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Home , Acute liver failure, Haemobilia, Hepatic encephalopathy

4 , Biliary System and Pancreas 4.1 Presenting Problems 4.1.1 Ref: Davidson P. 936, Andre Tan Ch10, JC56, GIL17, Block A TC (jaundice), Uptodate A. Physiology of Excretion Bilirubin: non-toxic breakdown product of heme □ Formed in reticuloendothelial system (RES) □ Two forms: → Unconjugated (indirect) bilirubin: - Not water soluble → bound to plasma - Cannot be excreted directly in urine → Conjugated (direct) bilirubin: - Water soluble - Can be excreted directly in urine

Hepatic handling: □ Unconjugated bilirubin taken up by □ Bilirubin conjugated by UDP-glucuronyl transferase □ Secreted into bile canaliculi into

Enterohepatic circulation: □ Conjugated bilirubin reduced into urobilinogen by intestinal flora → 10% reabsorbed into portal circulation → secreted in kidney as urobilin → confers straw colour of urine □ Unabsorbed urobilinogen oxidized into stercobilinogen and then stercobilin → confers brown colour of faeces

Features of cholestatic jaundice: □ Tea-coloured urine: excretion of conjugated bilirubin in urine (bilirubinuria) □ Pale stools: reduced stercobilin content in stools □ Pruritus: retention of bile acid in blood

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B. Causes of Jaundice Pre-hepatic Hepatic Post-hepatic Suggestive - Lemon yellow jaundice - Yellow jaundice - Greenish jaundice features - Dark stools (↑stercobilin) - Normal stools - Pale stools - Normal urine - Tea-coloured urine - Tea-coloured urine - Pruritus ± scratch marks LFT - ↑unconj. bilirubin - ↑conj. bilirubin - ↑conj. Bilirubin - AST/ALT normal - ↑↑↑AST/ALT - ↑AST/ALT - ALP/GGT normal (AST>ALT = toxins) - ↑↑↑ALP/GGT (ALT>AST = viral) - normal - Albumin normal - ↑ALP/GGT - ↓albumin (if subacute) Causes Haemolytic anaemia Acute liver Cholangitis/RPC - Congenital: - Viral : A, B, E Choledocholithiasis Membrane - Malignant biliary (spherocytosis) - Drug-induced hepatitis obstruction (MBO) Metabolic (G6PD) - - Cholangiocarcinoma: hilar Hb (thalassaemia) Chronic liver (Klatskin tumour), CBD - Acquired: - : B, C - LNs: HCC, gallbladder, lymphoma, stomach Immune (auto-, allo-, - Alcoholic drug-induced) - Non-alcoholic fatty liver - CA head of pancreas - CA ampulla or duodenum Fragmentation disease (microangiopathic) - Metabolic: Wilson’s disease, Benign strictures haemochromatosis, (parasitic, - Post-ERCP α -antitrypsin deficiency bacterial) 1 - Stones, chronic - Autoimmune: autoimmune Drugs and toxins hepatitis Other obstruction Congenital causes - HCC - Mirizzi syndrome - Gilbert syndrome Congenital causes - Choledochal cyst - Crigler-Najjar syndrome - Dubin-Johnson syndrome - Biliary atresia (very rare) - Rotor syndrome Medical causes - PBC - PSC - Intrahepatic Ix CBC with reticulocyte Clotting profile U/S of HBP Peripheral blood smear AFP ERCP/MRCP if dilated LDH, haptoglobin Hepatitis serology: biliary system Direct Coomb’s test Acute: anti-HBc + anti-HAV IgM Contrast CT abdomen Chronic: HBsAg, anti-HCV if highly likely to be MBO Autoimmune panel: Autoimmune panel ± liver ANA, anti-smooth muscle, biopsy if no dilated biliary anti-LKM1 (for AI hepatitis) system Metabolic screen: AMA for PBC Cu: , 24h urine Cu p-ANCA for PSC (if segmental Fe: iron profile dilatation on ERCP) Abdominal USG: , splenomegaly, *Cannot distinguish between hepatic vs post-hepatic by direct:indirect ratio (both ~2:1).

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C. Approach to Jaundice 1. History Is it truly jaundice? – r/o other causes of yellow skin □ Inspect the mucous membrane of sclera, mouth, palms and soles under natural light → Protected from the sun → minimizes photodegradation of bilirubin □ Other causes of yellow skin: → Diet: consumption of large quantity of food with lycopene or carotene139 → Drugs: rifampicin, quinacrine, TCMs Is it conjugated or unconjugated hyperbilirubinaemia? □ Conjugated (direct): → Tea-coloured urine → Pale stools → Pruritus ± scratch marks □ Unconjugated (indirect): none

Is it hepatic jaundice? Hepatic causes of jaundice: □ Chronic liver disease: Hx of chronic liver disease and its All medical doctors aren’t very happy complications Alcohol, Metabolic, Drugs, □ Alcoholic: Hx of Autoimmune, Virus, HCC □ (Metabolic) □ Drugs: recent drug Hx, TCM intake □ (Autoimmune: Hx of autoimmune ) □ Virus: → Feco-oral (A/E): travel Hx, ingestion of seafood → Blood-borne (B/C): hep B/C status, FHx of hepatitis and HCC, blood transfusion, risk factors for blood-borne transmission (transfusion, IVDU, needle stick injury, MSM) □ (HCC): usually late with replacement of hepatic parenchyma (unless underlying cirrhosis) or compression of bilateral bile ducts or porta hepatis LN mets

Is it post-hepatic jaundice? □ Cholangitis: → Charcot’s triad: jaundice, fever, RUQ pain → Reynold’s pentad: jaundice, fever, RUQ tenderness, , confusion → Past episode (recurrent pyogenic cholangitis) □ Choledocholithiasis (CBD stone): → Episodic, painful jaundice in young individuals → symptoms: episodes of severe RUQ pain → Hx of diseases, past , ERCP □ Malignant biliary obstruction: → New onset, painless, progressive jaundice in old individuals → CA pancreas: constant, dull, boring epigastric pain radiating to back (usually late feature) → Constitutional symptoms: LOA, LOW, malaise → Metastatic symptoms: bone pain, dyspnoea, neck lump □ Post-ERCP jaundice

139 Lycopene = 茄紅素. Carotene = 胡蘿蔔素.

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Are there any complications? □ Liver decompensation: , hepatic fetor, worsening ascites □ : abdominal pain radiating to the back with and vomiting → Due to stone disease □ Fat : → Steatorrhoea: fatty, loose stools (floaters) → Vitamin deficiency (A, D, E, K):

2. Physical Examination General examination □ Vitals: fever, haemodynamic stability □ General inspection: jaundice, distension, ankle oedema □ Specific signs: xanthomata (PBC), Kayser-Fleischer rings (Wilson’s disease), hyperpigmentation (haemochromatosis)

Abdominal examination □ Scars: previous HBP □ Stigmata of chronic liver disease: ascites, caput medusae, gynaecomastia □ Generalized distension: ascites can be due to malnutrition, peritoneal malignancy, malignant portal vein obstruction □ Palpable masses: → Hepatomegaly: primary liver tumour, metastatic disease, biliary obstruction (usually mild) → Enlarged palpable gallbladder: indicates MBO if a/w painless jaundice → Splenomegaly: Digital rectal examination for pale stools

Metastatic screen: LNs, bony tenderness, respiratory examination

D/dx of epigastric mass + jaundice can be: □ Hepatomegaly (mild) due to biliary obstruction □ Hepatomegaly due to metastasis or HCC □ LN metastasis to coeliac axis and porta hepatis □ CA stomach with metastatic LN in porta hepatis □ Tumour obstructing both duodenum and → distended stomach + jaundice

3. Investigations Bilirubin level and type of bilirubin → conjugated vs unconjugated hyperbilirubinaemia Liver enzymes: □ Parenchymal pattern: indicates hepatocellular diseases, eg. hepatitis, cirrhosis… □ Ductal pattern: indicates obstructive jaundice □ Normal: consider possibility of prehepatic jaundice (haemolytic anaemia, Gilbert) Clotting profile: ↑INR may be due to hepatocellular dysfunction (unresponsive to vitamin K) or cholestasis (responsive to IV vitamin K) Subsequent Ix based on type of jaundice

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4.1.2 Malignant Biliary Obstruction Ref: Davidson P. 936, Andre Tan Ch10, JC56, Uptodate D/dx for obstructive jaundice: (red = malignant causes) Intrahepatic Extrahepatic dysfunction (hepatitis of any Intraluminal cause, end-stage liver disease) CBD stones (hepatocyte dysfx → ↓excretion) Cholangitis (or RPC) Drugs: anabolic steroids, OC pills, chlorpromazine, arsenic Parasitic (eg. Ascaris lumbricoides, liver flukes) Mural Primary biliary cholangitis (A/I destruction of small ducts) Benign strictures: post-instrumentation, , No enteric intake (TPN, post-operative) (↓CCK secretion → ↓GB contraction) Primary sclerosing cholangitis Intrahepatic cholestasis of pregnancy Sphincter of Oddi dysfunction (intermittent) (a/w ↑oestrogen levels) Cholangiocarcinoma Intrahepatic compression of bilateral Extramural bile ducts due to massive liver SOL (very uncommon) Gallbladder stone in Mirizzi syndrome Acute and chronic pancreatitis (uncommon) Carcinoma of head of pancreas Carcinoma of Ampulla of Vater or duodenum140 Porta hepatis LN (CA stomach, gallbladder, HCC)

Clinical presentation: Courvoisier’s law (sign): □ Symptom: painless progressive obstructive jaundice Presence of palpable gallbladder in a → Jaundice: indicates bilirubin ≥2× ULN (~40-50) patient with painless obstructive → Stool/urinary changes: pale/clay-coloured stools jaundice is unlikely to be due to stone + tea-coloured urine (普洱茶咁深色) disease. Reason: a gallbladder that gives rise to CBD → Generalized pruritus (non-specific, not reliable) stone is likely to have been chronically □ Signs: painless enlargement of GB with jaundice inflamed leading to fibrosis and therefore (Courvoisier sign) would not be palpable. Blood tests: Exceptions: (1) Double stone (CBD + cystic duct) □ LFT showing classical obstructive pattern (2) Recurrent pyogenic cholangitis → ↑bilirubin (3) In situ CBD stones → ↑ALP (± GGT) > AST/ALT (mildly ↑) (4) Mirizzi syndrome (rare) (classical picture more often in CA than gallstones) (5) Pancreatic stone (rare) □ CBC for anaemia, leukocytosis and

□ RFT for suitability of contrast CT Take tumour markers with extreme □ for any concomitant biliary pancreatitis caution in MBO! □ Clotting profile for coagulopathy due to vit K malabsorption, DIC CA19-9 is excreted via bile or liver disease therefore invariably ↑ in any cholestasis. Always take CA19-9 □ Tumour markers: limited utility in acute setting after relief of obstruction. → CA19-9 for CA pancreas, cholangiocarcinoma (and GI cancers) CEA is highly non-specific and → CEA for adenocarcinoma probably has little role in initial diagnosis. Take it pre-operatively. → AFP for HCC (>400 diagnostic of HCC) AFP is rarely useful as HCC is □ Blood C/ST for biliary rarely the cause of MBO.

140 CA ampulla is classically a/w silvery stools (Thomas’s sign) where there is a combination of clay and tarry stools.

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Imaging: Goals of imaging □ Trans-abdominal ultrasound of hepatobiliary system (US HBS) (1) Extrahepatic vs intrahepatic → As first-line to confirm extrahepatic cholestasis (vs intrahepatic) cholestasis □ Direct : gold standard, by (2) Level of obstruction → Endoscopic retrograde cholangiopancreatography (ERCP) (3) Identify exact cause (4) Staging of cancer → Percutaneous transhepatic cholangiography (PTC) if ERCP C/I □ MR cholangiopancreatography (MRCP) if intervention is not required □ If malignancy present/likely, then can consider → Triphasic CT scan for diagnosis ± staging (can skip US if highly suspicious of malignancy) → Endoscopic US (EUS) for diagnosis, staging and Bx → ± PET-CT for staging

Ultrasound of hepatobiliary system: first-line imaging □ Main aim: look for any dilated biliary system → indicates extrahepatic cholestasis □ Other possible findings: → Choledocholithiasis: dilated CBD (>6mm), CBD stone → Gallstone disease: GB stone/sludge, thickened GB wall, pericholecystic oedema, stranding (if ) → Cholangitis: thickened CBD wall → Others: enlarged LNs, liver secondaries, ascites □ Disadvantages: usually unable to visualize primary tumour and distal biliary system (CBD, ampulla, pancreas obscured behind D2)

CT abdomen with pancreas protocol: □ Role/timing: can be initial Ix if suspicious for MBO → Before USG as a +ve USG will need CT for dx/staging anyway → Before ERCP as endoscopic stenting will affect evaluation of tumour □ Pancreatic protocol: best visualizes pancreatic lesions CT contrast phases in general: → Oral water contrast to improve image quality + ↓artefacts Non-contrast: for baseline anatomy → Early arterial phase (25s) to visualize aorta/SMA invasion Early arterial/angiogram phase (15-20s): → Pancreatic phase (40s) to visualize parenchymal lesions only show arteries not organs → Delayed phase (70s) to visualize liver secondaries (Late) arterial phase (35-40s): □ Findings: enhancement in arterially supplied organs (eg. pancreas) → Double duct sign indicates CA ampulla or head of pancreas (Late) portal/hepatic phase (50-60s): → Ductal dilatation (>6mm): when not a/w stones, likely enhancement in portal venous supplied indicates malignant strictures structures (eg, liver parenchyma) → Hypoenhancing pancreatic mass in CA pancreas Nephrogenic phase (100s): homogenous enhancement of kidney parenchyma → Hypovascular liver mass in liver secondaries Delayed phase (>5min): wash out of contrast in most structures except fibrotic structures and urinary tract

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Cholangiography: as diagnostic (visualize obstruction) and therapeutic (drain obstruction) □ Options: → Percutaneous transhepatic biliary drainage (PTBD) → Endoscopic retrograde cholangiopancreatography (ERCP) → Magnetic resonance cholangiopancreatography (MRCP) if intervention is not needed □ Timing/indication of biliary decompression: → NOT URGENT – effect of liver function is slow in onset → to be done after CT abdomen if no indications for early decompression to allow better tumour assessment → Indications for early drainage include - Biliary sepsis or stones: stone formation usually indicates contaminated biliary system - Poor liver function due to prolonged cholestasis → to be optimized pre-operatively → Bear in mind that drainage procedures are a/w significant risks → balance risk vs benefit

Endoscopic retrograde cholangiopancreatography (ERCP): □ Indications: Diagnostic Therapeutic Obstructive jaundice for workup Endoscopic sphincterotomy Suspected CBD stone (not for others) Stent insertion and removal (over guidewire) Suspected biliary pancreatitis (not for others) Dilatation of strictures (by balloon) Suspected periductal malignancies Retrieval of stones (by basket or balloon) (extrahepatic cholangioCA, CA HOP, CA ampulla) Brush biopsy (Sens ~60% only) Suspected sphincter of Oddi dysfunction Snare ampullary resection in CA ampulla Suspected biliary strictures and RPC (not curative) □ Pre-procedural preparation: → Fasting following usual 2-4-6-8 rule (2h clear fluid, 4h breast milk, 6h light meal, 8h heavy meal) → Blood tests: LFT, clotting, CBC → Correct coagulopathy + stop anticoagulant ×5d if sphincterotomy anticipated (may require bridging LMWH if high thrombotic risk) → Prophylactic till end of procedure if immunocompromised or drainage is likely to be incomplete → empirical (augmentin, ciprofloxacin) or specific (based on prior culture) □ Periprocedural preparation: → Premedications: sedation () + (opiates) ± antispasmodic141 (buscopan) → Positioning: usually prone (allow AP fluoroscopy and easier cannulation of ampulla) but LLD/supine possible → Scope: has a side view + channel (unlike other scopes where you are looking at where you are going) □ Reading a cholangiogram: → Reverse film (black = radio-opaque) is usually preferred → Identify normal anatomy (see RHS) → Abnormal findings: - Dilated CBD = larger than the scope - Strictures or extrinsic compression - Prior with surgical clip - Filling defects: can be stones, tumour, gas (d/dx by attempting aspiration/turning patient) - Others: stent in situ, contrast leakage

141 Role of antispasmodic is to ↓GI peristaltic activity for better visualization of ampulla.

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□ Biliary stenting: plastic (temporary) vs self-expanding metallic (permanent) → Metallic stents: cannot be removed (permanent), therefore usually used in palliative stenting where prolonged biliary drainage is required and frequent changing is not desirable (but may still become clogged) → Plastic stents: can be removed (temporary), can be double/single pigtailed or straight, usually used in temporary stenting eg. when residual stone is suspected but require changing Q3mo due to lower patency rates □ Post-procedural care: closely of any Cx, consider routine serum amylase for post-ERCP pancreatitis □ Complications: overall morbidity 8%, mortality 0.4% (not low) → Sedation-related: hypoxaemia/resp suppression, hypotension, arrhythmias, tachycardia (a/w buscopan)

→ Endoscopy-related: hypercapnia (due to CO2 insufflation), perforation → Pancreatitis (3-4%): most common Cx of ERCP - Cause: mechanical injury from instrumentation of pancreatic duct, hydrostatic injury from contrast injection - S/S: epigastric/RUQ pain, tenderness, ↑amylase/ - Tx: most are mild and self-limiting but watch out for inadequate decompression in persistent pancreatitis → Ascending biliary (1-2%): due to introduction of enteric bacteria into sterile biliary system - (1.4%): usually due to failure in complete drainage, typically ~24-72h after ERCP in patients with failed biliary drainage - Acute cholecystitis (≤0.5%): due to introduction of contaminated contrast into a poorly emptying GB → GI (1-2%) due to sphincterotomy

Percutaneous transhepatic cholangiography or biliary drainage (PTC, PTBD): □ Indication: usually when ERCP is not possible/too risky → Distorted anatomy rendering ERCP impossible (eg. previous hepatobiliary reconstruction) → Inaccessible papilla in CA ampulla, duodenal obstruction → Distal complete obstruction, eg. advanced cholangioCA (ERCP impossible) → High-risk patients (ERCP is generally a/w ↑risks, but is less painful) □ Procedure: → Preparation: LA, sedation, Abx prophylaxis → Puncture: USG-guided percutaneous access to biliary tree into left or right hepatic duct by 21G needle - May need to put in bilateral PTBD in hilar obstruction → Cannulation: Seldinger technique to insert guidewire + cannula → contrast injection → Interventions: balloon dilatation, stone extraction, brush biopsy → ± internalization: to be done after biliary dilatation subsides (usu days/weeks), guidewire to duodenum → external-internal stent inserted □ External vs internal-external drainage: → External: ↓risk of ascending infection but a/w significant loss in fluid, electrolytes and bile - Can be done by nasobiliary drainage and PTBD → Internal-external: less fluid/bile losses (but may also drain SB content) but a/w ↑risk of infection □ Complications: → Bacteremia and sepsis due to liver puncture → Severe (0.2-4%) if puncture artery → Biliary due to dislodgement of PTBD

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Magnetic resonance cholangiopancreatography (MRCP): □ Indication: non-invasive, useful when intervention is not needed (diagnostic only) and when contrast injection is C/I □ Technique: use of T2W images to visualize fluid in → reconstructed into cholangiogram □ Performance: sensitivity 90-100% for dilated ducts, reveals level of obstruction in 80-100% □ Advantages: no contrast required (suitable for contrast allergy), non-invasive (little morbidity), allow evaluation of ducts above + below stricture, identify any intrahepatic mass lesions □ Limitations: motion artifacts, image artifacts (fluid in duodenum/diverticula), lower resolution (can miss smaller lesions)

Endoscopic ultrasound (EUS): □ Involves: → Visualization of tumour and surrounding structures → Intraductal USG (IDUS) may be performed → Guide FNAC of suspected lesions (usu if large) □ Role: may be useful when → Other means fail to visualize distal tumours (periampullary tumours are often difficult to be visualized by TAUS as bowel gas often obscures the pancreas, distal CBD and GB) → diagnosis is needed if dx in doubt

Choice of diagnostic/locoregional staging Ix: generally USG + CT first ± other Ix depending on □ Site of obstruction: prefer ERCP/EUS for distal obstruction vs MRCP/PTC for proximal □ Whether drainage is required: prefer direct cholangiography □ Whether stone disease is suspected or to be r/o: prefer direct cholangiography □ Whether tissue dx is required: prefer EUS-FNAC or direct cholangiography + brush Bx

Staging investigation: □ Locoregional staging: CT A+P ± cholangiography ± EUS □ Systemic staging: CT thorax (for cholangioCA) or PET-CT (controversial) □ Laparoscopic staging: may be useful in selected Periampullary tumours = tumours individuals where disease is borderline resectable arising within 2cm of ampulla of Vater - CA head of pancreas General approach to surgical Mx of MBO: - Distal cholangiocarcinoma (CBD) □ Assess operability: patient and tumour factors - Periampullary duodenal CA □ Laparotomy if clinically and radiologically operable - CA ampulla → Bypass if spread → Radial resection if confined □ Palliative drainage if inoperable → ERCP/PTBD ± metallic stent (internal drainage) → Endoscopic stenting for GOO

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Patient factors Tumour factors Age P/E for any signs of inoperability Hx of any known comorbidities Left supraclavicular LNs (bx if uncertain) Screening for unknown comorbidities Hepatomegaly with irregular surface Spirometry for function if RFs present Sister Joseph’s nodule, ascites and POD (FEV1 and FVC <70% predicted, FEV1/FVC <65%) deposits (Blumer’s shelf) ECG Imaging for any signs of inoperability Other lab tests, eg. RFT, blood glucose SMA, coeliac trunk encasement (i.e. encircling >1/2 of vessel circumference) Liver and peritoneal metastasis SMV, portal vein, hepatic a. encasement (relative C/I – although a/w a poorer outcome, some centres operate on these pt as these structures can still be surgically reconstructed)

Laparotomy if patient + tumour factors suitable pre-operatively □ Intraoperative assessment of resectability: pre-operative imaging often miss occult metastasis and therefore should not provide promise on resectability before operation □ Radical dissection if tumour is confined (aim to achieve tumour-free resection margin) → Tumour and part of organ of origin → Regional LNs □ Palliative bypass if tumour has spread (NOT done if initially inoperable on imaging) → Single bypass: choledochojejunostomy or hepaticojejunostomy - Relieve biliary obstruction → Double bypass: CJ/HJ + gastrojejunostomy (when reconstructed by roux-en-Y, sometimes also known as triple bypass, i.e. HJ + GJ + JJ) - Relieve biliary + duodenal obstruction (seldom done) → Triple bypass: CJ/HJ + GJ + pancreaticojejunostomy - Relieve biliary + duodenal + pancreatic obstruction (RARELY done142) □ Perioperative Mx of MBO: controversial, see discussion in section on cholangioCA □ Outcome: very risky (26-28% mortality) due to → Cancer cachexia → malnutrition → Liver function impairment → Often superimposed biliary infections

Palliative options: usually non-operative means to relief obstruction □ Biliary drainage: ERCP vs PTBD ± metallic stent (only insert if certain of unresectable disease) □ Relief of GOO: by endoscopic stenting but a/w poor outcome

142 The reason of this is because the only symptom of pancreatic duct obstruction is pain and it is usually well-controlled by analgesics. Moreover, triple bypass is more risky as anastomotic leakage will lead to digestion of surrounding tissues and therefore chemical and secondary bacterial peritonitis.

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4.1.3 Deranged Liver Function Ref: Davidson P. 928, 935, GI teaching clinic (jaundice), UpToDate Components of liver function test: □ Liver enzymes: → Parenchymal enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST) → Ductal enzymes: (ALP), γ-gutamyl transferase (GGT) □ : albumin and globulin □ Bilirubin: total, conjugated, unconjugated □ Others: LDH, PT, INR (sometimes included) Significance: □ Liver injury is reflected by ↑serum liver enzymes level (released by injured liver into serum) □ Liver function is reflected by → ↓albumin due to ↓production by liver - Half-life = 25d → insensitive, only ↓ in subacute liver diseases - Reversed A:G ratio (i.e. G>A) in cirrhosis143, multiple myeloma, nephrotic syndrome, SLE → ↑bilirubin due to ↓excretion by liver → ↑PT (or INR) due to ↓production of factors by liver

- Most sensitive marker for liver synthetic function (t1/2 of F VII only 12h) Three main patterns of LFT abnormalities144: □ Hepatocellular pattern: ALT/AST elevation >> ALP → ± ↑bilirubin, ↓synthetic function □ Cholestatic pattern: ALP/GGT elevation >> ALT/AST → ± ↑bilirubin, ↓synthetic function □ Isolated hyperbilirubinaemia, i.e. jaundice

A. Hepatocellular Pattern Significance: usually indicates liver parenchymal damage (ALT) (AST) Ref range 29-33 IU/L (M); 19-25 IU/L (F) 10-40 IU/L (M); 9-32 IU/L (F) Distribution Liver (more specific) Liver, skeletal muscle, kidney, brain… Location Exclusively cytosol Cytosol + mitochondria Transfer of amino group from L-alanine to Transfer amino group from aspartate to Function α-ketoglutarate, forming pyruvate and L-glutamate α-ketoglutarate, forming oxaloacetate and glutamate Also called Serum glutamate-pyruvate transaminase (SGPT) Serum glutamic oxaloacetic transaminase (SGOT)

143 Postulated mechanisms include (1) opening of leading to ↓removal of antigens; (2) cirrhotic liver produces Ag and stimulate immune response. 144 Abnormalities of markers of liver function are seldom seen in isolation and when they do, it is usually due to extra-hepatic diseases such as and nephrotic syndrome.

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Degree of elevation has aetiological implications (see next page) De Ritis ratio (AST/ALT): □ For most liver diseases, ALT > AST □ Reversed de Ritis ratio (i.e. AST > ALT) in → (macromitochondria) → HCC or metastasis (↑mitochondrial content) → NASH, viral hepatitis: occ reversed but AST:ALT often low (<2:1) → Wilson’s disease: often >2

Marked/moderate elevation (>5× ULN) Mild elevation (<5× ULN) Acute viral hepatitis Chronic viral hepatitis Acute -E Chronic , C, D Acute exacerbation of hepatitis B Non-alcoholic Drug-induced liver injury Non-alcoholic steatosis , idiosyncratic Non-alcoholic (NASH) Toxic liver injury Alcoholic liver disease TCM, poisoning Alcoholic steatosis Common Alcoholic steatohepatitis causes Ischaemic liver injury Others Autoimmune hepatitis Acute autoimmune hepatitis Chronic insidious form Acute alcoholic steatohepatitis Others Acute hepatitis of Wilson’s disease Chronic hepatitis of Wilson’s disease Budd-Chiari and veno-occlusive disease Haemochromatosis Pregnancy-related liver disease, eg. HELLP syndrome, Extrahepatic causes: thyroid disorders, muscle Acute fatty liver of pregnancy disorders, , Hx of alcohol and drug use (esp TCM) Hx of alcohol and drug use Acetaminophen level and toxicology screen HBsAg, anti-HBs and anti-HBc IgM anti-HAV and IgM anti-HEV Anti-HCV HBsAg, anti-HBs and IgM anti-HBc USG for fatty liver Workup Anti-HCV and HCV RNA Ig pattern, ANA, anti-smooth muscle Ab Ig pattern, ANA, anti-smooth muscle Ab Doppler USG for vascular pathologies Serum ceruloplasmin and K-F rings Serum ceruloplasmin and urine copper Serum iron, TIBC and Tf saturation in woman with childbearing potential Thyroid function tests Liver Bx if all –ve Liver Bx if all -ve

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B. Ductal Pattern Alkaline phosphatase (ALP) Gamma-glutamyl Transpeptidase (GGT) Ref range 45-115 IU/L (M); 30-100 IU/L (F) 8-61 IU/L (M); 5-36 IU/L (F) Source Liver and bone (and intestines) Liver only Alcoholism due to enzyme induction Drugs eg. phenytoin, rifampicin, cimetidine, Isolated ↑bone turnover when there is ↑osteoblast activation145 barbiturates elevation Physiological: puberty, pregnancy NAFLD in Pathological: osteomalacia, bone metastasis Others, eg. , MI, renal failure, COPD, DM,… When elevated, can distinguish between bone Sensitive but not specific for liver disease and liver origin by: NOT usually measured as part of routine Use Heat stability index (HSI): bone burns, liver lasts LFT to avoid unnecessary workup GGT level: ↑GGT = liver disease Only used when ALP is elevated

Causes: ≥4× ULN more specific for Marked elevation (≥4× ULN) Mild to moderate elevation (<4× ULN) Extrahepatic cholestasis Hepatic causes Choledocholithiasis ± cholangitis ANY hepatic disease Malignant biliary obstruction Eg. cholestatic phase of hepatitis Biliary strictures Primary sclerosing cholangitis with extrahepatic stricture Non-hepatic causes Recurrent pyogenic cholangitis Physiological in puberty and pregnancy Iatrogenic, eg. post-ERCP, post-LT High bone turnover Parasitic infections, eg. liver flukes, Ascaris lumbricoides Growth Intrahepatic cholestasis Healing fractures Drug-related, eg. androgenic steroids, phenytoin, ACEIs Osteomalacia Primary biliary cholangitis Hyperthyroidism and hyperparathyroidism Bone metastasis SOL of liver Other extrahepatic diseases HCC and metastatic tumour Eg. DM, peritonitis, myeloid metaplasia, subacute thyroiditis, gastric ulcers, extrahepatic tumours Amyloidosis Primary sclerosing cholangitis TPN-related cholestasis Intrahepatic cholestasis of pregnancy Benign post-operative cholestasis

145 Note that ALP is not elevated in multiple myeloma as it involves osteoclasts only.

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Evaluation of ↑ALP: □ Confirm hepatic origin: GGT level and heat-stability index (HSI) □ Hyperbilirubinaemia vs normobilirubinaemia: → ↑bilirubin indicates complete obstruction → Normal bilirubin indicates SOL of liver pressing onto hepatic sinusoids146 □ USG liver for dilated intrahepatic ducts → indicates extrahepatic cholestasis → May also indicate underlying pathology, eg. gallstones, SOL of liver □ For extrahepatic cholestasis (i.e. with dilated bile duct), should workup for → ERCP, PTC or MRCP for direct visualization of obstruction ± Bx ± intervention → ANA, ANCA for primary sclerosing cholangitis □ For intrahepatic cholestasis (i.e. no dilated bile duct), should workup for → Clinical Hx for drugs, TPN use and infiltrative diseases → Anti-mitochondrial (AMA) and Ig pattern for PBC → IgM anti-HAV, HBsAg/anti-HBc, anti-HCV, IgM anti-HEV for cholestatic phase of hepatitis → if persistently >2× ULN for >6mo w/o identifiable cause

4.1.4 Ref: Davidson P. 932, WCS66, 67, UpToDate Liver failure: insufficient liver metabolic or synthetic function for the need of patient Usually classified temporally into □ : no previous cirrhosis or chronic liver disease □ Acute-on-chronic liver failure: acute liver insult on top of underlying chronic liver disease □ Chronic liver failure (decompensated cirrhosis): decompensating chronic liver disease In general, liver failure is characterized by: Both acute + chronic Usually only in chronic General, non-specific malaise Skin changes due to □ Spider angioma Ascites □ Palmar erythema Jaundice (usually late) Endocrine changes Fetor hepaticus (usually late) □ Hypoandrogenism with 147 Circulatory changes: hyperestrogenism 148 □ ↑CO □ Hyperaldosteronism □ ↓PVR due to NO-induced vasodilatation Coagulopathy □ ↓renal blood flow □ ↓clotting factor production (except F8) 149 : □ ↓ □ ↑ + ↓ production □ ↑ □ Changes in AA metabolism □ ↓albumin synthesis

146 Bilirubin can be re-secreted into bile in other areas of liver, but ALP/GGT cannot. As long as bile duct obstruction is not extensive, bilirubin elevation may not occur. 147 In cirrhosis, there is reduced breakdown of estrogen by the liver as well as increased conversion of androgen into oestrogen. 148 Hyperaldosteronism arises from splanchnic vasodilatation leading to systemic underfilling. 149 Mechanism of thrombocytopenia in liver disease may include (1) ↓hepatic TPO production leading to ↓platelet production (2) bone marrow suppression from hep C or alcohol use (3) ↑platelet sequestration in the spleen.

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Risk of infection: very common, bacteremia up to 25% □ Reason: dysfunctional reticuloendothelial system, ↓opsonization □ Site: esp common in resp and urinary tracts □ Bacteriology: → Staphylococcus, Streptococcus and G- bacilli most common → Risk of fungal infections, esp Candida □ Mx: → Consider regular surveillance microbiological workup, eg. daily CXR, regular MSU/blood → Consider broad-spectrum Abx prophylaxis

Coagulopathy: mainly manifest as □ Platelet dysfunction: both quantitative and qualitative → Mx: platelet transfusion if <50 (if active bleeding or invasive procedure) or <20 (prophylactic) □ ↑PT/INR: important prognostic indicator → Mx: FFP only if active bleeding or doing invasive procedures

A. Acute Liver Failure Definition: □ Development of severe acute liver injury □ With encephalopathy and impaired synthetic function (INR ≥1.5) □ In a patient without pre-existing cirrhosis or chronic liver disease Classification: depends on the interval between time of onset of Sx and development of encephalopathy □ Hyperacute: usually paracetamol or hepatitis → Usually better □ Subacute: usually idiosyncratic drug reaction → Usually less marked coagulopathy and HE → May be confused with chronic liver disease Acute liver failure is distinguished Causes: from chronic by a time interval from onset of the disease and □ Drug-related (70-80%) development of liver failure → Paracetamol overdose: of less than 26 weeks. - Commonest cause of ALF in Western countries - Dose-dependent: rarely occurs in therapeutic doses, i.e. up to 4g/d Hepatotoxic drugs include → Idiosyncratic drug reaction (i.e. NOT dose-related) (1) NSAIDs → Herb-related, eg. TCM, mushroom food poisoning due to (2) Statins (very rare) Amanita phalloides (3) Anti-TB drugs (isoniazid, □ viral hepatitis (5%): hep A, B, E but NOT C rifampicin, pyrazinamide) □ Others (rare): (4) Certain other antimicrobials → Wilson’s disease (ciprofloxacin, cotrimoxazole, ) → Ischaemic liver injury and Budd-Chiari syndrome (5) Anticonvulsants (valproate) → Acute fatty liver of pregnancy (AFLP) (6) Rheumatological (methotrexate, → Massive malignant infiltration… azathioprine) □ Cryptogenic (5-10%) (7) Amiodarone

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Clinical features: □ Hepatic encephalopathy: cardinal manifestation, discussed in later sections → Esp commonly a/w cerebral oedema (uncommon in chronic liver failure) □ Generalized malaise □ Fetor hepaticus: sickly sweet odour, usually occurs late □ Jaundice: usually develops late (esp in ) Hepatomegaly is unusual in □ Multiorgan failure: esp hypotension and resp failure ALF and when a/w sudden onset massive ascites, can → CVS: high-output failure, subclinical myocardial injury suggest Budd-Chiari syndrome. → : acute lung injury, ARDS → GI: pancreatitis (esp Panadol-related) → Haematological: BM suppression, immunoparesis, systemic inflammatory response → Kidneys: renal dysfunction or failure, AKI → Adrenals: impaired glucocorticoid production and hypotension □ Other features, eg. splenomegaly, ascites, oedema, are uncommon Laboratory findings: □ Prolonged PT: ALF defined by INR ≥1.5 In acute liver failure, decreasing aminotransferases may indicate □ ↑↑↑aminotransferases: often marked elevation spontaneous recovery but may also □ ↑bilirubin imply worsening with loss of □ Thrombocytopenia hepatocyte mass. The bilirubin and □ ↑arterial ammonia in hepatic encephalopathy PT will however continue to rise. □ AKI: complicates 30-70% of acute liver injury150 Evaluation of cause: □ Blood: → Basics: CBC, RFT, ABG, arterial ammonia → Liver panel: LFT, PT/INR, (factor V) → Toxicology: serum paracetamol, blood/urine toxicology → Viral serology: anti-IgA IgM, HBsAg, IgM anti-HBc, IgM anti-HEV (esp if pregnant), anti-HSV, anti-VZV, IgM anti-CMV, monospot test → Autoimmune serology: ANA, anti-smooth muscle, anti-LKM, anti-SLA, Ig pattern □ Imaging: USG for Budd-Chiari syndrome, portal hypertension, hepatic steatosis □ Transjugular liver Bx if still unknown cause (percutaneous C/I due to bleeding risk) → If transplant will be done, then histology should be done on the resected liver instead Pattern of findings: Paracetamol poisoning Ischaemic liver injury Very high aminotransferase (>3500IU/L) Very high aminotransferase (25-250× ULN) Low bilirubin (anicterus in early stages) Elevated serum LDH High INR Fulminant hepatitis B Wilson disease151 High aminotransferase (1000-200IU/L) Coombs-negative haemolytic anaemia ALT > AST levels Aminotransferase <2000IU/L, AST:ALT >2 HBsAg+, IgM anti-HBc+ Rapidly progressive renal failure Low uric acid levels

150 Reason of renal impairment in acute liver failure is incompletely understood but may be related to systemic and intrarenal haemodynamic changes similar to those seen in (i.e. due to systemic underfilling). 151 Note that neurologic WD may be confused with HE. Features suggestive of neurologic WD including presence of dysarthria, , or

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Prognostic index: King’s College Criteria

Management: largely supportive □ Supportive care in standard ICU care □ Treatment of underlying cause: → N- for paracetamol intoxication or when the cause is unknown152 - Can dramatically improve prognosis of patients with acetaminophen toxicity - Given in accordance to Rumack-Matthew normogram - However, should consider clinical context as doses as low as 4g/d can cause in regular alcohol users → Antivirals for fulminant hepatitis B are controversial → Others, eg. TIPS for Budd-Chiari syndrome, activated charcoal for □ Management of complications: → Correct metabolic abnormalities → Mx of hepatic encephalopathy: , controversial, may not be useful in acute liver failure → Mx of ↑ICP153: mannitol, hyperventilation, barbiturate (if refractory) → Mx of : usually phenytoin or short-acting → Mx of acute renal failure: usually require continuous renal replacement therapies → Mx of : □ if unlikely to recovery spontaneously → King’s College criteria: most widely used to predict poor prognosis

152 In fact, there is some evidence that NAC may be effective in ALF due to causes OTHER than acetaminophen. 153 Dexamethasone is NOT useful in ↑ICP due to acute liver failure.

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B. Acute-on-Chronic Liver Failure Definition: □ Acute liver insult manifesting as jaundice and INR >1.5 □ Complicating within 4 weeks by ascites and/or encephalopathy □ In patients with underlying chronic liver disease (which may be undiagnosed) Causes: many □ Hep B-related: → Severe exacerbation of hepatitis B → Immunosuppressive agents, eg. steroids, rituximab □ Infections: → Superimposed hepatitis A and E → Other systemic infections □ External agents: → Hepatotoxic drugs or herbs: usually idiosyncratic → Alcoholic hepatitis

Prognostic index for transplantation: no universal consensus □ Model for end-stage liver disease (MELD) □ Child-Pugh score □ King’s college criteria C. Chronic Liver Failure (Decompensated Cirrhosis) Decompensated cirrhosis: defined as the development of symptomatic cirrhotic complications □ Predicts a poorer prognosis Causes: □ Cirrhosis of any aetiology → Alcoholic cirrhosis → Metabolic: NAFLD, haemochromatosis, Wilson’s disease → Autoimmune: autoimmune hepatitis, PBC, PSC (or secondary biliary cirrhosis) → Viral: HBV, HCV → Others: Budd-Chiari syndrome □

Clinical features: cirrhotic complications □ Hepatic insufficiency: hepatic encephalopathy and jaundice □ Portal hypertension: ascites ± spontaneous bacterial peritonitis and variceal haemorrhage □ Hepatorenal syndrome

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Prognostic indices: □ Child-Pugh score and classification: → Considers HE, ascites, bilirubin, albumin and PT/INR → ↓prognosis from class A to C → NOT used for transplantation because - Limited differentiation: only 8 levels between Child B and C with same scores for different bilirubin and encephalopathy severity - Subjective assessment in ascites and encephalopathy - Variability of PT/albumin in different labs □ Model for End-stage Liver Disease (MELD) score: → Based on bilirubin, INR and serum Cr → Excellent in predicting 3mo mortality → Clinically important for prioritization of chronic liver disease patients for transplant - ≤14 → does NOT benefit from LT - 15-17 → equivocal benefit - ≥18 → definitely beneficial 4.1.5 RUQ Pain Ref: Andre Tan Ch8-10, WCS64, UpToDate Cause Features Biliary (commonest) Fat, female, fertile, forty as risk factors for cholesterol gallstone Intense, dull discomfort in RUQ or epigastrium Biliary colic - Severe, constant with excruciating exacerbations (false colic) (and Sphincter of Oddi dysfunction) - Usually last ≥30min and plateau within 1h and resolves ≤6h if uncomplicated - P/E: upper abdominal tenderness and guarding or may be normal Often a/w nausea, vomiting, diaphoresis ± jaundice (if CBD stone) Sudden, prolonged RUQ or epigastric pain - May radiate to back or tip of right scapula Acute cholecystitis - Prolonged (>4-6h), exacerbated by moving and breathing - P/E: upper abdominal tenderness and guarding with Murphy’s sign A/w fever Charcot’s triad and Reynold’s pentad: RUQ pain Acute cholangitis Fever: intermittent fever with chills Obstructive jaundice: scleral icterus, pale stools, dark urine ± mental obtundation and hypotension Liver (due to liver capsule distension) Dull mild RUQ ache due to liver capsule distension - Characteristically mild and occurs in the pre-icteric phase (1-2w before onset of jaundice) Acute hepatitis A/w viral syndrome (low-grade fever, anorexia, fatigue, myalgia) A/w GI upset (vomiting, nausea, diarrhoea) if hep A or E Followed by marked jaundice with cholestatic features (dark urine, pale stools)

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RUQ pain a/w guarding or rebound tenderness Fever is a prominent feature (occurs in 90%) Liver abscess ± hepatomegaly, jaundice (if compress onto bile ducts) ± diarrhoea (due to intestinal Amoebiasis) Travel history to endemic region (ameobic) or I/C state (pyogenic) HCC or metastasis: underlying cirrhosis or HBV carrier, other primary tumours Budd-Chiari syndrome: RUQ pain with massive ascites, LL oedema, jaundice, features of portal Others hypertension, often a/w acute liver failure, thrombotic RFs Portal vein : background cirrhosis, acute RUQ pain, fever, dyspepsia Fitz-Hugh-Curtis syndrome: pleuritic RUQ pain ± radiation to right shoulder Pancreatic Sudden onset progressive upper abdominal pain that radiates to the back - Usually occurs in epigastrium but may be felt in RUQ or LUQ Acute pancreatitis - Typically ↓by sitting up and leaning forward Prominent nausea and frequent vomiting Hx of gallstone disease, unusually large meal or alcohol intake Gastrointestinal Upper abdominal burning pain that is characteristically related to eating - May occasionally be experienced in RUQ May be a/w UGIB symptoms and with Hx of NSAID intake and H. pylori infection Colorectal diseases May be due to diseases of the hepatic flexure. Others Urological Pyelonephritis, renal infarct, obstructive uropathy, renal stone, RCC conditions Thoracic conditions Basal , , basal MI Other conditions Herpes zoster, abdominal wall pain

Approach: □ Basic: CBC/D, L/RFT, amylase/lipase □ USG HBS: 1st line, can visualize most hepatobiliary pathologies → Problem: sonographic Murphy’s sign may be equivocal, distal bile duct obscured by bowel gas □ MRCP: 2nd line (if a/v), more sensitive than CT □ CT abdomen □ ERCP: diagnostic ± therapeutic for gallstone disease and cholangitis □ Operation for definitive Mx

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4.1.6 Hepatomegaly Ref: Bailey and Love Ch61, Andre Tan Ch8, JC65, UpToDate Benign palpable liver Malignant palpable liver Palpable but not enlarged Primary liver tumour Riedel’s lobe Hepatocellular carcinoma (HCC, 85%) Hyperexpansion of lungs Cholangiocarcinoma (CC) Infiltrative/replacement of parenchyma Secondary tumours Fat: alcoholic liver disease, NAFLD Solid organ malignancies: GI, other primaries Metabolic: Wilson’s disease, haemochromatosis, Haematological: leukaemia, lymphoma amyloidosis, other infiltrative diseases Cysts: simple liver cysts, polycystic liver Abscess: pyogenic, amoebic Benign tumours: Expansion of parenchyma Hepatitis: infective, ischaemic, metabolic, autoimmune ‘Obstructive’ Vascular: Rt HF, TR, Budd-Chiari syndrome Biliary: PBC, biliary atresia

Anatomy of liver: □ Normal size: <16cm (on USG) along MCL (from 5th ICS to Rt costal margin) □ Surfaces and peritoneal reflections: → Triangular ligament superiorly fixing superior surface of liver onto diaphragm → Falciform ligament anteriorly attaching anterior surface of liver onto abd wall → Ligamentum teres as remnant of umbilical v. running within falciform ligament to umbilicus → Ligamentum venosum as remnant of ductus venosus running along posterior surface of liver from lig. teres to IVC → Hepatoduodenal lig (lesser omentum) running from posteroinferior surface of liver to stomach, laterally bound by hilar vessels (f. of Winslow) □ Blood supply: 80% from portal v., 20% from hepatic artery □ Venous drainage via left, middle and right hepatic veins □ Porta hepatis structures: DR ALVIn → CBD: towards the Right → Hepatic Artery: towards the Left → Portal Vein: towards the Inferior side → Divides into left and right branches 2cm from liver □ Internal structure divided → By Cantlie’s line (MHV to GB) into left and right surgical lobes (NOT by falciform ligament) → By vascular supply into 8 Couinaud’s segments (see next page)

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Clinical evaluation: Hx P/E Pain: usually indicates significant enlargement General: cachexia, pallor, jaundice stretching the liver capsule Cervical LNs Jaundice ± obstructive jaundice Peripheral stigmata of chronic liver disease GI symptoms, esp changes in bowel habits Hepatomegaly itself: upper and lower Constitutional symptoms and fever border154, surface, edge, consistency, Systemic screen for any primary tenderness, bruit Hx and RFs for chronic liver disease Other abd findings: splenomegaly, other FHx for malignancy masses, ascites PR exam for rectal masses

Further Ix: □ Bloods: CBC, L/RFT, clotting, tumour markers (AFP, CEA, CA19-9) □ Imaging: CXR, USG, triphasic CT, dynamic contrast MRI □ Endoscopy: upper and lower (if suspicious for GI primaries) □ Bx: only if dx uncertain + no plan for radical excision (eg. plan for RFA, palliative systemic Tx)

154 Liver span on P/E usually correlate poorly with that in USG.

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