Abnormal Liver Function Tests (Adults) Dr Allister J Grant Leicester Liver Unit http://hepatologist.eu

Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase  -Glutamyl transferase Bilirubin Albumin

LIVER FUNCTION TESTS

Abnormal LFT’s in well patients

1) Isolated raise in bilirubin 2) ALT rise predominant 3) ALP rise predominant

1) Isolated raise in bilirubin

• Differential Gilberts vs Haemolysis • Gilberts unconjugated hyperbilirubinaemia • Haemolysis Unconjugated hyperbilirubinaemia splenomegaly, anaemia , DCT, haptoglobin, reticulocyte count, film

2) ALT elevated

• Hepatitic illness • Acute – Age – Sex – Drugs – Alcohol – Travel – Contacts – Risky behaviour – Autoimmunity – Fever – AF/BP/CCF – Pregnant?

• Chronic – Age/sex – Ethnicity – BMI – Lipids – Diabetes – Alcohol – Travel – Risky behaviour – FHx • Autoimmunity • Unexplained Cirrhosis

The majority of abnormal LFTs in asymptomatic people occur in those with: • Diabetes or metabolic syndrome (increased risk of NAFLD) • Excessive alcohol intake • Chronic hepatitis B • Chronic hepatitis C • Drugs

ALT elevated

• Hepatitic illness • Acute – Hep A,B,C,E – EBV, CMV, TOXO – Drugs screen?

– Immunoglobulins – Autoimmune profile – Caeruloplasmin (<50) • Chronic – TFT – Diabetic screen – Hep B, C – Lipids – Immunoglobulins – Autoimmune profile – Ferritin – Caeruloplasmin (<50) – α-1 antitrypsin – TTG – ACE

3) ALP Elevated

• Cholestatic Illness ( With or without jaundice) • Acute – Age/Sex – Drugs/Antibiotics – FHx gallstones – Abdo Pain – Red flag symptoms – Jaundice?

Differentiate from bony • Chronic – Family Hx – Metabolic syndrome – Recurrent Fever – Itch/lethargy – Dry eyes/mouth – Colitis – Pain – SOB/Resp symptoms – CCF

Liver ALP Elevated

• Cholestatic Illness • Acute – CBD stones/Gallstones – Tumours 1º or 2º – Pancreatic pathology – Drugs – Infiltration – SOD • Chronic – PBC – Sclerosing Cholangitis • 1º or 2º – NASH – α-1 antitrypsin – Sarcoid – Amyloid – HIV

Drug Induced Cholestasis

• Intrahepatic Hepatocellular Cholestasis • Intrahepatic Ductular cholestasis • Ductopenic • Granulomatous • Allopurinol Antithyroid agents Augmentin Azathioprine Barbiturates Captopril Carbamezepine Chlorpromazine Chlorpropamide Clindamycin Clofibrate Diltiazem Erythromycin estolate Flucloxacillin Isoniazid Lisinopril Methyltestosterone Oral contraceptives (containing estrogens) Oral hypoglycemics Phenytoin Trimethoprim-sulfamethoxazole

Investigation of Cholestasis

Raised ALP Check  GT if isolated rise 1) Stop alcohol 2) Stop hepatotoxic drugs 3) Advise weight loss if BMI>25 4) Recheck LFT’s after an interval Persistently raised ALP Dilated bile ducts Non-dilated bile ducts Full liver screen Consider MRCP ERCP Other imaging Diagnosis made Treat disease Non diagnostic Ix consider Liver biopsy

4)



-Glutamyl transpeptidase

• The high sensitivity and very low specificity seriously hampers the usefulness of this test • If ALP is elevated and GGT is elevated then the raise in ALP is likely to be hepatic in origin • Elevated in – a whole host of liver diseases – Drugs/Alcohol – Obesity/ dyslipidaemia/ DM – CCF – Kidney, Pancreas, Prostate

Case 1

Mr X 52 y Admitted to LRI Nov 04 with 6 mo lethargy SOA (8 weeks ↑) Recently returned form USA Had HCV Ab done and found to be + in 2003 Frusemide 1 year Some PR bleeding

PMHx RTA 1983 PE Hypertension #femur, ankle ,toes SHx Lived in USA 8 yrs Marriage broken down related to HCV Ab status No risk factors for acquisition Recently returned to UK Construction worker Occasional alcohol Non smoker

OE ? Vasculitic rash on legs SR PSM SOA++ Liver edge Splenomegaly ? Ascites Hb 11.9

WCC 4.7

Plt 42 INR 1.7

ALP 146 ALT 31 Bili 54 Alb 32 U&E normal

What investigations?

USS “Irregular liver, splenomegaly, PV patent” Liver screen HBV sAg HCV Ab Endoscopy- OGD Flexi Sig Auto Ab IgG IgA and M Ferritin Copper Caeruloplasmin A1AT

1 week post admission DSH Waited till after drug round, drew curtains Cut wrists with scissors OD (once previously Oct 04) Suicide note Salicylate ↑ Paracetamol↑ Treated appropriately Transferred to  unit.

OPD PCR negative x2 A1AT <0.3

Transjugular Liver Biopsy A1AT phenotype Pi ZZ

Accumulation Histology and EM

Case 2-

Mr Y

• 53 year old married man presented at GGH -end Aug 09 • Chest Pain/Abdo pain and loose stools • Troponin negative • Abnormal LFT’s ALT 212 ALP 522 Bili 21 ALB 37 Amylase 33

Initial liver screen

• IgG slightly elevated • IgM slightly elevated • Caeruloplasmin • A1AT level • Ferritin • TFT

Imaging

• USS – echogenic mass in left lobe -5x4x2cm – Probably complex haemangioma- some doppler flow and some other small similar lesions By week later ALP>1000 Transferred to Liver Unit

• HBsAg neg • HCV ab neg • EBV IgG pos • CMV neg • Autoantibodies neg • Tumour markers neg • CT – Multiple haemangiomata – Multiple enlarged nodes at porta 12mm – ? SB polyp – RMZ consolidation

Rash on palms and soles biopsied 9/9/09- non specific Liver biopsy arranged and done 17/9/08 periductal fibrosis and biliary inflammation

• VDRL/TPHA Positive • Commenced on penicillin • Referred to GUM • LFT’s completely normalised in 2 months

The End

“All right, let's not panic.

I'll make the money by selling one of my livers.

I can get by with one “ Doh!

Non-Alcoholic Fatty Liver Disease

NAFLD

• NAFLD is a spectrum of disease which includes Fatty liver disease and NASH, but only NASH is known to progress to cirrhosis.

Fatty Liver

Obese BMI>28 Centipetal (apple) Bright liver on USS Normal ALT 2 nd hit

NASH

Obese BMI>28 Bright liver on USS Abnormal ALT Features of metabolic syndrome Dyslipidaemia DM HBP

Cirrhosis

Bright/ small liver on USS + splenomegaly Abnormal ALT Thrombocytopaenia Obesity Poorly controlled DM Poorly controlled lipids Hypertension

How common is NAFLD?

• The most common cause of abnormal liver function tests in the United States.

• Estimated 30.1 million with NAFLD and 8.6 million with NASH • Affects 10-24% of the population • 58-74% of the obese population

Age Adjusted Prevalence (%) of Overweight and Obese Americans Aged 20-74y

Fatty Liver

• Better detected by abdominal imaging than blood tests • Common in individuals who are – Overweight/obese – Type 2 diabetic – Dyslipidaemic – Regular alcohol consumers

NAFLD

Fatty Liver: Macrovescicular steatosis with nucleus positioning at cell periphery NASH: Mallory bodies, ballooning, degeneration, lobular neutrophil inflammation and perisinusoidal fibrosis AGA Technical Review on Nonalcoholic Fatty Liver Disease. Gastroenterology 2002;123:1705-1725

Steatosis

NASH

Cirrhosis

NASH

The rates of progression to cirrhosis have been estimated at between 5% and 20% over 10 years.

There aren't any non-invasive means of predicting which patients are at risk of progression, and there are no agreed guidelines on how to monitor progression.