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

2. 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.

3. 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.

4. Liver function test (LFT)
Normal values

5. 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

6. 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

7. 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

8. 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

9. Common causes of raised transaminases

10. 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:
Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

11. 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

12. 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

13. 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:
Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

14. 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

15. Causes of raised GGT

16. 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

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

18. 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

19. 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

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

21. 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

22. 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

23. 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

24. 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

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

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

27. 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)

28. 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

30. 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)

32. 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

33. 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

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

38. 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

44. 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

47. 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

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

49. 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, Hepatology 2002;36(suppl 1): S3–20.
Lo Re V , and Kostman J R Postgrad Med J 2005;81:
Copyright © The Fellowship of Postgraduate Medicine. All rights reserved.

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

52. 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

55. 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

57. 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

59. 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

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

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

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

64. 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?

65. 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.

67. Thank you!