Dr Kumudith Ekanayaka 15 August 2018 Liver Cases Dr Kumudith Ekanayaka 15 August 2018

Case 1 65 year old female No EtOH BMI 21 Pruritis & fatigue LFT’s Bil 63 (0-24) AST 40 (0-45) ALT 65 (0-55) GGT 430 (0-60) ALP 290 (40-110)

Case 1 Other Bloods to check? INR 1.8 (<1.2) Alb 32 (35-47) What other tests? What is the cause? What would you do?

Case 1 SWE – 15.2 kPa Liver Screen – Negative apart from positive AMA USS – Mild splenomegaly, coarse echotexture SWE – 15.2 kPa Liver Screen – Negative apart from positive AMA AFP – 4.0 (Normal) Likely Primary Biliary Cholangitis Treated with Ursodeoxycholic acid Cirrhosis followup

Case 2 23 year old European female Unwell 2 days Abdominal pain, Jaundiced and drowsy Depression otherwise well OE: Jaundiced, No signs of CLD LFTs Bil 250 ALP 160 GGT 200 ALT 2380 AST 1960

Case 2 Other Bloods: Liver Screen Imaging Pattern of LFT Disturbance INR 2.3, Cr 85, pH 7.40, Paracetamol 120 Liver Screen Negative (HAV and HBcoreIgM – Negative) Imaging USS: Normal Pattern of LFT Disturbance Hyperbilirubinaemia, Hepatitic Picture ALT>1000 Diagnosis Paracetamol Overdose

Case 2

Case 2 Liver Transplant Criteria (Kings College) Paracetamol Arterial pH < 7.3; or All three: INR>6.5, Cr>300, G3-4 Encephalopathy Non Paracetamol INR >6.5; or Three of the following five criteria Patient age <11 or >40; Bilirubin >300; Time from onset of jaundice to enceph. greater than 7 days; INR >3.5; or, Drug toxicity

Case 3 Heavy alcohol consumption – Many years Stopped 4 weeks ago Gradual jaundice, confusion and lethargy OE: Jaundiced, Spider Naevi, Small liver LFTs Bil 406 GGT 198 ALP 137 AST 126 ALT 52

Case 3 Other Bloods: Liver Screen Imaging Pattern of LFT Disturbance INR 1.8, Albumin 30 Liver Screen Negative Imaging USS: Coarse Liver Echotexture Pattern of LFT Disturbance Mixed, significant hyperbilirubinaemia, AST>ALT Diagnosis Alcoholic Hepatitis

Case 3

Case 3 Treatment Abstinence from Alcohol Monitor for withdrawal Vitamin K In Hospital 3 weeks Good improvement Prednisone 30mg Daily for 4 weeks Cirrhosis follow up

LFT’s, tests of liver function & Cirrhosis Dr Kumudith Ekanayaka 15 August 2018

Normal Liver Anatomy Hepatic Artery Bile Duct Portal Vein Central Vein

Aetiology of Abnormal LFT’s in my clinic(n= 672)

Liver Function Tests (LFT’s) Routinely ordered AST not routinely performed by the lab 1-4% of asymptomatic patients have abnormal values Test results can fluctuate, 30% of abnormal results can normalise (Lazo et al.) Diagnosis can be reached non invasively

LFT’s Liver Enzymes Cholestasis Hepatitis Synthetic Function ALP (<110 iU/L) GGT (<60 iU/L) Hepatitis ALT (<55 iU/L) AST (<45 iU/L) Synthetic Function Bilirubin (<24 umol/L) Albumin (35-47 g/L) Prothrombin Ratio (<1.2)

Patterns of raised LFT’s A purely cholestatic or purely hepatitic picture - uncommon Cholestatic ALT / ALP < 2 Mixed ALT / ALP 2 - 5 Hepatitic ALT / ALP > 5 [ Ratio = ALT (x ULN) / ALP (x ULN)]

Causes of Cholestasis Mechanical Bile duct obstruction Medications Stones, tumour, surgery, parasites Medications Clavulanic acid, Flucloxacillin, Erythromycin Liver congestion / heart failure Sepsis / systemic inflammatory disorders Hormonal Pregnancy, OCP Chronic biliary disorders Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis Inherited conditions Biliary atresia, Cystic fibrosis, PFIC

Choledocholithiasis (CBD Stones) Normal Stones & dilated CBD

Alkaline phosphatase (ALP) Produced in many tissues but raised levels usually come from the biliary epithelium, bones, or placenta. Raised in children and pregnancy Unlikely from liver if GGT normal Cholestasis causes increased synthesis of ALP and “leakage” of ALP in to the circulation

Gammaglutamyl transpeptidase (GGT) Found in cell membranes throughout the body including hepatocytes and biliary epithelium – thought to have a role in AA transport Levels are not raised in bone disease or pregnancy – unlike ALP Raised serum levels almost always have a liver origin (usually relating to cholestasis or fatty liver) Serum levels can be elevated in the absence of liver disease due to enzyme induction by anticonvulsants (phenytoin) or EtOH

Causes of hepatocellular damage ( Hepatitis) Acute Viral hepatitis EBV, HAV, HBV Drugs & herbal remedies Paracetamol OD Ischaemic / hypoxic Rare: Autoimmune (AIH) Wilson’s disease, BCS, Acute Fatty Liver Pregnancy Chronic (>6 months) Viral hepatitis HBV,HCV Fatty Liver Disease NASH / NAFLD EtOH Medications Rare: Haemochromatosis, Wilsons Disease, Autoimmune

Alanine Aminotransferase (ALT) Catalyses the formation of pyruvate in the cytosol Found in many tissues but by far the highest levels are in the liver (elevated levels are relatively specific for liver disease) More sensitive marker of liver disease in chronic viral hepatitis than the AST

Aspartate Aminotransferase (AST) Catalyses the formation of oxaloacetate in the cell cytosol and mitochondria. Found in many tissues but high levels in liver and muscle (cardiac & skeletal) Elevated levels are not as specific for liver disease as an elevated ALT Less sensitive marker of hepatic inflammation than ALT

Transaminases (ALT & AST) In chronic liver disease the ALT & AST are usually only mildly elevated (typically 1.5 - 3 x ULN). May be normal. In most causes of hepatitis the AST / ALT ratio is < 1. Alcohol related hepatitis is the exception where the ratio is usually > 2. Levels < 10x ULN are non-specific, but there are only a few conditions that cause an ALT or AST > 1000 IU/L

Transaminases > 1,000 iU/L Ischaemic hepatitis (shock) Acute viral hepatitis (HAV, HBV) Drugs (Paracetamol OD, halothane, Carbemazepine) [Alcoholic hepatitis ALT & AST < 300 IU/L]

Transaminases (ALT & AST) The degree of elevation of the does not correlate well with the degree of histological damage in the liver Levels may go in to the many thousands acutely and the liver recover completely Falling levels usually denote recovery but are an ominous sign if the liver synthetic function is worsening.

Tests of Liver Synthetic Function Bilirubin Albumin Prothrombin Ratio (PR, INR)

Bilirubin 80% comes from breakdown of haemoglobin Taken up by hepatocytes and conjugated with glucuronic acid and excreted in bile Normally > 95% of serum bilirubin is unconjugated (indirect). Only conjugated (direct) bilirubin can be excreted in the urine.

Hyperbilirubinaemia / Jaundice: In the absence of liver disease isolated unconjugated hyperbilirubinaemia may occur due to over production of bilirubin (haemolysis) or inherited disorders of bilirubin conjugation (Gilbert’s syndrome) Conjugated (direct) hyperbilirubinaemia and bilirubinuria occur only in hepatobiliary diseases

Bilirubin - Prognosis Poor sensitivity for detecting liver dysfunction. Large reserve capacity of the liver to remove bilirubin without the development of hyperbilirubinaemia. In acute cholestatic disease (such as choledocholithiasis) when the hepatocyte synthetic function is normal and the degree of hyperbilirubinaemia does not influence prognosis. In viral hepatitis, alcoholic hepatitis and PBC the serum bilirubin does correlate with the degree of injury on biopsy and the prognosis

Albumin Made in the liver. Quantitatively the most important protein in the blood (500g in body fluids), important role in maintaining colloid osmotic pressure. Up to 30g / day can be synthesised in a normal liver Serum albumin level is determined by the rate of synthesis, rate of loss / degradation and the volume of distribution.

Albumin A low serum albumin is a good indicator of liver synthetic failure in the presence of chronic liver disease, however other causes of hypoalbuminaemia need to be considered: Renal loss (Nephrotic syndrome) Protein-calorie malnutrition Haemodilution (raised)plasma volume

Prothrombin ratio (PR, INR) Most clotting factors are synthesised in the liver. Liver transplantation is a surgical cure for haemophilia ! In the setting of both acute and chronic liver failure the INR is a very useful indicator of liver synthetic function and prognosis, however other causes of a raised INR need to be excluded: Vitamin K deficiency (prolonged cholestasis) Increased clotting factor consumption (DIC) Warfarin therapy

Prothrombin ratio In chronic liver failure the INR rarely rises above 2.0 In acute or fulminant liver failure the INR may rise rapidly to very high levels (>10), this is associated with a very poor prognosis and liver transplantation should be considered. Even an INR of 1.3 in the setting of an acute severe hepatitis is of concern and should be repeated after 6-8 hrs

Liver Failure Acute (FHF) Chronic (Cirrhosis) Patient unwell for hours or days ALT & AST usually > 1,000 INR & Bilirubin rise rapidly Alb falls rapidly Death within days of cerebral oedema, sepsis or multi-organ failure Chronic (Cirrhosis) Patient unwell for months or years ALT & AST usually < 200 INR & Bilirubin rise slowly Alb falls slowly Death from variceal haemorrrhage, sepsis, encephalopathy or other complications

Liver Cirrhosis

Cirrhosis May be the end result of chronic cholestatic or hepatitic disease. Liver synthetic function may be impaired or normal The enzymes may be of any pattern or may be normal if the underlying aetiology is inactive or no longer present.

Cirrhosis (histopathology)

Examination Findings Asterixis

Examination Findings Dupytrons Contracture

Examination Findings Palmar Erythema

Examination Findings Gynaecomastia

Examination Findings Spider Naevi

Grading of ESLD (Child-Pugh Score)

Survival according to Child-Pugh Score

Cirrhosis - Importance Why Important? Hepatoma 1-2% per annum Variceal Bleeding Decompensation – Risk of Liver Failure Suggested By Bloods ↓Platelets, ↓Albumin, ↑INR, ↑Bilirubin Clinical Examination Liver Specific / Other Organ injury Imaging: USS / CT Irregular contour, ↑PV size, Splenomegaly, Varices Endoscopy Varices, Portal Hypertensive Gastropathy (PHG)

Middlemore Hospital Audit - Cirrhosis New patients presenting each year Gerred et al. 2012

Cirrhosis – New Case Aetiology Gerred et al. 2012

Liver Screen FBC LFT’s, CK< TFT’s Coagulation AFP Hepatitis Serology A, B, C, D, E Protein & Ig Ferritin Transferrin Sats, HFE Auto Ab, ANA, Tissue Antibodies, AMA, LKM, SLA Alpha-1-AT Copper, Ceruloplasmin AFP