Abnormal LFTs GP CME 2014 Workshop Fri 55 mins Dr Alasdair Patrick Macmurray Center GP CME 2014
Dr Alasdair Patrick Gastroenterologist
Overview Liver Function Tests Cholestasis Hepatocellular / Hepatitic Tests of Liver Synthetic Function Bilirubin, Albumin & INR Clinical aspects Cases Cirrhosis Middlemore Cirrhosis Audit
Normal Liver Anatomy Hepatic Artery Bile Duct Portal Vein Central Vein
Liver Function Tests (ULN) Nature of liver disease Synthetic Function Cholestasis ALP (110) GGT (60) Bilirubin (<24) Albumin (35-47) Prothrombin ratio (<1.2) Hepatitis ALT (45) AST (45)
Patterns of raised LFT s A purely cholestatic or purely hepatitic picture is uncommon Cholestatic ALT / ALP < 2 Mixed ALT / ALP 2-5 Hepatitic ALT / ALP > 5 [ Ratio = ALT (x ULN) / ALP (x ULN)]
Cholestatic Enzymes Alkaline phosphatase (ALP) Produced in many tissues Raised levels usually come from the biliary epithelium, bones, or placenta If GGT normal unlikely hepatic source Cholestasis causes increased synthesis of ALP and leakage of ALP in to the circulation
Cholestatic Enzymes Gammaglutamyl transpeptidase (GGT) Found in cell membranes throughout the body including hepatocytes and biliary epithelium Levels are not raised in bone disease or pregnancy 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 Cholestasis Bile duct obstruction Stones, tumour, surgery, parasites Drugs 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
Cholestasis Normal Stones & dilated CBD
Cholestasis Normal PSC
Hepatocellular 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
Hepatocellular 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
Hepatocellular Damage Acute Viral hepatitis EBV, HAV, HBV Drugs & herbal remedies Paracetamol OD Ischaemic / hypoxic Rare: Autoimmune (AIH) Wilson s disease, Budd Chiari Syndrome, AFLP Chronic (> 6 months) Viral hepatitis HBV, HCV Fatty liver (NALFD) EtOH (AFLD) Drugs Haemochromatosis Autoimmune Wilson s
Transaminases Rules of thumb Chronic liver disease - ALT & AST are usually only mildly elevated ( typically 1.5-3 x ULN) - May be normal Ratio AST / ALT ratio is < 1 in most liver disease Alcohol related hepatitis is the exception where the ratio is usually > 2 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 Levels < 10x ULN are non-specific
Causes: Transaminases > 1000 IU / L Ischaemic hepatitis (shock) Acute viral hepatitis HAV, HBV Drugs Paracetamol OD, halothane, Carbemazepine [Alcoholic hepatitis ALT & AST < 300 IU/L]
Two primary sources Bilirubin Indirect (unconjugated): old red cells, removed by the spleen, sent to the liver Liver adds glucuronic acid, making these cells water soluble for excretion; now called direct (or conjugated)
Synthetic Function 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); if conjugated - hepatobiliary diseases Only conjugated (direct) bilirubin can be excreted in the urine Unconjugated hyperbilirubinaemia may occur due to over production of bilirubin (haemolysis) or inherited disorders of bilirubin conjugation (Gilbert s syndrome)
Bilirubin and 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 (stone disease) 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
Synthetic Function Albumin Made in the liver (30g/day) Quantitatively the most important protein in the blood (500g in body fluids), important role in maintaining colloid osmotic pressure 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
Synthetic Function 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
PR/INR In chronic liver failure 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 transplanation 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
LFT s & Liver Failure Acute (FHF) ALT & AST usually > 1,000 INR & Bilirubin rise rapidly Alb falls rapidly Patient unwell for hours or days Death within days of cerebral oedema, sepsis or multi-organ failure Chronic (Cirrhosis) ALT & AST usually < 200 INR & Bilirubin rise slowly Alb falls slowly Patient unwell for months or years Death from variceal haemorrrhage, sepsis, encephalopathy or other complications
Clinical aspects Please call out what these signs are!!
Examination Findings Dupytrons Contracture
Examination Findings Palmar Erythema
Examination Findings Gynaecomastia
Examination Findings Spider Naevi
Patient with abnormal LFTs History Alcohol: try to quantify Blood products or IVDU Past history Diabetes, hyperlipidaemia Medications Including OTC Paracetamol, Amoxicillin-clavulanic acid, erythromycin, HMGCoA reductase inhibitors, NSAIDS Family history Travel history
Questions to ask yourself Is the illness a primary liver disorder or is it secondary to another condition? Clue can be in the LFTs Is the source of the liver test extra-hepatic? An abnormality of a single test may be due to a non hepatic cause Is this an acute illness or chronic? If chronic, is it compensated or decompensated? Do the tests signify a serious illness? What is the diagnosis and prognosis?
Suggested work up Screen Fasting lipids and glucose Viruses HBV HCV (EBV CMV) Auto immune markers ANA, AMA, SMA Immunoglobulins Coeliac serology, Iron studies, Thyroid function tests USS focal lesions, fatty liver, portal hypertension Second run Alpha one anti-trypsin, Copper and ceruloplasmin in pt <40, Anti LKM, SLA
Case 1: AS23 Unwell 2 days Abdominal pain and lethargy Depressed but otherwise well OE: Jaundiced, No signs of CLD LFTs Bil 250 ALP 160 GGT 200 ALT 2380 AST 1960 Thoughts?
Case 1: AS23 Other Bloods: 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 1: AS23 Paracetamol Treatment Nomogram x
Paracetomol overdose 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
Paracetomol overdose Follow up Gradual improvement of LFT s and synthetic function Treatment Close Observation Frequent Blood test repeat Rx n-acetyl cysteine (NAC) Psychiatry
Case 2: GH66 Gradual Itch Previous autoimmuine thyroid disease OE: Normal apart from scratch marks LFT s Bil 15 ALP 502 GGT 438 ALT 65 AST 48 Thoughts?
Case 2: GH66 Other Bloods: INR 1.0, Alb 40 Liver Screen AMA Positive, ANA 1:80 Imaging USS: Normal Pattern of LFT Disturbance Choleststatic picture with preserved synthetic function Diagnosis Primary Biliary Cirrhosis
Primary biliary cirrhosis Auto-immune disease of the liver Slow progressive destruction of small bile ducts Female to male ratio 9:1 Prevalence 1:4000
Primary biliary cirrhosis Treatment Ursodeoxycholic acid Reduce the cholestasis - improves LFT s results Minimal effect on symptoms Whether it improves prognosis is controversial Cholestyramine (bile acid sequestrant) Absorb bile acids in the gut Alternative agents: Naltrexone & Rifampicin Ongoing follow up
Case 3: GF 56 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 Thoughts?
Case 3: GF 56 Other Bloods: INR 1.8, Albumin 30 Pattern of LFT Disturbance Mixed, significant hyperbilirubinaemia, AST>ALT Liver Screen Negative Imaging USS: Coarse Liver Echotexture Diagnosis Alcoholic Hepatitis
Alcoholic hepatitis
Alcoholic hepatitis Treatment Abstinence from Alcohol Monitor for withdrawal Vitamin K In Hospital 3 weeks Good improvement Prednisone 30mg Daily for 4 weeks Cirrhosis follow up
Case 4: 22 Chinese lady who says she has Hep B ALT normal sag +ve, eag +ve, anti HBE ve HBV DNA 10*9 What would you do? Watch 6/12ly and get flare and seroconverts
Case 5 47 year old Indian man Ex boozer ALT 55 What else would you check? HBsAg positive HBe Ag-ve, anti HBe +ve What would you do now? Rpt 6/12 ALT 127 What would you do now? Fibroscan- cirrhosis
Viral Hepatitis
Viral Hepatitis : Hepatitis A Food, water borne; heat labile Faecal - oral contamination; contagious Usually self limited, lasting days to weeks 99% spontaneous recovery, no treatment Tests: HAV IgM antibody = acute infection HAV total antibody (IgM & IgG) = exposure only, could be post infection or vaccination
Viral Hepatitis : Hepatitis B Blood, semen, saliva, vaginal secretions Highly contagious; sexually transmitted 90-95% self limited over 6 months Chronic infection: >6 months DNA virus: incorporates into host with chronic infection
Viral Hepatitis : Hepatitis B HBV at risk groups (who to test) Maori, Pacificans, Asians, contacts of those with HBsAg patients, IVDU, MSM Abnormal liver function tests
HBV Serology HBV s Ag: surface antigen; + infection HBV s Ab: surface antibody; - infection HBV c Ab: core antibody IgM, IgG; only + with infection, not vaccination HBV e Ag: envelope antigen; if + actively replicating virus HBV DNA: actual viral load in blood
Serologic markers of infection and their significance Acute hepatitis B Recovery from acute hepatitis B Chronic HBeAg + disease Chronic HBeAg disease Successful vaccination HBsAg Anti-HBs Anti-HBc IgM Anti-HBc IgG HBeAg Anti-HBe (in some cases) DNA (PCR if required)
HBV Treatment Decision E- Antigen Status Likelihood of progression ie significant fibrosis now Likelihood of adhering to treatment Lamivudine (not first line) Entecavir Adefovir (Lam Resistant) Tenofovir Pegylated interferon
Why treat Hepatitis B? To prevent complications of cirrhosis ie decompensated cirrhosis and its complications eg HCC Ultimate Goal cure, permanent suppression, roadmap concept Once decision made, more or less life long
Viral Hepatitis : Hepatitis C Blood borne, not in food or water; not highly sexually transmitted* Not highly contagious 20% self clearing; 80% chronicity RNA virus: does not incorporate into host
Viral Hepatitis: Hepatitis C HCV Ab: + means past exposure; can take 3-6 months to form; not found if acute ELISA: used to confirm Ab; + rules out false positives HCV PCR RNA: confirms actual viral presence in blood; can be +/- or a viral count (qualitative vs. quantitative) HCV Genotype: there are at least six (6) different (geno)types of HCV virus
Viral Hepatitis : Hepatitis C HCV Genotypes: different mutations of same virus (different branches, same tree) Can vary by global geography Not predicative of damage or symptoms Can predict response to treatment Can be used to determine who is the best treatment candidate G1 & 4: most stubborn; G2 & 3: most responsive; G5 & 6: most rare
HCV: When to refer to a HCV Ab + RNA + specialist Suitability for treatment alcohol use, ongoing drug use, motivation, mental state eg depression (consider SSRI at the time of referral) Treatment improving all the time Expect 70-90% cure with new drugs
Case 5 Asymptomatic 40 year old man Screening LFTs Bili 38 ALT 15 IU/ml ALP 85 GGT 30 Alb 36 What other information would be helpful?
Case 5 Otherwise well No alcohol No family history What bloods would you check? Diagnosis: Gilberts syndrome How could you confirm this? unconjugated hyperbilirubinaemia Often increases in infections but also on starving
Case 6 46 year old European man Feeling tired Gaining weight Wt 120kg, BMI 32 Occasional alcohol LFTs T bili 20 GGT 198 ALP 88 AST 40 ALT 65 Thoughts?
Non-alcoholic fatty liver disease (NAFLD) Spectrum of severity Mild fatty infiltration Non-alcoholic steatohepatitis Fibrosis, cirrhosis Most common cause of abnormal LFT s in primary care Hepatic manifestation of metabolic syndrome
Associated with NAFLD Obesity - central Type-2 diabetes Hypertension Hypertriglyceridaemia FHx of type-2 DM common in absence
NAFLD Thought to affect up to 24% population 70% of obese 50% of type-2 DM Mostly benign. Cirrhosis and hepatocellular carcinoma? Cirrhosis risks - age, obesity, DM
Symptoms NAFLD - Clinical Usually none Fatigue, RUQ discomfort Laboratory Elev GGT and ALT If AST > ALT suspect ETOH, or cirrhosis if denied Elev TG/Chol, glucose USS (CT also)
Hepatomegaly Altered echogenicity Ultrasound Can t distinguish mild form from steatohapatitis/cirrhosis
Differential Should exclude other causes Viral hepatitis Drugs - esp alcohol Autoimmune (ANA, SMA) Metabolic (iron, copper) High ferritin with normal transferrin saturation common in NAFLD If saturation >45% ---> HH studies in Caucasians Investigate for metabolic syndrome if not known Almost always assoc with insulin resistance High risk of type 2 diabetes
Role of liver biopsy Not clearly elucidated Consider in Pts at risk severe disease Concerning lab studies AST>ALT, low platelets
Not really known Management Evidence accumulating that reducing BMI and improving insulin resistance with diet/exercise can reverse Some evidence that there are promising drugs coming Bariatric surgery?
Aim 0.5-1kg/wk Weight loss Faster can precipitate steatohepatitis or gallstones Decrease refined sugars Increase fibre Cholesterol improving and DM diet
Exercise Increases oxidative capacity of myocytes Increases insulin sensitivity Check LFTs monthly Should see improvements in 2-3/12
Metformin Insulin resistance Improves insulin sens of all tissues Improves transaminases in NASH Reverses fatty liver in mice Glitazones Other classes under investigation
Statins Lipids Reduce LDL and TG Improves LFTs in NASH Fibrates Gemfibrozil Increases HDL, decreases TG Modest effect only on NASH
Helpful points Fatty liver can lead to cirrhosis Females and elderly do worse Often asymptomatic USS usually sufficient for diagnosis No established treatment Steady weight loss first line if obese Rapid weight loss may be dangerous
Cirrhosis Normal Cirrhosis
Liver 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 - 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)
Survival according to Child- Pugh Score POINTS 1 2 3 Encephalopathy None Grade 1, 2 Grade 3, 4 Ascites None Mild Moderate Bilirubin < 35 35-50 > 50 Albumin > 35 28-35 < 28 INR < 1.3 1.3 1.5 > 1.5 Grade Score 1 year 5 year 10 year A 0 6 84% 44% 27% B 7 9 62% 20% 10% C 10-15 42% 21% 0% Pugh et al. Br J Surg, 1973
Middlemore Hospital Audit - Cirrhosis New patients presenting each year 2011 2010 2009 2008 2007 2006 2005 2004 2003 2002 2001 Before 2001 Number Linear (Number) 0 20 40 60 80 100 Gerred et al. 2012
Y e a r Cirrhosis: Patients removed from the database 2 0 1 1 2 0 1 0 2 0 0 9 2 0 0 8 2 0 0 7 2 0 0 6 2 0 0 5 2 0 0 4 2 0 0 3 2 0 0 2 2 0 0 1 p r e 2 0 0 1 T ra n s p la n te d L o s t o r m o v e d D e c e a s e d 0 2 0 4 0 6 0 8 0 C a s e s w ith d ra w n fro m F o llo w -u p Gerred et al. 2012
Cirrhosis: Number of patients under Follow-up 2011 2009 2007 2005 Number Linear (Number) 2003 2001 0 100 200 300 400 500 Gerred et al. 2012
Y e a r o f p re s e n ta tio n Cirrhosis New Case Aetiology 2 0 1 1 2 0 1 0 2 0 0 9 2 0 0 8 2 0 0 7 2 0 0 6 2 0 0 5 2 0 0 4 2 0 0 3 2 0 0 2 2 0 0 1 O th e r N A F L D H C V H B V A L D 0 5 0 1 0 0 1 5 0 N u m b e r o f N e w C a s e s Gerred et al. 2012
Cirrhosis: Primary Aetiology and Gender Number of patients 250 200 150 100 50 Male Female M ale F emale 0 HBV HCV ALD NAFLD Other Primary Aetiology of Cirrhosis 35% 20% 18% 14% 12% Gerred et al. 2012
A g e Cirrhosis: Age of presentation & 8 0 Aetiology 7 0 6 0 5 0 P <0.001 4 0 3 0 A L D H B V H C V N A F L D A e tio lo g y Gerred et al. 2012
A g e Cirrhosis: Race 8 0 6 0 4 0 5 5 y rs 5 9 y rs 5 7 y rs 5 2 y rs 5 6 y rs 2 0 A s ia n E u r o p e a n In d ia n M a o r i P I E th n ic ity Gerred et al. 2012
E th n ic ity Aetiology of Cirrhosis and Ethnicity P I M a o r i In d ia n O th e r N A F L D H C V H B V A L D E u r o p e a n As ia n 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 N u m b e r o f c a s e s Gerred et al. 2012
P e rc e n t s u rv iv a l Cirrhosis: Survival & Aetiology 1 0 0 C h a r t-5 : S u r v iv a l & A e tio lo g y 8 0 6 0 A L D H B V 4 0 H C V N A F L D 2 0 P<0.001 0 0 5 1 0 1 5 Y e a rs o f F o llo w -u p Gerred et al. 2012
P e rc e n t s u rv iv a l Cirrhosis: Survival & Ethnicity C h a r t-4 : S u r v iv a l & E th n ic itie s 1 0 0 8 0 In d ia n M a o ri P a c ific 6 0 4 0 A s ia n E u ro p e a n 2 0 P=0.002 0 0 5 1 0 1 5 Y e a rs o f F o llo w -u p Gerred et al. 2012
Cirrhosis: Complications - 4yr FU Variceal bleed ALD HBV HCV NAFLD 24% 6% 10% 18% SBP 12% 6% 7% 6% Ascites 57% 24% 21% 34% Encephalop athy 35% 11% 13% 14% HCC 11% 25% 13% 13%
Transplant and death - 4yr FU ALD NAFLD HBV HCV OLT 2% 3% 7% 6% Liver Death Other Death Total Death 22% 17% 20% 12% 26% 18% 7% 7% 48% 35% 27% 19%
HCC Surveillance Period (-1:1 st 6 months, -2:2 nd 6 months)
Cirrhosis Middlemore - Conclusions Number of Cirrhotic patients under follow-up has quadrupled in the last 10 years HCV and NAFLD are driving rising numbers of new cases in recent years Generally patients with cirrhosis are living longer but death and complications remain common Poor prognosis in Maori despite predominantly HBV and young Poor prognosis in ALD and NAFLD - older and sicker at presentation
Take home messages: Patient care Jaundice and evidence of liver failure Immediate discussion and consider admission Jaundice, no liver failure Immediate discussion?admission Urgent USS, (haemolysis screen) Major elevation ALT/ AST (10 X ULN) Immediate discussion?admission Repeat and review within 24 hours with synthetic function
Take home messages: Patient care Moderate elevation LFTs (5 X ULN) INR, Bilirubin, early Repeat with 48 hours with liver screen Early referral Evidence of cirrhosis, no liver failure Abnormal LFTs, abnormal USS, low platelets Early referral with liver screen
Take home messages: Patient care Mild Elevation of LFTs (2-3x ULN) Repeat Liver screen USS Referral A methodical approach will usually yield the diagnosis!
Dr Alasdair Patrick Gastroenterologist