of acute pancreatitis

1) Epigastric tenderness & pain, with radiation to back
- dull, continuous, severe
- worsen when supine & post prandial

2) Nausea, vomiting, anorexia

3) Low grade fever, hypotension, tachycardia

4) Decreased or no bowel sounds (-> partial ileus)

5) Abdominal distention

6) Retroperitoneal haemorrhage signs
- Grey Turner sign
- Cullen sign
- Fox sign (ecchymosis of inguinal ligament)


Diagnostic investigations of acute pancreatitis

1) Lab tests
- Elevated serum amylase (if more than 5 times of upper limit than quite specific)
- Elevated serum lipase (specific)
- LFT/RFT (might find ductal pattern if gallstone; might show alcoholic liver disease if alcoholism)
- Arterial hypoxemia
- Hyperglycaemia (due to decreased insulin & increased glucagon release)
- Hypocalcaemia (might cause tetany)
- Prognostic investigations based on the Ranson Criteria, i.e. "GA LAW, C HOBBS" glucose, LDH, AST, WBC, Ca, Hematocrit, PaO2, BUN, base deficit

2) Radiological assessment
i) CT scan of andomen

- fuzzy, non-well defined pancreas

ii) AXR
‚Äč- "sentinel loop" (LUQ air filled bowel), "Colon cut-off sign" (transverse colon abruptly ending)
- rule out perforation, other causes
- pancreatic calcification suggests chronic pancreatitis

iii) US
- gallstone
- calcification suggests chronic pancreatitis
- quite useless

iv) MRI with MRCP

v) ERCP with EUS


Acute pancreatitis complications

1) Pancreatic necrosis, infection, abscess
- sterile
- infected (high mortality rate)

2) Pancreatic pseudocyst
- encapsulated fluid collection (without epithelial lining) 2-3 weeks after attack
- Pseudocyst might cause rupture, infection, gastric outlet obstruction, fistula

3) Hemorrhagic pancreatitis
- hypovolemic shock
- hemoperitoneum

4) Ascending cholangitis

5) Pancreatic ascites or pleural effusion

6) Adult respiratory distress syndrome

7) Vascular complications
- pseudoaneurysm
- Thrombosis 



Ranson Criteria

For prognosis (mortality) of acute pancreatitis

Admission criteria
Glucose >10
Age > 55
LDH >350
AST >250
WBV >16,000

Initial 48-hour criteria
Calcium Hematocrit decrease >10%
PaO2  BUN increase >8mg/dL
Base deficit >4mg/dL
Fluid Sequestration >6L

Score 0 to 2 : 2% mortality
Score 3 to 4 : 15% mortality
Score 5 to 6 : 40% mortality
Score 7 to 8 : 100% mortality 


Imaging modalities of the liver (general function of radiology in liver)

1) Ultrasounds
+ major screening for cirrhosis
+ assessment of tumour and vessel patency
+ great for liver abscess
+ aid in biopsy
- intercostal sections of liver might be obscured

2) CT scan
+ Tumour staging
+ identification of cirrhosis and its complications (varices etc)
+ great for liver abscess

3) MRI
+ lesion characterisation

+ staging

5) Hepatic angiography
+ vessel patency
+ TACE for therapeutic purpose

6) Fibroscan
+ assess extent of fibrosis


- Confirm suspected focal or diffuse liver lesion
- investigate Abnormal LFT
- Staging of known extrahepatic malignancy
- Assessment of portal vein patency and flow
- To facilitate placement of needles for biopsy 


Radiological findings in cirrhosis

1) US:
Major screening tool for cirrhosis:
- Coarse, heterogenous echotexture of parenchyma
- Surface nodularity, with non-smooth irregular contour
- Segmental hypertrophy
- Reverse doppler flow if Portal venous hypertension
- Splenomegaly 
- can be ascitic fluid above

2) CT
Insensitive in early cirrhosis
- Heterogenous enhancement
- Nodularity, with regeneration/dysplastic nodules
- Irregular outline
- Segmental hypertrophy
- Fatty changes, iron accumulation
- Portal hypertension signs, i.e.  portal vein enlargement, portal venous thrombosis, varices, ascites 

3) Fibroscan (transient elastography)
- quantify liver fibrosis


Hepatomegaly DDx

1) Neoplastic
- primary malignancy (e.g. HCC, cholangiocarcinoma)
- Metastases (usu GI tract; others are lung, kidneys, breast, gynae)
- Leukemia, lymphoma
- Benign tumours (e.g. Adenoma, Hemangioma, Focal nodular hyperplasia)

2) Metabolic
- Fatty liver
- Alcoholic liver disease
- Polycystic liver disease

3) Infective
infection & inflammation, thus enlargement
- Liver Abscess
- Liver cyst
- Acute hepatitis (acute; will be small if chronic)
- Infective mononucleosis (EBV)
- Malaria

4) Vascular
Increased back-up of venous pressure leading to vascular engorgement
- Congestive heart failure
- Hepatic venous occlusion (Budd-Chiari syndomre; primary or secondary)

5) Infiltrative
By deposition of non-liver cells/materials
- Sarcoidosis
- Amyloidosis
- Haemochromatosis
- Haemosiderosis
- Storage Disease (e.g. Gaucher disease)


History to ask in Hepatomegaly

1) Symptoms
- onset, time, character, pain, related symptoms
- jaundice? obstructive jaundice?
- other symptoms

2) Cause determination
- constitutional symptoms? History of malignancy? (cancer)
- symptoms of other primary (e.g. breast, change in bowel habits, urinary symptoms)
- leukemia, lymphoma?
- Dyspnoea, orthopnoea? (heart failure)
- fever? (infective)
- Travelling history, esp Africa?
- surgical & medical Hx

3) Risk factors
- drinking, smoking
- family Hx of malignancy
- Vaccination history in childhood
- Hep B, Hep C status (e.g. have you donated blood?)
- ask about past blood transfusion, tattoo, recreational drug use (possible route of Hep C)


What to report of the liver after examination?

1) Liver span:
- cm along MCL
- upper border location; lower border (cm below costal margin along MCL)
- lower border (cm below sternum)

2) Consistency
- soft
- firm
- stony hard

3) Surface
- regular, smooth (Alcoholic liver disease, hemat malignancy)
- irregular, nodular (HCC, cholangiocarcinoma, liver met, polycystic liver)

4) Edge
- sharp
- irregular

5) Character
- Tender?
- Pulsatile?

6) Hepatic bruit
- HCC, Hemangioma
- Alcoholic liver disease


What are the risk of biopsy for peritoneal lesions?

Biopsy carries the risk of:

- Needle track seeding (if malignancy)

- Profuse bleeding

‚ÄĒ> therefore, only consider biopsy when truly necessary e.g. Confirmation of chemotherapy,¬†Determination of benign vs malignant


Hepatomegaly radiological investigations

1) Ultrasound

2) CT scan
- Triphasic CT scan to see whether it is HCC

3) MRI

4) Endoscopy (for suspected GI primary) 
- Colonoscopy

5) Biopsy 
- US guided percutaneous FNAC
- Trucut core biopsy



What should we consider if AFP assay is high?

1) Investigate liver
- consider HCC

2) Investigate testes
- testicular cancer will increase AFP in men

3) Rule out pregnancy (including ectopic pregnancy)
- AFP level will be raised


Risk factors for Hepatocellular carcinoma

1) Hepatitis B (80% of HK HCC)

2) Hepatitis C

3) Alcohol & other types of cirrhosis

4) Hemachromatosis

5) Aflatoxin 


Pathology of HCC

macroscopic types:
- massive
- diffuse
- nodular 

Histological types:
1) Non fibrolamellar
(most common)
- associated with Hep B, Hep C, cirrhosis
- unresectable with short survival time

2) Fibrolamellar
- usu not associated with Hep B, C, cirrhosis
- longer survival time due to resectability
- more common in westerner, adolescents and young adults


HCC clinical presentation

1) Subclinical

2) RUQ pain, hepatomegaly

3) Constitutional symptoms
- weight loss, anorexia, malaise

4) Cirrhosis signs (jaundice, ascites, portal hypertension, flapping tremor, encephalopathy)

5) Tumour rupture (intraperitoneal haemorrhage)

6) Paraneoplastic features 
- erythrocytosis
- thrombocytosis
- hypercalcemia


Diagnostic results suggestive of HCC

Lab test:
1) Elevated AFP > 400 ng/ml (AFP normal in 30%)

2) LFT
- shows a parenchymal picture
- PT time is increased

3) Hepatitis B, C serology might be positive

Non-Lab tests:
1) Liver biopsy 
- for definitive diagnosis

2) USG

3) CT scan, MRI

4) hepatic arteriography


HCC radiological features

1) US
- can be focal, multifocal, or diffuse
- usually a slightly hypoechoic lesion, with hyperechoic acoustic enhancement behind it
- note a heterogenous cirrhotic background liver

2) CT Scan
- Contrast injection for triphasic CT
- HCC enhanced greatly at the arterial phase (if it’s a secondary tumour in liver, will be hypoenhanced in arterial phase)
- Rapid washout during portal venous phase (it becomes hypoattenuated (or indistinct)

3) MRI scan
- Hypervascular lesion taking up contrast

4) Hepatic Angiography (Digital Subtraction Angiography)
- hypervascular tumour
- threads and streaks pattern: sign of tumour thrombus in portal vein
- Can be therapeutic for TACE

- Staging, identification of extrahepatic disease, charaterise liver lesions and monitor treatment response of HCC 


HCC management

Curative Surgical Treatment includes:
1) Hepatic resection

2) Liver transplantation 
- only for HCC - if >5cm, usually indicates advance disease with distant met

Locoregional treatment for unresectable ones:
3) Transarterial chemoembolization 
- Lipiodol + cisplatin + gelfoam 

4) Percutaneous ethanol injection 

5) Cryotherapy 
- For tumors - thawling might cause bleeding

6) Microwave or radiofrequency thermoablation 

Systemic pharmacological therapy:
7) Sorafenib is the only proven effective systemic therapy
- add daunorubicin, tamifixen, Interferon


Metastatic Cancer to Liver source

1) Commonest site of primary is from GI tract (Colon, stomach, pancreas, biliary tree); liver is the commonest site of metastasis for GI primary

2) Other common sites of primary e.g.
- lung
- kidney
- Breasts
- gynecological tract 


Management of metastatic liver cancer

1) Hepatic Resection
- can prolong survival in patients with resectable colorectal metastasis 

- useful for palliation of symptoms from carcinoid & neuroendocrine tumors

- Resection is NOT indicated in metastasis from pancreas, lung, etc

2) Locoregional treatment
- TACE is useful for palliation of symptoms from carcinoid & neuroendocrine tumors

- Local ablative therapy e.g. RFA 

3) Chemotherapy
- depends on response of the type of tumour 


Lobes of liver

Divide into 8 lobes by the Inferior vena cava, heptaic portal vein, & left and right hepatic veins:

1 = caudate lobe

See pic


A image thumb

What are the types of liver abscess?

1) Pyogenic liver abscess
- caused by bacterial infection

2) Amoebic liver abscess
- caused by Entamoeba histolytica (reach the liver via the hepatic portal vein)
- Fecal-oral transmission, especially common in homosexual men


Pyogenic Liver Abscess causes

- Biliary tract obstruction (most common)
- GI infection (diverticulitis, appendictitis) spread via the portal venous system
- Penetrating liver trauma (e.g. gunshot, surgery)
- Haemotological spread to liver (in immunocompromised)
- Cryptogenic


Causative organisms in pyogenic hepatic abscess

‚ÄĘ E-coli (G ‚Äďve)

‚ÄĘ K. pneumoniae (G -ve)

‚ÄĘ Bacteroides (anaerobic)

‚ÄĘ S milleri (G +ve)

‚ÄĘ Enterococcus sp. (G +ve)¬†


Clinical features of liver abscess

- fever

- malaise, anorexia, weight loss

- nausea, vomiting

- RUQ pain

- Jaudice

- Diarrhoea if amoebic


Investigation results in suspected liver abscess

1) CBC
- signs of infection (leucocytosis)

2) LFT
- parenchymal pattern from liver damage
- cholestatic pattern if biliary obstruction is the cause

3) Blood culture

4) Serological testing
- IgG enzyme immunoassay to look for Entamoeba hisolytica infection

5) E histolytica stool antigen test (not really sensitive)

Radiological: (to confirm liver abscess)
6) US

7) CT
- Centre of lesion is hypodense with rim enhancement
- Septation & Enlarged (see pic)
- Can be used for guiding draining tube


A image thumb

Management of liver abscess

Fatal if untreated:

1) IV metronodazole

2) Image guided percutaneous aspiration of abscess (esp if the abscess is large)

3) Surgical drainage might be necessary


Liver failure types (& their definition)

1) Acute liver failure
Development of severe acute liver injury manifesting as encephalopathy and impaired synthetic function (INR >1.5), without pre-existing cirrhosis / chronic liver disease 

2) Acute-on-chronic failure
Development of severe acute liver injury manifesting as jaundice and impaired synthetic function (INR >1.5), complicating within 4 weeks by ascites or encephalopathy, in patients with underlying chronic liver disease.

3) Decompensated cirrhosis (chronic liver failure)

Note it's difficult ot differentiate acute liver failure from acute-on-chronic liver failure as the background chronic liver disease might be undiagnosed


DDx for acute liver failure (or A-o-C liver failure)

1) Drug induced hepatitis
- Paracetamol Overdose, NSAIDs
- INAH-related Hepatotoxicity (TB)
- Rifampicin-related Hepatotoxicity 
- Pyrazinamide-related Hepatotoxicity
- Statins (actually very rare)
- Rheumatological (methotrexate, azathioprine) 
- Amiodarone 
- Other drugs
- Herbal-related, TCM

2) Viral hepatitis
- acute HBV or acute exacerbation of HBV
- other systemic infection e.g. CMV

3) Other external agents
- Alcoholic hepatitis
- Mushroom poisoning (Amanita phalloides)

4) Wilson's Disease


Causes of drug induced hepatoxicity in TB patient

In Hong Kong, TB is treated with PIER for 2 months, followed by 4 months of IR.

Hepatotoxicity is one of the major adverse effects of isoniazid, rifampicin and pyrazinamide 


Known Risk Factors for Hepatotoxicity of Anti-TB drugs 

Old age

Female sex


High alcohol intake


Chronic liver disease and viral hepatitis

Acetylator status (i.e. slow acetylator)
- In HK, fast/slow acetylators is about 3:1


Forms of INAH-related Hepatotoxicity 

i.e. isoniazid induced hepatitis:

1) Mild, non-specific hepatitis 
- self-limiting
- no clear relationship to sex, ethnic groups & acetylator status 

2) Overt hepatitis 
- age, female sex, alcohol use 
- 50% within 2 months of use of INAH, can occur much later 
- case fatality rate approximates 10% 


Pathway of INAH Metabolism 

A image thumb

Rifampicin-related Hepatotoxicity 

Rifampicin is used in anti-TB regimen, as well as meningococcus prophylaxis (related to orange urine):

3 effects on the liver:

1) Predictable, dose-dependent impairment of hepatic intake of bilirubin and the effect is reversible

2) Potent inducer of P450, thus affecting drug metabolism - potentiates the hepatotoxicity of INAH (usually INAH and rifampicin used together)

3) Acute viral hepatitis-like reaction - actual incidence unclear 



Pyrazinamide-related Hepatotoxicity 

Some structural resemblance to isoniazid

‚ÄĘ Dose-dependent

‚ÄĘ Experience with low dose regimens suggests that there is only a small risk of hepatocellular injury¬†


How to manage TB therapy related hepatotoxicity

- Stop PIER

- switch to quinolones first

- monitor progress


How can we assess the severity of acute liver failure?

1) King's College Criteria
- "Poor Prognostic Factors for Acute Liver Failure"
- specific item for paracetamol poisoning

2) Child-Pugh Score 
- for acute-on-chronic liver failure for Cirrhosis

3) MELD Score
- Model for End-stage Liver Disease (MELD) score 


King's College Criteria

Poor Prognostic Factors for Acute Liver Failure:

1) For paracetamol poisoning:
- Arterial pH or all 3 of:
- PT >100s
- Creatinine¬†> 300 őľmol/l
- Grade III or IV encephalopathy 

2) Non-paracetamol poisoning:
- PT >100s
or 3 of following:
- PT >50s
- age 40
-¬†bilirubin >300 őľmol/l¬†
- >7 days duration of jaundice before encephalopathy
- Drug toxicity (nonA, nonB, halothane, idiosyncratic), regardless of whether it was the cause of the acute liver failure 



Child-Pugh Score 

Prognostic Factors for Cirrhosis
5-6 points = Child A
7-9 = Child B
10-15 = Child C

5 area (ABCDE), each area range from 1-3 points:

Cotting (PT prolongation)
Distention (Ascites)


Disadvantage of Child Pugh Score


1) limited discrimination
- only 8 levels between Child B and C
- same score for different values of albumin, bilirubin, PT etc.

2) Subjective assessment of ascites and encephalopathy

3) Variability of PT and albumin in different laboratories 

4) Parameters like albumin, PT can also be affected by supportive treatment


MELD Score

Model for End-stage Liver Disease 

- Very good in prediction of 3-month mortality, useful to prioritize patients for liver transplant 

- If MELD score is 14 or more, then start to work-up for liver transplant (max score is 40)

- Calculated from (BCC) Bilirubin, Creatinine, Clotting (INR). January 2016 update includes sodium.



Staging of fibrosis in cirrhosis

Fibrosis can be assessed by liver biopsy, or transient elastography (fibro-scan):

F1 = Portal fibrosis

F2 = Portal fibrosis with few septa

F3 = Septal fibrosis

F4 = Cirrhosis


A image thumb

Acute Liver Failure - Management 

1) Supportive 

2) Treat the underlying cause, stop drugs

3) Give N-acetylcysteine anyways
- esp when history is unclear
- antidote for paracetamol overdose 

4) Manage complications, e.g.
- stop variceal bleeding if any
- Manage ascites and SBP by diuretics, therapeutic paracentesis, TIPS
- manage HE by Lactulose, Rifaximin, protein-restriction diet

5) Liver transplantation 


Complications and manifestation of liver failure (esp cirrhosis)

0) Jaundice

1) Portal hypertension

2) Varices
- esophageal varices
- gastric varices
- caput medusae
- rectal varices

3) Ascites
- will cause dilutional hyponatremia

4) Spontaneous bacterial peritonitis

5) Hepatic encephalopathy
- due to porto-systemic shunting of ammonia
- Asterixis
- Fetor hepaticus
- Rigidity
- Hyperreflexia

6) Hypoalbuminaemia
- leuconychia

7) Hepatorenal syndrome
- renal vessel vasoconstriction leading to renal hypoperfusion

8) Hepatopulmonary syndrome
- Platypnoea due to V/Q mismatch

9) Hyperestrogenism
- Spider angioma
- Palmar erythema
- Gynaecomastia
- Testicular atrophy

10) Coagulopathy
- secondary to decreased clotting factor synthesis
- Prolonged PT; prolonged aPTT if severe

11) Some soft tissue manifestations
- Finger clubbing, HPOA
- Duputyren's contracture

12) Hepatocellular carcinoma


Pathogenesis of ascites in cirrhosis

1) Cirrhosis leads to splanchnic vasodilation, as a result arterial underfilling and hypoperfusion of kidneys. Thus activating the RAAS, leading to water preservation. 

2) Hypoalbuminemia due to reduced protein synthetic function of the liver also plays a minor role.


Investigations on ascitic fluid

Perform a Diagnostic paracentesis and look for:

1) Colour
- straw color, blood stained, chylous?

2) Serum-ascites albumin gradient (SAAG)
- High gradient (>1.1g/dL) means transudative (i.e. portal hypertension from cirrhosis, heart failure, renal failure, Budd Chiari)
- Low gradient (

3) Rate of reabsorption 
-¬†900 ml/day (In tense ascites, may ‚ÜĎ to 1.5 l/day)¬†

4) Cell count
- to screen for SBP (leucocytosis, esp neutrophilia i.e. high WBC, PMN)

5) Microbiology
- Gram stain & culture screen for SBP
- AFB stain & TB panel

6) Some not quite useful parameters
- Protein level
- Glucose level
- Look for Malignant cells (


How to manage ascites

Lifestyle modification (For mild ascites):
1) Bedrest (for in hospital patients)
2) Salt restriction (1‚ĀĄ2 - 2 gms/day)
3) Fluid restriction (0.8 ‚Äď 1 /day)¬†

Pharmacological therapy:
4) K+ sparring diuretics
- Start with aldosterone antagonists, if not tolerable then ENaC blocker
- Spironolactone (gynaecomastia very common, esp alcoholic cirrhosis), Eplerenone ($$$)
- Amiloride, triamterine 

5) Add loop diuretics if K sparring diuretics is not enough
- Bumetadine 
- (Frusemide absorption unreliable in portal hypertension)

6) Albumin infusion + IV diuretics

If tense ascites
7) Therapeutic Paracentesis 

8) Correct portal hypertension
- Peritoneovenous shunt


Complications of therapeutic paracentesis

- Bleeding from puncture site (due to deranged PT)

- Infection, Sepsis

- Perforation of caecum with R-sided punctures 

- Shock

- Electrolyte disturbance

- Renal impairment

- Encephalopathy 


Diagnosis and pathogen of SBP

1) Ascitic fluid cell count
- Suspicious if >500 WBC/mm3

- >250 PMN/mm3 if symptomatic

- >500 PMN/mm3 if asymptomatic

2) Ascitic Fluid Gram stain & Culture
- E coli (most common)
- Klebsiella
- Streptococcus pneumoniae


Early Forms of SBP

1) Monomicrobial bacterascites
- Positive for a single organism
- 3
- A mild form of infected ascites

2) Culture negative neutrocytic ascites
-¬†‚Č• 250 (or 500) PMN/mm3
- No antibiotics therapy
-¬†No alternative cause of ‚ÜĎ in PMN
- Almost certainly an early form of SBP 


Pathogenesis of SBP

In cirrhosis, bacteremia occur because of:

- Deficient Serum Complement Activity 

- Poor Endothelial System Function 

- Gastrointestinal Hemorrhage 

- Invasive procedures (e.g. paracentesis)


Management of SBP

1) Empirical Broad spectrum antibiotics 
- take ascitic fluid sample for culture before antibiotics 
- IV Cefotaxime, for 5 days
-¬†can stop antibiotics as soon as PMN count ‚ȧ 250 /mm3

2) Long-term selective intestinal decontamination
- Use norfloxacin 


Why is norfloxacin selected for SBP prevention

-  incompletely absorbed by gut

-  highly active against gram neg bacilli

-  low activity against anaerobes

-  rarely causes bacterial resistance

-  low side-effects 


Possible causes of bleeding in cirrhotic patients 

- Varices (oesophageal & gastric)

- Portal hypertensive gastropathy

- Peptic ulceration

- Generalized bleeding tendency

- Others, e.g., Mallory Weiss syndrome 


Pre-requisites of variceal bleeding

associated with vessel wall-stress:

1) Portal hypertension (unlikely to bleed if pressure

2) Large vessels with THIN WALLS 


Management of varices in cirrhosis

0) Resuscitation
- Fluid/electrolyte resuscitation
- monitor vitals
- Vit K1 infusion

1) Endoscopic therapy
- Band ligation
- Sclerotherapy
- Variceal obliteration by tissue adhesive 

2) Pharmacological therapy
- IV Octreotide (first line)
- IV Terlipressin (not routinely used due to ADRs)
- IV somatostatin

3) Balloon tamponade
- Sengstaken Blakemore Tube

4) Emergency surgery 

5) Pharmacological prophylaxis
- ő≤-blocker e.g.¬†Propanolol, nadolol¬†as prophylaxis
- combined with vasodilators, e.g., isosorbide mononitrate

6) Long-term band ligation
- recent trial shows superiority over pharmacological prophylaxis with less re-bleeding, less complications & better survival

- Transjugular Intrahepatic Portosystemic Stent-Shunt 

8) Liver Transplant


Disadv and complications of endoscopic sclerotherapy/band ligation of varices

Only for esophageal varices, cannot reach gastric varices

- transient oesophageal pain
- oesophageal ulcers (rarely bleed)
- sloughing of bands during subsequent endoscopies
- stricture
- medinastinitis
- aspiration pneumonia 



Explain pharmacological therapy mechanism for variceal bleeding

IV Octreotide, Terlipressin, Somatostatin

1) Splanchnic vasoconstriction (reduces sup mesenteric & splenic arterial flow), thus reducing hepatic portal venous pressure

and ideally:
2) Vasodilation of hepatic vasculatures, thus reducing intrahepatic vascular resistance and portal venous pressure (peripheral resistance is not affected)


Sengstaken Blakemore tube disadvantage

-  patient discomfort

-  oesophageal ulceration or necrosis

-  asphyxia (choking) due to balloons

-  aspiration pneumonia 


Explain pharmacological therapy mechanism in preventing variceal bleeding in cirrhosis

ő≤ blocker plus isosorbide mononitrate is used:

ő≤ blocker
- reduces heart rate and cardiac output, thus reduce portal blood flow, correcting portal hypertension

Isosorbide mononitrate 
- a vasodilator
- vasodilation of hepatic vasculature, thus reducing hepatic portal venous resistance, and lower the portal venous pressure


Procedure of TIPS

Transjugular intrahepatic porto-systemic stent-shunt

1) Transjugular access to middle hepatic vein

2) Puncture and catheterization of Rt branch of hepatic portal vein (difficult)

3) Dilatation of needle tract (painful)

4) Implantation of stent joining hepatic and portal vein branch 

A image thumb

TIPS indications and contraindications

- Variceal bleeding (resistant & recurrent)
- Refractory ascites
- Refractory cirrhotic hydrothorax
- Budd- Chiari syndrome
- Prophylactic portal decompression prior to transplant 

- Severe liver failure not for transplant
- Liver abscess / cholangitis

- Cavernous formation of hepatic portal vein
- Thrombosis of R and L int jugular vein, SVC / IVC 


Complications of TIPS

1) Procedural complications
- fatal intraabdominal bleed from perforation of liver capsule or stent at portal bifurcation 
- Haemobilia 
- Liver hematoma

2) Thromboembolism with clot in stent 

3) Volume overload with heart failure 

4) Renal failure (related to dye) 

5) DIC

6) Sepsis

1) Hepatic encephalpathy
- due to enhanced hyperammonaemia from portosystemic shunting

2) Recurrent bleeding 
- non portal hypertensive bleed 
- inadequate portal decompression 

3) Stent stenosis / occlusion 


Causes of Renal Failure in Liver Disease 

1) Hepatorenal Syndrome
- at end stage liver diseases

2) Hypovolemia
- diuretics use
- GI bleeding

3) Sepsis

4) Nephrotoxic drugs

5)  Parenchymal renal disease 


Hepatorenal Syndrome diagnostic criteria

- Urine volume

- Urine sodium

- Urine osmolality > plasma osmolality

- Absence of hematuria


Pathogenesis of hepatorenal syndrome

Vasoconstriction of renal arteries, leading to hypo-perfusion of kidneys (i.e. pre-renal cause). Pathogenesis of renal artery vasoconstriction starts with splanchnic & systemic vasodilation, which causes:

1) Lowering of systemic blood pressure 

2) Activation of the sympathetic nervous system, causing renal vasoconstriction

3) Increased formation of local vasoconstrictor (vasoactive mediators) 

4) Inhibition of atrial natriuretic factors 


Hepatorenal syndrome management

A. Pharamcological therapy
1) Glypressin/Terlipressin +/- Albumin
- Splanchnic vasodilation
- Improves BP & renal perfusion pressure 
- Suppresses sympathetic nervous system activation

2) Norepinephrine

3) Octreotide
- splanchnic vasodilatation 

B. Paracentesis
- drainage of tense ascites may temporarily improve renal haemodynamics and renal function



DDx of neurological symptoms in a cirrhosis patient

1) Hepatic encephalopathy

2) Stroke
- Subdural haemorrhage, due to clotting defects
- Thromboembolism from TIPS

3) Functional psychosis 

4) Metabolic encepholopathies, e.g.
- hypoglycaemia in alcoholics
- uraemia if hepatorenal syndrome
- dilutional hyponatremia
- respiratory failure (hypercapnia, hypoxia) in hepatopulmonary syndrome

5) Alcoholism related
- delirium tremens
- Wernicke's encephalopathy
- Korsakoff's psychosis


Pathogenesis of Hepatic encephalopathy

Ammonia pass through BBB and activates Microglial, and the increase of proinflammatory cerebral cytokines (e.g. TNF) and subsequent neuroinflammation leads to HE. It is precipitated by:

1) Hyperammonaemia, due to 
- inability of liver to detoxify NH3 to urea 
- Porto-systemic shunting of ammonia to systemic circulation
-¬†‚ÜĎ cerebral metabolic rate and permeability to NH3¬†

2) Enhanced Blood-brain barrier permeability 
- Proinflammatory state increases permeability of BBB, allowing entry of NH3 into the brain
-¬†‚ÜĎ Cerebral lactate, manganese accumulation in basal ganglia, GABA receptor upregulation
- Patient genetics e.g. Alzheimer type II astrocyte makes patients susceptible to HE due to higher permeability

A image thumb

Etiology of hepatic encephalopathy

Hyperammonaemia due to:

1) Cirrhosis

2) Fulminant hepatitis
- viral hepatitis
- drug induced (e.g. paracetamol, INAH, rifampicin, TCM)
- metabolic, e.g., pregnancy, Reye syndrome, Wilson’s disease)
- alcoholism, mushroom
- etc

cerebral oedema is uncommon in chronic encephalopathy but frequent in acute fulminant failure 


Contributing factors to HE in cirrhosis

Main process:
1) Spontaneous portal-systemic shunts

2) Progressive hepatic failure thus reduced detoxification of ammonia to nitrate

3) Increased nitrogenous waste through:
- Diet, Digestion of variceal bleeding, constipation
- renal failure
- sepsis
- transfusion

4) Additional precipitating factors 
- Artificial PS shunt e.g. TIPS
-¬†‚Üstvascular vol ‚Üí ‚Üď O2 to liver¬†
- overdiuresis
- excess paracentesis with inadequate albumin replacement 
- diarrhoea & vomiting
- Acid base & electrolyte imbalance 
- Sedatives 


Grading of hepatic encephalothy

Grade 0 to 4 based on:

A) Consciousness and Intellect 
- 1 = forgetfulness, irritability
- 2 = Lethargic, amnesia 
- 3 = Somnolent but rousable 
- 4 = coma

B) Clinical features 
- 1 = Tremor, apraxia, impaired writing
- 2 = asterixis, hyporeflexia
- 3 = asterixis, hyperreflexia, Babinski's
- 4 = Decerebrate posture, no more tremor

- 1 to 3 = Slow 5 cps triphasic waves
- 4 = Slow 2-3 cps delta waves 


Diagnosing hepatic encephalopathy

1) Bedside Psychometric tests 
- constructional apraxia (drawing a five-pointed star; interlocked pentagons) 
- number connection (Reitan’s) test 

2)¬†Complex Psychometric Tests for ‚ÄúMinimal‚ÄĚ HE¬†
Not performed in HK due to time consuming:
- Inhibitory Control Test 
- Critical Flicker Frequency 

3) EEG
- Slow 5 cps triphasic waves
- Slow 2-3 cps delta waves 

4) Arterial ammonia 
- not always raised in HE
- normally 40% by bacterial action, 60% directly from protein breakdown 

5)¬†‚ÜĎ CSF glutamine level
- almost never done for diagnostic purposes


Management of hepatic encephalopathy

1) Lactulose enema
-¬†‚Üď NH3¬†in 2-3 hrs because of immediate contact with bacteria¬†

2) Rifaximin 
- Antibiotic that alterates colonic flora (esp urease producing)
- Combined used with lactulose 

3) Moderate protein diet w/ BCAA supplement
- Protein around 40-60g/day (except in active GI bleeding)
- vegetable protein diet might be better
- IV or oral supplement of branched-chain amino acid (to redress an imbalance)

4) Ornithine-aspartate 
- Lowers NH3 concentration by enhancing metabolism of NH3 to glutamine 
- effective in mild HE, but not in acute liver failure


mechanism of Lactulose in HE

Degradated in colon by urease-negative lactobacilli into lactic, acetic and formic acid, which: 

1) Osmotic laxative 

2) Decrease colonic pH
- inhibit urease-producing bacteria esp. E coli
- traps luminal NH3 and convert them to ammonia NH4 
- draws NH3 from mucosal blood to gut 


ADRs of lactulose

Used in HE:

1) adversion to sweet taste

2) nausea and vomiting

3) flatulence

4) osmotic diarrhoea, which leads to
- dehydration
-¬†‚ÜĎ Na, ‚ÜďK

5) pneumatosis coli 


Wilson Disease pathogenesis

1) Mutation of ATP7B gene, leading to impairment of copper excretion to bile; impairment of copper incorporation into ceruloplasmin

2) Thus, copper accumulates in liver cell, as hepatocytes die, copper leaks into plasma & peripheral organs e.g. brain, kidneys, cornea (thus may present late).


Clinical features and diagnosis of Wilson disease

Clinical features:
- Acute hepatitis, cirrhosis, fulminant hepatic failure
- Kayser-Fleischer rings
- Extrapyrimidal symptoms (Parkinonism, chorea, drooling) due to basal ganglia accumulation
- Psychiatric problems (e.g. depression, psychosis)
- Aminoaciduria, nephrocalcinosis

- Decreased serum ceruloplasmin level ( - significantly elevated copper concentration in liver biopsy


Ceruloplasmin level interpretation (+ false negatives)

- Raised in inflammation (acute phase reactant)
- pregnancy, estrogen use

Decreased ( - Wilson Disease 

False negatives:
- protein deficiency state (e.g. nephrotic syndrome, malabsorption, protein-losing enteropathy, and malnutrition)


Pros and cons of US for hepatobiliary system

1) no ionizing radiation 
2) cheap
3) accessible, available, mobile, portable
4) Not dependent on organ function
5) sensitive and accurate for intra and extrahepatic bile duct dilatation
6) allows image guided biosy 

1) Operator dependent
2) Easily obscured by:
- bone (infracostal liver cannot be seen)
- gas (pneumobilia, bowel gas)
- fat in obesity
- post surgical scar, dressings, tubes, clips, peritoneal gas 


Indications of CT for hepatobiliary system

1) suboptimal US

2) Identification of lesions, characterisation

3) evaluation of other abdomen and pelvis for other pathology, esp stageing for metastasis

4) Assessment of complications such as:
- GB perforation with pericholecystic abscess, empyema;
- pseudocyst formation post pancreatitis

5) CT-guided interventions 


Pros and cons of hepatobiliary CT

- non-operator dependent
- minimal obscuration from bowel gas, surgical scar etc
- High spatial and temporal resolution, tissue characterisation better than USG
- Covers larger area, thus objective and comprehensive assessment
- Multiplanar reformatting and data post-processing 

- not sensitive for cholangitis
- ionizing radiation
- IV contrast injection related complications e.g. contrast nephropathy & perforation
- relatively expensive
- not portable 


Indications of MRI for hepatobiliary system

1) Unsuccessful ERCP 
- thus perform MRCP

2) Contraindicated ERCP, e.g.
- previous gastric surgery, bypass surgery

3) Evaluation of other abdominal pathology


Pros and cons of hepatobiliary MRI

- No ionising irradiation
- Better contrast resolution and tissue characterisation than to CT scan 
- less contrast related complications than CT
- True multiplanar images 

- Artefacts from surgical clips and other ferromagnetic objects near region of interest
- Not suitable for e.g. cochlear implants or pacemakers (pacemaker will heat up causing arrhythmia)
- Relatively long scanning time, hence prone to motion artefacts (thus not suitable for non-cooperative patients)
- Spatial and temporal resolution slightly inferior to CT scan 
- Very Expensive & not readily available; non-mobile thus require patient transfer
- not suitable for claustrophobic 


Transmission of hepatitis viruses

A: Oral-fecal, rarely parenteral
- Not well-cooked shellfish from infected water, especially bivalve
- Ingestion of infected water e.g. salad
- Faecal contamination (children, sex, health care worker)
- Parenteral (Transfusion, acupuncture, tattoo)

B: Blood

C: Blood

D: Blood

E: Oral
- Waterborne for genotype 1 & 2
- Zoonotic disease from animals, esp. swine 

G (GB): Blood


Chronicity of Hepatitis viral infection

A: Never chronic

B: Varies with age
- chronic if infant
- rarely chronic if adult

C: 70-85% chronic

D: Depends on B status

E: Never chronic except in transplant patients

G (GB): Chronic



Best index for progress and prognosis of hepatitis?

1) Factor VII
- half life of 12 hours
- PT is done as surrogate

2) AST
- half life about 17 hours
note: Bilirubin (mainly direct) may be elevated for a long time after clinical and essential histological recovery 


Acute viral hepatitis symptoms

1) Preicteric phase
·  Low grade fever (usually ·  Severe loss of appetite
·  Severe fatigue, myalgia
·  Diarrhoea
·  RUQ dull ache due to liver capsule distension
·  Darkening of urine colour
·  Transient pruritus

2) Icteric phase
+ Jaundice

3) Convalescent phase 


Management of acute viral hepatitis

Nothing really (NO known drugs or herbs that hastens recovery):

1) Rest for malaise

2) No alcohol for 6 months aftter acute viral hepatitis (for life if chronic)



Transmission of Hepatitis A virus

Virus shed into faeces during incubation; not excreted 7-10 days after onset of jaundice 

1) Fecal-oral route MAINLY
- ingestion of undercooked shellfish from infected waters
- ingestion of infected water e.g. salad
- Faecal contamination (children, sex, health care workers)

2) Parenteral route RARELY
- Transfusion
- Acupuncture, tattoo
- Outbreak in Italian haemophiliacs (factor VIII conc. contamination)


Atypical clinical course of Hepatitis A 

1) Prolonged cholestasis
- High bilirubin, decreasing AST, ALT
- Centrilobular cholestasis with periportal inflammation 
- Always complete resolution 

2) Relapse
- biphasic or polyphasic 
- IgM anti-HAV remains positive
- HAV in stool; HAV RNA in serum
- Steroid increases relapse
- Always resolves 

3) Extrahepatic manifestations (RARE)
- Immune complex diseases 
- Rash (purpuric), arthralgia, cryoglobulinaemia 


Diagnosis of HAV infection

1) IgM anti-HAV
- for acute infection
- detected in serum usu:
  · 1-2 weeks after jaundice
¬†¬†¬∑¬†2-3 weeks after ‚ÜĎ AST/ALT
  · Occasionally delayed 
- Peaks at acute stage
- Persists rarely over 12 months 

2) IgG anti-HAV 
- for past infection
- persists for decades 

3) HAV viral particles in stool

4) RT-PCR for:
- HAV RNA in serum 


Prevention of Hepatitis A

1) Careful cooking of shelled seafood, kill virus by:
-¬†Dry heat at 100¬įC in 1 min
-¬†Wet heat at 100¬įC in 5-10 min
-¬†Not killed at 60¬įC even in 12 hrs

2) Chlorination of drinking water 

3) Passive immunization 
- Prevents/reduces severity of infection 
- Protection 

4) Vaccine
- Inactivated whole virus from cell cultures 
- 2 doses IMI 
- Effective protection within 3-4 wks after 1st dose 
- For non-immune adult travellers 


Epidemiology of Hepatitis A & E in Hong Kong

Hepatitis A: Decreasing incidence

Hepatitis E: Increasing incidence 


Transmission of Hepatitis E

4 genotypes: 1 & 2 from humans 3 & 4 zoonotic

1) Waterborne
- Genotype 1 & 2

2) Zoonotic disease from animals, esp. swine first described in Japan and USA
- Genotype 3 & 4


Mortality of Hep A & E

Rules of 2:

Hepatitis A: 
- 0.2% 

Hepatitis E: 
- 1-2% 
- Up to 20% in pregnant women (pregnant woman more sensitive to endotoxin effects as HEV damages Kupffer cells)


Diagnosis of HEV infection

1) anti-HEV IgM
- coincides with symptoms
- persists for ~ 3 months

2) anti-HEV IgG
- follows rise of anti-HEV IgM
- can persist for several years

3) HEV particles in stool

4) RT-PCR assay
- HEV-RNA in stool


Prevention of HEV infection

1) Better sanitation

2) Ig for passive immunization

3) Vaccine 
- Recombinant vaccine containing genotypes 1 & 4
- 3 doses at 0, 1 & 6 months
- Protective effect after 4.5 years
- Licensed in China, but not in HK  


Which is the only DNA hepatitis virus?

Hepatitis B virus


Hepatitis Viral Panel components

Hepatitis A
- Anti-HAV IgM (for acute infection)
- Anti-HAV IgG (for past infection)

Hepatitis C
- No marker or HCV RNA (for acute infection?)
- Anti-HCB (cannot distinguish acute & chronic)

Hepatitis E
- Anti-HEV IgM (for acute infection)
- Anti-HEV IgG (for past infection)

Hepatitis B
- HBV DNA (quantitative with correlation to viral activity)
- HBsAg (shows presence of virus)
- Anti-HBs (shows immunity against HBV)
- Anti-HBc IgM (acute infection)
- Anti-HBc IgG (chronic or recent infection)
- HBeAg (shows presence of virus; early marker for acute infection)
- Anti-HBe (shows seroconversion i.e. entering inactive carrier phase, but can be absent in variants of Pre-C mutation)


Interpreting HBV serology panel

1) HBsAg (+); Anti-HBs (-); Anti-HBc (+)
- acute infection if Anti-HBc IgM
- chronic carrier if Anti-HBc IgG

2) HBsAg (-); Anti-HBs (+); Anti-HBc (+)
- past infection with immunity

3) HBsAg (-); Anti-HBs (+); Anti-HBc (-)
- past infection with immunity
- post vaccination

4) HBsAg (-); Anti-HBs (-); Anti-HBc (+)
- Acute infection if Anti-HBc IgM
- Past infection
- False positive 
- ‚ÄúLow-grade‚ÄĚ chronic¬†infection (i.e. Occult infection e.g. Rituximab user)

5) HBsAg (+); Anti-HBs (-); Anti-HBc (-)
- Very early incubation period of acute infection
- Late chronic infection with HBV DNA integration into host 



Why is Anti-HBs assay negative in Chronic HBV infection??


Demonstrates the lack of immunity against HBsAg:

- Anti-HBs do exist, but the excess HBsAg forms complex with anti-HBs, rendering them UNDETECTABLE by the serological tests


Global epidemic areas of HBV

Chinese, Africans, Eskimos


Pathogenesis of Hepatitis B

HBV not directly cytopathic;¬†Damage to liver through cytolytic T cells and cytokines (TNF-őĪ, IL-Iő≤):

1) Proteolytic cleavage of viral proteins in infected hepatocytes (probably cytoplasmic core antigen HBcAg)

2) Peptides carried and presented to cell surface by class I HLA

3) cytolytic T cells activates and releases cytokines that damage and kill hepatocytes by cytolysis



Mortality of chronic HBV carrier

25% die of liver diseases:
- 50% for males
- 14% for females 


Transmission of HBV

Parenteral only:

- At birth (mother-to-child)
- Early postnatal period
- Playmates
- Needles: IV addicts, Acupuncture, Tattoo
- Sexual contact
- sharing of e.g. toothbrushes, razors 
Some study suggests possible transmission via saliva e.g. premastication of food, sharing sweets; no definite proof:
-  Report of high levels of HBV DNA in saliva of carriers


Chances of Chronicity in HBV Infection 

Varies with age:

‚ÄĘ Neonates (up to 1yo) = 90%

‚ÄĘ 1-6yrs = 30%

‚ÄĘ >6yrs =


Reasons for HBV chronicity in neonate

Viral factor
1) HBeAg probably a tolerogen; it can cross human placenta from mother to embryo

Host factor
1) Immuno incompetence of neonates
- relative cytokine deficiency 
- excessive suppression of immune system 
- deficient NK and cytotoxic T cells 

2) Failure of host to recognise infected hepatocytes
- covering of viral antigen on infected hepatocytes by maternal anti-HBc 


Anti-HBs trend in neonates

A image thumb

Natural Hx of Chronic HBV infection 

1) Viral tolerance phase
- minimal host immune reaction
- normal LFT
- high HBV DNA, HBeAg+, no Anti-HBe
- normal histology
- lasts 2-3 decades 

2) Viral Clearance phase
- cytotoxic T cells kill infected hepatocytes 
- fluctuating LFT
- fluctuating HBV DNA, HBeAg+, no Anti-HBe
- histology: intermittent hepatitis with perhaps cirrhosis

3) Late / residual phase (Low replicative phase)
- Variable immune response
- Normal LFT
- After seroconversion, thus HBeAg-; anti-HBe positive; low HBV DNA 
- hisology:¬†normal, or cirrhosis, ¬Ī HCC

4) Reactivation phase (in 30%)
- HBeAg-negative hepatitis 
- may lead to HBeAg reversion


Causes of acute hepatitis in chronic HBV carrier

1) Reactivation of HBV
-¬†‚ÄúSpontaneous‚ÄĚ reactivation of HBV (anti-HBc IgM levels rises but not as high as acute)
- Should be HBeAg negative hepatitis 
- may be HBeAg reversion, thus HBeAg positive

2) Emergence of resistant variants / non-compliance
- during nucleoside analogue therapy 

3) Corticosteroid withdrawal

4) Superinfection by hepatitis D 

5) Superinfection with other viral agent esp HAV and HEV 

6) Drug-induced hepatic injury
- esp alcohol 


Hepatitis B Molecular Virology 

- Circular surface
-  Hexagonal core 
- ds-DNA
-¬†Smallest DNA virus, overlapping open reading frame for ‚Äúeconomical‚ÄĚ manufacture of proteins¬†


Open reading frame genes in HBV DNA

Regulatory sequences  
1) GRE Glucocorticoid responsive element (regulates enhancers; stimulated by steroids)
2) Enhancer I stimulates protein expression esp. the core protein 
3) Enhancer II stimulates surface gene promoters 
4) Direct Repeat I (DRI) initiates long strand synthesis
5) Direct repear II (DRII) initiates short strand synthesis

Protein sequence
1) Gene S produces HBsAg 
2) Gene C produces HBcAg (which remains in hepaticytes not in serum)
3) Gene P Encodes polymerase and reverse transcriptase
4) Pre-S1 encodes peptides recognised by cell surface receptors for HBV 
5) Pre-S2 encodes peptides binding to cell surface receptors; polyalbumin-binding sites 
6) S+S1 = middle protein
7) S+S2 = large protein
8) Pre-C produces signal peptide for processing HBeAg 
9) Region x encodes products for transactivation (thus carcinogenesis by transactivating adjacent oncogenes)



What is the significance of Pre-C mutation in HBV

Mutant strain with stop codon (TAG) causes inability to produce HBeAg:

- the lack of HBeAg allows virus to evade host response at the early stage of infection 

- These patients will be HBeAg (-), anti-HBe (+), HBV DNA +ve, but still have an active disease (i.e. active disease despite apparent e-seroconversion, but not entering Chronic carrier stage)


Infection and replication process of HBV

1) Adsorption via cell surface receptors 

2) release of relaxed circular HBV DNA, with completion of plus-strand DNA 

3) Relaxed circular HBV DNA transport to nucleus, convert to supercoiled cccDNA (covalently closed circular DNA) exclusively in the nucleus

4) transcription of 4 mRNA classes by cccDNA, namely cytoplasmic mRNAs & "pregenomic mRNA"

5) Cytoplasmic mRNAs transported to cytoplasm and translate to viral proteins e.g. HBsAg, HBcAg

6) "Pregenomic mRNA" transported to cytoplasm and translate to HBV DNA polymerase & Reverse transcriptase

7) plus strand DNA synthesis by HBV DNA polymerase ; reverse transcription of pregenomic RNA to produce full length minus-strand DNA

8) partially ds relaxed circular DNA formed, migrate to ER

9) In ER, the DNA core acquire capsule formed from cytoplasmic viral protein, then exocytosis

10) Partially ds DNA can enter nucleus to replenish cccDNA


why is cccDNA difficult to attack and eliminate?

1) 10-50 copies/cell 

2) no direct replication, thus no effective target
- e.g. reverse transciptase inhibitor has no effect on cccDNA
Note: cccDNA might be eliminated in long term due to natural hepatocyte death



Elevated unconjugated bilirubin DDx

1) Increased bilirubin production
- Haemolysis e.g. Thal, G6PD def
- ineffective erythropoiesis
- resorption of massive haematoma

2) Decreased hepatic uptake
- e.g. rifampicin

3) Decreased conjugation
- Gilbert’s syndrome
- Criggler-Najjar syndrome (die


Gilbert’s Syndrome (pathogenesis & presentation)

Lack of conjugation of bilirubin due to low enzyme (UDP glucuronyl transferase) activity:

- Autosomal recessive, heterogenous in severity 
- Male:female = 4:1
- Incidence : as high as 5% in males 

- Unconjugated bilirubinaemia
- Normal LFT, no hemolysis
- Disease wax and wane 


Exacerbating and relieving factors for Gilbert's Syndrome

Aggravated by:
1) infection

2) fasting e.g. low lipid 400 calorie diet 

Relieved by:
1) phenobarbitone (epilepsy drug) as it is an inducer for UDPGT


Indications for liver transplant

1) Fulminant hepatic failure
- except when cerebral edema, coning, or uncontrolled infection

2) Acute on chronic liver failure

3) Chronic liver failure
-¬†Worsening liver function (‚ÜĎÔÉ©INR,‚ÜĎbilirubin, ‚Üďalbumin)
- Emergence of complications e.g. bleeding varices, intractable ascites)

4) Metabolic diseases

5) Small unresectable hepatocellular carcinoma 


When not to transplant in fulminant hepatits?

1) Cerebral edema & coning

2) Uncontrolled infection, e.g.
- severe bronchopneumonia
- fungal septicemia


Chronic liver failure DDx

‚Äď hepatitis B
‚Äď hepatitis C
‚Äď alcoholism
‚Äď primary biliary cirrhosis
‚Äď secondary biliary cirrhosis
‚Äď autoimmune hepatitis
‚Äď Budd-Chiari syndrome¬†


sources of liver donation

1) Brain-stem dead donors

2) Living donors


Pre-requisites of liver donation from brainstem dead donor

1) No extracranial malignancy 

2) No HBV, HCV, HIV infection 
- unless the recipient is positive too


The Diagnosis of Brain Death 

1) Fixed & dilated pupils, not responding to light

2) Absent corneal reflexes

3) No motor response to painful stimuli

4) No reflex activity except spinal cord origin

5) No oculocephalic reflex (doll’s eyes)

6) No vestibulo-ocular reflexes

7) No gag or cough reflex to bronchial stimulation

8) No respiratory movements if MV stopped to ensure pCO2 > 60 mmHg 


Liver harvesting operation from brainstem dead patient

1) In-situ flushing
- cannula in aorta
- portal cannula through Inferior Mesenteric Vein
- flushing using "University of Wisconsin Solution", an organ preservation solution, at 4¬ļC

2) Liver harvest
- for orthotopic liver transplant


Function of components of organ preservation solution 

i.e. University of Winconsin solution:

1) Hydroxyethyl starch (HES)
- support colloidal pressure 

2) Lactobionate 
- prevent cell swelling 

3) Glutathione 
- inhibit oxygen free-radical generation 

4) Adenosine
- enhance ATP synthesis after reperfusion 

5) Allopurinol
- inhibit oxygen free-radical generation 


Anastomoses in orthotopic liver transplant

‚ÄĘ Suprahepatic IVC

‚ÄĘ Infrahepatic IVC

‚ÄĘ Hepatic portal vein

‚ÄĘ Hepatic artery

‚ÄĘ Bile duct¬†


Liver transplantation Technical complications 

‚ÄĘ Bleeding
‚ÄĘ Reperfusion injury
‚ÄĘ Air embolism
‚ÄĘ Anastomosis stenosis
‚ÄĘ Graft failure¬†


Who gets the brain-dead organ first? 

1) According to urgency
- i.e. higher MELD score

2) Fulminant hepatic failure usually get organs first

3) Chronic liver failure patients are prioritized according to the liver function grading 


Feasibility of Liver donation from living person 

-  Age

-  No HBV, HCV, HIV infection

-  No medical diseases

-  Altruistic

- ¬†Remnant liver ‚Č• 30% total liver volume

-  Remnant liver regenerates to almost 100% in 3 months 


Cost & Benefit of LDLT 

Live donor liver transplant

- Life saving & improvement for repcipient
- Earlier & planned operation for recipient
- Healthy graft for recipient
- Satisfying for donor

- Small-for-size graft for recipient
- Extra mortality & morbodity to donors
- Surgical scars to donors


Different kinds of LDLT

1) Left liver transplant
- Larger remnant for donor (2/3 remains)
- Smaller graft for recipient
- From larger body size donor to smaller recipient (e.g. adult to child)
- limited applicability

2) Left lateral segment graft 
- even smaller graft than left liver transplant
- Segment II, III, and a little of IV

3) Right liver transplant
- smaller remnant for donor (1/3 remains)
- Larger graft for recipient
- From small body size donor to large recipient (e.g. adult-to-adult)
- Expanded applicability


Donor morbodity of liver donation

- Cholestasis

- Biliary injury

- Wound infection

- Hemorrhage

- Deep vein thrombosis, pulmonary embolism

- Pressure ulcer

- Portal hypertension

- Scar

- Financial burden

- Missing School 


Postoperative medication for Liver transplant recipients (same as kidney transplant!)

1) Immunosuppressants
+ Prednisolone

+ Calcineurin inhibitor (cyclosporin A or Tacrolimus)

+ Azathioprine or Mycophenolate mofetil or Sirolimus (mTOR inhibitor)

+ IL-2 (CD25) receptor antagonist (Basiliximab aka Simulect) 

2) Antibiotic, Antifungal agents, Anti-viral agents 


Iatrogenic consequences of post-transplant medical therapy

1) Steroids
- iatrogenic Cushing syndrome
- Osteonecrosis & steroid induced osteoporosis
- Hypertension
- DM

2) Cyclosporine 
- hairy face (hypertrichosis)
- nephrotoxicity 
- hypertension

3) Tacrolimus aka FK506
- nephrotoxicity
- neurotoxicity
- hypertension

4) Sirolimus 
- hyperlipidemia 

5) mycophenolate mofetil
- leucopenia (viral infections)