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10 Top Tips in Liver Disease Dr Allister J Grant Consultant Hepatologist University Hospitals Leicester NHS Trust. LIVER FUNCTION TESTS. Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase Bilirubin Albumin. Abnormal LFT’s in well patients.
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10 Top Tips in Liver Disease Dr Allister J Grant Consultant Hepatologist University Hospitals Leicester NHS Trust
LIVERFUNCTION TESTS Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase Bilirubin Albumin
Abnormal LFT’s in well patients • Isolated raise in bilirubin • ALT rise predominant • 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
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 2) ALT elevated
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
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 ALT elevated
Cholestatic Illness (With or without jaundice) Acute Age/Sex Drugs/Antibiotics FHx gallstones Abdo Pain Red flag symptoms Jaundice? Differentiate from bony Chronic Recurrent Fever Itch/lethargy Dry eyes/mouth Colitis Pain SOB/afrocarribean CCF 3) ALP Elevated
Cholestatic Illness Acute CBD stones/Gallstones Tumours 1º or 2º Pancreatic pathology Infiltration Drugs Flucloxacillin Augmentin TB drugs Chronic PBC Sclerosing Cholangitis 1º or 2º Sarcoid Amyloid Liver ALP Elevated
Liver ALP Elevated • Imaging USS/CT Abdo MRCP ERCP If imaging shows no cause then liver biopsy may be appropriate • Auto Ab • AMA, ANCA • Immunoglobulins (IgM)
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
5) Making a clinical diagnosis of cirrhosis • Suspicion- history and clinical findings • Thrombocytopenia • Low Alb • USS/Other Imaging • irregular liver outline • splenomegaly • Collaterals/ recanalisation of umbilical vein • Ascites
5) Making a diagnosis of cirrhosis • Liver Biopsy –Percutaneous/Transjugular • Fibrotest • Fibroscan
6) Surveillance in Cirrhosis • Surveillance for Hepatoma 6 monthly AFP and USS
Confirm with second mode of imaging • Triple phase CT • Contrast enhanced USS • Avoid biopsy
HCC Treatment • Liver Transplant –Milan Criteria • Resection • Standard • Laparoscopic • Ablation Techniques • RFA • MWA • Alcohol • TACE
Surveillance in Cirrhosis • Surveillance for Oesophageal Varices
Primary prophylaxis • Propranolol 40mg tds • Aim to reduce HR by 25% • DEXA Scanning Surveillance for Bone Disease
Mr M.A 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 #femur, ankle ,toes PE Hypertension 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 ALP 146 U&E normal WCC 4.7 ALT 31 Plt 42 Bili 54 INR 1.7 Alb 32
USS “Irregular liver, splenomegaly, PV patent” Liver screen HBV sAg Endoscopy- OGD HCV Ab 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
7) Making a diagnosis of HCV infection and what to do about it?
20 Clear the HCV 80 Develop Chronic Hepatitis 20 No Harmful Effects 60 Signs/symptoms Age Gender Alcohol 20% at 20yrs 50% at 30yrs Liver Failure CIRRHOSIS 3.9% pa Liver Cancer 1.4% pa HCV- Natural History 100 Infected HCV Ab pos PCR neg PCR pos Transplantation
Prevalence of Hepatitis C virus 2001 WHO
Risk Factors Associated withTransmission of HCV • Injecting drug use • Transfusion or transplant from infected donor • Hemodialysis (yrs on treatment) • Accidental injuries with needles/sharps • Sexual/household exposure to anti-HCV-positive contact • Multiple sex partners • Birth to HCV-infected mother
UK HCV Prevalence <1% IV Drug Use Blood Donation 200,000 Migration
Historical Perspective • IFN monotherapy - SVR <20% • IFN 3MU s/c 3x week + Ribavirin po - SVR ~ 40%
Manns M et al Lancet 2001 1530 pts PEG IFN 1.5mcg/kg/wk +Ribavirin PEG IFN 1.5mcg/kg/wk For 4 wks then 0.5mcg/kg/wk +Ribavirin IFN 3MU 3xwk +Ribavirin
Mr RP 59y Architect Type 2 DM 15 yrs on diet alone BMI 35 Hypertension Amlodipine , Ramipril Minimal Alcohol
Mr RP • Generally unwell for 2 years • Cytopaenia • Low Hb/platelets • Normal haematological Ix (peripheral consumption) • May 07 • LGH admission with ataxia/drowsiness • Extensive Ix
Mr RP • CT abdo • cirrhotic liver, portal hypertension, splenomegaly • OPD referral • Alb 28, Pl 65, LFT’s normal, INR 1.5 • Imaging compatible with cirrhosis • Reversal of sleep pattern, lack of concentration • Daytime somnolence, intermittent confusion • OGD- varices
NAFLD • NAFLD is a spectrum of disease which includes Fatty liver disease and NASH, but only NASH is known to progress to cirrhosis. 2nd hit Fatty Liver Obese BMI>28 Centipetal (apple) Bright liver on USS Normal ALT 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
NASH Steatosis 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.
NASH Management All patientsshould be encouraged to exercise, as there is good evidence that even in the absence of weight loss exercise improves NASH. Diabetic Patients Good diabetic control (HbA1c <6.5%) Metformin Thiazolidinediones (glitazones) Dietician for re-education. Diabetologist if glucose control is difficult.
NASH Management Patients with Hyperlipidaemia and abnormal LFT’s Dyslipidaemia should be aggressively addressed Dietician Review Hypercholesterolaemia -Statins Hypertriglycerideaemia -Fibrate. Lipid Clinic Obese Patients Weight reducing diet (aim for 10%, 1-2lb per week) In patients with BMI>28 with risk factors, or >30 without risk factors, consider treatment with Orlistat. Avoid Drugs amiodarone, glucocorticoids, methotrexate, nifedipine, synthetic estrogens, tamoxifen
HBeAg Anti-HBe HBV-DNA ALT immunetolerance immuneclearance inactivecarrier reactivation Viral fluctuation patterns are different in different stages of the disease
Prevalence of HBeAg negative Chronic HBV in Italy HBeAg positive HBeAg negative 1975-85: 539 patients 2001: 837 patients 10% 58% 42% 90% Giusti et al, 1991 Gaeta et al, 2003
Inactive carrier? HBeAg(-) CHB Detection limit Inactive carrier Detection limit
1010 HBeAg (+) CHB 109 108 HBeAg (-) CHB 107 106 Serum HBV DNA (copies/ml) 105 104 103 Inactive Carrier State 102 10 HBV DNA Thresholds
How do we manage eAg neg patients in clinic? • HBV DNA every 3 months in the first year • If HBV DNA consistently <103 then see yearly • If HBV DNA >104 then consider Rx depending on the clinical situation • Low threshold for biopsy • If significant fibrosis then treat (whatever the DNA)