LIVER DISEASES
LEARNING OBJECTIVESLiver function tests Viral Hepatitis Autoimmune hepatitis Primary Biliary Cirrhosis Hemochromatosis Wilsons
Complications of end stage liver disease Ascites SBP Hepatorenal Syndrome Encephalopathy
LIVER FUNCTION TESTS
ALT AST (SGOT) ALKALINE PHOSPHATASE BILIRUBINALT and AST
Enzymes, found in Hepatocytes Released when liver cells damaged ALT is specific for liver injury AST (SGOT) is also found in skeletal and cardiac muscleTransaminitis: < 5 x normal
ALT predominantChronic Hep B / CAcute A-E, EBV, CMVSteatosis / SteatohepatitisHemochromatosisMedications / ToxinsAutoimmune HepatitisAlpha-1-antitrypsinWilson’s DiseaseCeliac Disease AST predominant Alcohol-related liver dz Steatosis/ Steatohepatitis Cirrhosis Non-hepatic source Hemolysis Myopathy Thyroid disease Strenuous exerciseSevere AST & ALT Elev: >15x
Acute Viral Hepatitis does not predict outcome Bili > 20 poor prognosis Ischemic Hepatitis hypotension sepsis hemorrhage MIAutoimmune HepatitisWilson’s DiseaseAcute bile duct obstrHepatic Artery ligationBudd-Chiari SyndromeMedications / ToxinsacetaminophenCCl4
ALKALINE PHOSPHATASE
Found in hepatocytes that line the bile canaliculi Level is raised in Biliary obstruction (causes stretch of the bile canaliculi) BUT also found in BONE and PLACENTA GGT is also found in bile canaliculi and therefore can be used in conjunction with Alk Phos for predicting liver origin BUT GGT can be raised by many drugs including Alcohol and therefore non specific
BILIRUBIN
Water insoluble product of heme metabolism Taken up by liver and conjugated to become water soluble so it can be excreted in bile and into bowel. Patient looks Jaundiced if bilirubin >2.5 If patient is vomiting GREEN, then they have bowel obstruction below the level of the Ampulla of Vater.WHAT IS THE DEAL WITH DIRECT AND INDIRECT BILIRUBIN?
Prehepatic disease (eg hemolysis) causes high bilirubin which is non conjugated ie. Indirect fraction higher Hepatic disease causes increased conjugated and unconjugated bilirubin Post hepatic disease eg. Gallstones have increased conjugated (direct) bilirubin and lead to dark urine and pale stool.So these are markers of liver disease but are they tests of liver function?
NO!TESTS OF LIVER FUNCTION
PROTHROMBIN TIME/ INR ALBUMINPROTHROMBIN TIME/INR
Measure of the Vitamin K dependent clotting factors ie. II, VII, IX and X. The liver is involved in activating Vitamin K. Therefore in liver damage, these clotting factors cannot be produced. Before you believe that prolonged INR is due to liver disease just make sure the patient has adequate Vitamin K by giving 10mg sc. Giving Vitamin K has no effect on INR if patient has impaired synthetic function.ALBUMIN
Albumin has a half life of 21 days, so the drop that occurs with hepatic dysfunction does not occur acutelyThat said, acute illness can cause albumin to drop rapidly – a process thought to be due to cytokines increasing the rate of albumin metabolismHOWEVER, don’t forget that low albumin also occurs in NEPHROTIC syndrome, so always check the urine for protein.TYPICAL PATTERNS
HEPATOCELLULAR Increased transaminases Viral Hepatitis Drugs/alcohol Autoimmune NASH Hemochromatosis
CHOLESTATIC Increased Alk Phos and Bilirubin Also may cause increased transaminases Gallstones Primary Biliary Cirrhosis Sclerosing Cholangitis Pancreatic C/a
Alcoholic Liver Disease
AST > ALT2:1 - 3:1 ratioAST < 300Why the discrepancy?ETOH AST synthesisVit B6 def inhibits ALT ETOH Steatosis 90- 100% hepatitis 10- 35% cirrhosis 8- 20% GGTVIRAL HEPATITIS
All exam questions rely on you understanding that acute infection has IgM antibodies and chronic has IgGViral Hepatitis
NoneInterferon +
Interferon Ribavirin
IFN Lamivudine
NONE
Therapy
NONE
HBV vaccine
NONE
Immune globulin Recombinan vacc
Immune globulin Inactivated vacc
Prophylaxis
+
+
+
HCCancer
1 – 2%None 5 – 20 %Common 0.1 %Infect 80-90%Hepatitis –70% 0.1 – 1 %Neonates 90%Adults 1-10% 0.1 % None
Clinical Fulminant Progression to chronicity
Fecal - oral
+++ + ++
+++ variable +
Parenteral +++ Perinatal +++ Sexual ++
Fecal – oral Transmission
Acute
Acute / insidious
Insidious
Acute / insidious
Acute
Onset
4 – 12 weeks 7 weeks
4 – 12 weeks
Incubation
HEV
HDV
HCV
HEPATITIS A
RNA VirusFecal-oralIncubation 15-50 daysAnti -Hepatitis A IgM present during acute illness. TX/Prevention: Vaccine, Immune serum globulin for contactsPx: Good – doesn’t become chronic rarely fulminant liver failure.HEPATITIS B
DNA Virus Consists of surface and core Core consists of Core antigen and e-antigen Most infections are subclinical, but can present with arthralgias, glomerulonephritis, urticaria Parenteral or sexual transmission.Hepatitis B continued
Hepatocellular necrosis occurs due to the body’s reaction to the virus rather than due to the virus itselfTherefore patients who have a severe illness from hep B are more likely to clear the virus. SEROLOGY: Remember Acute infection has IgM chronic has IgGAnti Core IgM is present during acute phaseAnti Core IgG indicates chronic infection. Patients with Hep B e Ag have continued active replicationImmunized or previously exposed people have Negative HBsAg and HBeAg, they have IgG Anti HB Core, and Positive anti Hep Bs and e.Serological Patterns of Acute & Chronic Hepatitis B
Hepatitis C
RNA virus Blood bourne ie. Transmission from IV drug use and transfusion of blood products prior to 1990. Can also be transmitted by snorting cocaine. Sexual transmission is low. Testing involves Anti HCV Antibody, and then viral load if positive. 85% of patients develop chronic infection.
Complications of Hep C
Cirrhosis Hepatocellular carcinoma Cryoglobulinaemia Prophyria cutanea tardaManagement of Hep C
Interferon alpha with ribavirin for 6 to 12 months clears virus in approx 40% of patients. There is an algorithm which is used to decide who is treated, but basically anyone with Hep C, high ALT and less than 40 yo. If older than 40 should have biopsy first which should at least show periportal inflammation or fibrosis.New Direct Antivirals NS5A INHIBITORS Sofosbuvir simeprivir Daclatasavir Ledipasvir
Other issues re. Hep COnce pt with Hep C is cirrhotic their risk of developing hepatocellular Ca is 1-4% per year Alcohol increases risk
Other viral hepatitis
Hep E: Acute hepatitis just like hep A unless you are PREGNANT in which case can progress to fulminant hepatitis EBV, CMV, Herpes viruses can all cause acute hepatitis especially in immunocompromised.Three “autoimmune” liver diseases They are easily confused: Autoimmune hepatitis Primary Biliary Cirrhosis Primary Sclerosing Cholangitis
AUTOIMMUNE HEPATITIS
ANA positive Anti smooth muscle positive High bilirubin and ALT but normal Alk Phos (cf. Primary biliary cirrhosis) Presentation: tiredness, anorexia, RUQ pain, cushingoid facies despite no exogenous steroids. Stigmata of liver disease Pathology: Piecemeal necrosis with lymphocyte infiltration Tx: immunosupression, liver transplant Complications: All the complications of chronic liver diseasePrimary Biliary Cirrhosis
Increased Alk phos and Antimitochondrial positive Damage to intralobular bile ducts by chronic granulomatous inflammation Associated with other autoimmune diseases (Thyroid, RA, Sjogrens, Systemic Sclerosis) NB. See granulomas on Bx not piecemeal necrosis Unable to excrete bile, therefore present with malabsorption of fat soluble vitamins. And with evidence of portal hypertension. Present with lethargy, itching and increased Alk Phos in a middleaged woman. May have hyperlipidaemia Consider in any patient with autoimmune disease presenting with liver disease.NASH
Non-Alcoholic Steatohepatitis Common cause of elevated liver function tests Often patients have metabolic syndrome with obesity, hyperlipidemia and diabetes 20-30% progress to cirrhosis Weight loss, control of lipids and diabetes should reduce progression.Genetic Liver disease
Wilsons Hemochromatosis Alpha-1-Antitrypsin deficiencyHemochromatosis
Autosomal recessiveGene on Chromosome 6Increased Fe absorption from gut, depositied in tissues causing fibrosis and functional failure.Presentation: “BRONZE DIABETES”, but also arthralgias, Hepatosplenomegally and stigmata of liver disease, testicular atrophy, CCF due to restrictive cardiomyopathyDx: High Fe and Ferritin, low TIBC, Low testosterone, Diabetic. Joint XRays show chondrocalcinosisDual energy CT scan shows iron overloadLiver Bx shows Fe stainingNB. Hemochromatosis can be secondary to B Thalassemia and repeated blood transfusions.Skin color of Hemochromatosis
What is this sign called and what is it associated with ?
Wilson’s Disease Autosomal Recessive Deletion on Chromosome 13 Defective intrahepatic formation of caeruloplasmin therefore failure of biliary excretion and high total body and tissue levels of copper. Dx High serum caeruloplasmin, increased urinary copper. PRESENTATION: Cirrhosis, Kaiser-Fleischer rings, hypoparathyroidism, arthropathy, Fanconi syndrome (renal tubular acidosis) CNS: Psychosis, extrapyramidal syndrome, mental retardation and seizures. Think of this in a young patient with strange neurology and liver disease Tx: Copper chelation with penicillamine, can cure with liver transplant BUT the CNS sequalae will not resolve.Hepatocellular Carcinoma
Risk factors: Hep B and C, Cirrhosis of any cause, Exposure to Aspergillus Flavus toxinScreening – Alphafetoprotein should be checked annually in patients with cirrhosis. Need USS if highLess than 15% are resectable at diagnosis.What is the sign…and who was it named for?
MedusaStigmata of liver disease
HANDS: Palmar Erythema Clubbing Dupytrens Leuconychia FLAPPING TREMOR HEENT/UPPER BODY Jaundice Spider Angiomata Gynaecomastia and scant body hair Scratch marks ABDOMEN Ascites Hepatosplenomegally Caput Medusa Hemorrhoids on PR Small testesCirrhosis
4 Stages Liver cell necrosis Inflammatory cell infiltate Fibrosis Nodular regeneration which may be macronodular (alcohol), micronodular (viral) or mixedCirrhosis
4 Stages Liver cell necrosis Inflammatory cell infiltate Fibrosis Nodular regeneration which may be macronodular (alcohol), micronodular (viral) or mixed
CAUSES OF CIRRHOSIS
Alcohol Viral B/C Cryptogenic Primary Biliary Cirrhosis Hemochromatosis Wilsons Alpha 1 antitrypsin deficiency Autoimmune Sclerosing CholangitisCOMPLICATIONS
Portal Hypertension causing variceal bleed Splenomegally causing low platelets Ascites Encephalopathy SBP Hepatorenal syndromeAscites
Accumulation of free fluid in peritoneumAssessment involves taking sample of fluid and checking albumin contentSAAG: Serum Ascites Albumin GradientSAAG = Serum Albumin – Ascites AlbuminSAAG
HIGH ie. ≥1.1Portal hypertension presentCirrhosisAlcoholic hepatitisCongestive cardiac failureHepatic mets LOW ie <1.1 Inflammatory causes Peritoneal carcinomatosis Peritoneal TB Pancreatitis SerositisManagement of Ascites
Salt Restrict Fluid Restrict Diuretics Spironolactone 100-200mg /day to increase urinary sodium excretion. Aim to reduce weight by 1Kg per day May also need Lasix Large volume paracentesis Should give 6g Salt poor Albumin per liter of Ascitic fluid removed in patients with HIGH SAAG otherwise can cause precipitous fall in BP and Hepatorenal syndrome.Variceal Hemorrhage
Varices develop at Esophagogastric junction due to portal hypertension First bleed has 10-30% mortality Early endoscopy band ligation Octreotide decreases the portal pressure and may stop the bleeding 80% rebleed within 2 years B blockers esp Propranolol reduce portal pressure and may prevent rebleeding Serial endoscopy and banding to obliterate the varices is also indicated to prevent rebleeding