ABNORMAL LFT AND HEPATITIS UKM FAMILY MEDICINE TELECONFERENCE 21 JAN 2014 BY DR NURUL NADIA SUPERVISOR: DR NADIAH, PHYSICIAN HOSPITAL TUANKU JAAFAR SEREMBAN

General objectives The aim of this teleconference is to enable the postgraduate trainees to elaborate on the clinical approach to a patient with abnormal liver function test and discuss on the latest development in management of Viral Hepatitis, particularly chronic Hepatitis B and C.

Specific objectives Know how to approach patients with abnormal liver function test  Be able to discuss the diagnostic tools/methods available for patients with abnormal liver function test (especially for viral hepatitis A, B and C and fatty liver) Be able to identify the various viruses that could cause hepatitis and their peculiar course and prognosis of disease. Be able to outline on the management of patients with fatty liver and hepatitis especially A,B and C.

Liver function test (LFT) Normal values

LFT- bilirubin Formed from lysis of red cell Unconjugated bilirubin: bound to albumin, water insoluble Conjugated bilirubin: water soluble, appears in urine Parenchymal liver disease, biliary obstruction

Causes of isolated hyperbilirubinemia Unconjugated Conjugated Increased bilirubin production Hemolysis Ineffective erythropoiesis Blood transfusion Resorption of hematoma Decreased hepatic uptake Gilbert’s syndrome Drugs- rifanpicin Decreased conjugation Criggler-Najlar syndrome Physiological jaundice of newborn Dubin-Johnson Syndrome Rotor’s syndrome

LFT- albumin Low level with progressive liver disease reflecting decrease synthesis Level dependent on nutritional status, catabolism, hormonal factors, urinary/GI losses Albumin concentration does correlate with prognosis in chronic liver disease

LFT- aminotranferases Aspartate transaminase (AST) Found in liver, cardiac muscle, kidneys, brain, pancreas, lungs, leucocytes, red cells Less sensitive/specific Alanine transaminase (ALT) Highest concentration in liver More specific

Common causes of raised transaminases

Suggested algorithm for evaluating raised transaminases (ALT, alanine transaminase; HAV, hepatitis A virus; HCV, hepatitis C virus; PT, prothrombin time). Suggested algorithm for evaluating raised transaminases (ALT, alanine transaminase; HAV, hepatitis A virus; HCV, hepatitis C virus; PT, prothrombin time). Limdi J K , and Hyde G M Postgrad Med J 2003;79:307-312 Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

LFT- alkaline phosphatase Mainly from liver and bone Also present in intestine, kidney, placenta, leucocyte Elevation maybe physiological or pathological GGT is a good discriminator to identify source of ↑ALP, rise in liver but not bone disease

Causes of ↑ALP Physiological Pathological Women in 3rd trimester Adolescent Benign, familial (d/t ↑intestinal ALP) Bile duct obstruction Primary biliary cirrhosis Primary sclerosis cholangitis Drug induced cholestasis Adult bile ductopenia Metastatic liver disease Bone disease

Suggested algorithm for evaluating a raised ALP (ALP, alkaline phosphatase; ERCP, endoscopic retrograde cholangiopancreatography; GGT, gammaglutamyl transferase; PT, prothrombin time; MRCP, magnetic resonance cholangiopancreatography). Suggested algorithm for evaluating a raised ALP (ALP, alkaline phosphatase; ERCP, endoscopic retrograde cholangiopancreatography; GGT, gammaglutamyl transferase; PT, prothrombin time; MRCP, magnetic resonance cholangiopancreatography). Limdi J K , and Hyde G M Postgrad Med J 2003;79:307-312 Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

LFT- gammaglutamyl transferase Found in hepatocytes and biliary epithelial cells Sensitive test of hepatobiliary disease Usefulness is limited by lack of specificity Isolated ↑ GGT need to be followed up at few months interval If still persistent with abnormal AST/ALT further USS abd/ CT ± liver biopsy may be considered

Causes of raised GGT

International Normalised Ratio LFT- PT / INR Prothrombin Time International Normalised Ratio Measures rate of conversion of prothrombin to thrombin Prolonged in vit K deficiency, warfarin therapy, liver disease, consumptive coagulapathy Administration of vit K will reduce prolonged PT due to fat malabsorption but not due to intrinsic liver disease

History Recent travel Transfusion Drugs history including herbal Tattoos Unprotected sex Alcohol Occupation Medical hx: DM, obesity, dyslipidemia FHx

Examination Stigmata of chronic liver disease: icteric skin/ mucuos membrane, palmar erythema, bruising, spider naevi, gynecomastia Hepatomegaly Splenomegaly Ascites Obesity Any clues to the underlying cause e.g. lymphadenopathy Features suggestive of hepatic encephalopathy

Abnormal LFT- when to refer Unexplained liver abnormalities >1.5 time normal on 2 occasions, minimum of 6months apart Unexplained liver disease with evidence of hepatic dysfunction Known liver disease where treatment beyond withdrawal of the implicating agent is required

Tests to do before referal Viral hepatitis screening Antinuclear antibody Ceruloplasmin in <40y Iron studies Ultrasound of the liver especially suspected fatty liver

Hepatitis A Acute liver infection caused by a hepatovirus of the Picornavirus family hepatitis A virus 2nd most common vaccine preventable infection Most common form of viral hepatitis Associated with poor hygiene and overcrowding HAV is shed in stool of infected persons, can survive for weeks, can persist on hands for several hours and longer in food kept in room temperature, resistant to heat/freezing Transmission is via fecal/oral route, and can occur through direct person-person contact, occasional transmission through sexual contact and blood transfusion

Incubation period: 15-50 days Childhood infection is usually asymptomatic but in adult 75% develop icteric disease 4-10days of prodromal symptoms: fever, malaise, nausea, vomiting, weakness, anorexia Acute infection manifest as dark urine, followed by jaundice and pale stool 1-2 days later with gradual resolution of other symptoms

Malaise and anorexia may persist, hepatic discomfort and pruritus LFT usually normalise within a month Complications are unusual but rarely include fulminant hepatitis Chronic infection doesn’t occur but 10% have prolonged or relapsing symptoms over6-9 months

Hepatitis A - diagnosis Detection of anti HAV IgM in acute phase May from 3-6months after acute illness Anti HAV IgG indicates past infection or immunisation and likely to persist for life

Hepatitis A - treatment No specific Rx Supportive measures Usually with complete recovery

Hepatitis A - prevention Vaccine is recommended especially for travelers in endemic area Education on hygiene and food and water precaution

Hepatitis B Globally estimated 350mil persons chronically infected by hepatitis B virus Prevalence decrease with vaccination HBV is transmitted in blood and secretions infectious outside the body >7days Commonly acquired from infected mother (vertical transmission) or from family members (horizontal transmission)

HBV Double stranded DNA hepadnavirus HBV genome produces nucleocapsid contains hepatitis B core antigen (HBcAg) Has outer envelope called hepatitis B surface antigen (HBsAg) *for screening A segment of HBcAg results in production of hepatitis B e antigen (HBeAg) associated with viral replication and high infectivity

Hepatitis B- diagnosis Evaluation of patient’s blood HBcAg HBsAg HBeAg HBV DNA General liver investigations Liver biopsy- measure inflammation (current activity) and fibrosis (more chronic scarring)

Acute hepatitis B Acute infection may cause nonspecific symptoms: fatigue, poor appetite, nausea, vomiting, abdominal pain, low grade fever, jaundice, dark urine Physical exam: hepatomegaly, splenomegaly, liver tenderness Typically last 2-4 months Infants, child <5y, immunosuppressed adults usually asymptomatic In adult with healthy immune system, 95% of acute infection is self-limited and developed immunity <5% progress to chronic infection

Chronic hepatitis B Chronic necroinflammatory disease persists longer than 6 months Can be divided into HBeAg positive or negative Risk inversely related to age Occult HBV infection maybe reactivated by chemotherapy or immunosupressant Coinfection with HIV and HCV

Inactive HBsAg carrier state= persistent HBV infection of the liver without significant ongoing necroinflammatory disease

Treatment To reduce inflammation of the liver Prevent liver failure and cirrhosis Reduce risk of hepatocellular carcinoma by suppressing HBV replication Treatment is based on phase of infection Finite course of interferon therapy or long term viral suppression with neucloside/nucleotide analogue

Hepatitis C Leading cause for chronic liver disease Principal cause of death from liver disease and leading indication for liver transplant in the US Caused by hepatitis C virus single-stranded RNA virus Transmitted through percutaneous exposure of infected blood No vaccine

Most patients are asymptomatic Nonspecific symptoms: fatigue, nausea, anorexia, myalgia, arthralgia, weakness, weight loss Chronic infection leads to cirrhosis, increased risk of complication of liver disease: portal hypertension, ascites, hemorrhage, hepatocellular carcinoma

Factors associated with disease progression to cirrhosis Male Age >40 HIV or HBV coinfection Immunosupression Alcohol intake Hepatotoxic drugs

Natural history of hepatitis C virus infection.  Natural history of hepatitis C virus infection. Adapted from National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002-June 10–12, 2002. Hepatology 2002;36(suppl 1): S3–20. Lo Re V , and Kostman J R Postgrad Med J 2005;81:376-382 Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

Diagnosis HCV antibody enzyme immunoassay Recombinant immunoblot assay (confirmatory test) Quantitative HCV RNA PCR Liver biopsy

Treatment To slow or stop progression of fibrosis prevent complications and death recommended treatment: combination of pegylated interferon alfa and ribavirin Sustained virologic response used to evaluate effectiveness of therapy

Non alcoholic fatty liver disease (NAFLD) Definition evidence of hepatic steatosis by imaging or histology No causes for secondary hepatic fat accumulation Lack of alcohol consumption <21 drinks per week in men <14 in women

NAFLD Histologically can be divided into Nonalcoholic fatty liver (NAFL) = presence of hepatic steatosis with no evidence of hepatocellular injury Nonalcoholic steatohepatitis (NASH)= presence of hepatic steatosis and inflammation with hepatocyte injury with/without fibrosis

NAFLD - Management Treating liver disease and associated co-morbidities mainly for NASH To reduce aminotranferases and improve hepatic steatosis Lifestyle modification Diet - hypocaloric Exercise Weight loss

Metformin Thiazolidinediones Vitamin E Decrease in aminotransferases Improve in steatosis, inflammation, ballooning and resolution of steatohepatitis No effect on hepatic fibrosis

Ursodeoxycholic acid (UCDA), omega-3 fatty acids Bariartric surgery Statins are safe in patients with liver disease to treat dyslipidemia Reduce alcohol consumption

Treatment algorithm for NAFLD. Adams L A , and Angulo P Postgrad Med J 2006;82:315-322 Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

Case scenario 1 A 45 year-old lady comes for follow up for her Diabetes, Dyslipidaemia and Hypertension. She is asymptomatic. She is on Diamicron 80mg bd , Enalapril 10mg bd and Lovastatin 20mg ON, which she was on since 1 year ago. Her latest blood result shows HbA1c is 7%, FSL: TG is 2.1mmol/l , HDL is 1.0 mmol/l, LDL 4.1 mmol/l. Her liver function test shows ALT 66 iU/L (previously was 74). Other parameters in the liver function test are normal. How would you manage her?

Case scenario 2 A 30 year old man presents to the casualty with nausea, vomiting and general malaise for the past 4 days. Clinically he is jaundice with tender right upper quadrant. Proceed with your management.

Thank you!