Evaluation of Abnormal Liver Function Tests

Dr Florencio Dizon

Liver Function Test

classified in 3 groups synthetic function : albumin, PT hepatocyte injury : AST, ALT cholestasis : bilirubin, ALP, GGT PT, albumin, bilirubin-most common tests used as prognostic factors

Liver Function Test

Liver chemistry test ALT Clinical implication of abnormality Hepatocellular damage

AST
Bilirubin ALP PT

Hepatocellular damage
Cholestasis, impair conjugation, or biliary obstruction Cholestasis, infiltrative disease, or biliary obstruction Synthetic function

Albumin
GGT

Synthetic function
Cholestasis or biliary obstruction

Bile acids
5`-nucleotidase LDH

Cholestasis or biliary obstruction

Cholestasis or biliary obstruction Hepatocellular damage, not specific

Liver Function Test

Mild (times)
AST ALT ALP GGT <2-3 <2-3 <1.5-2 <2-3

Moderate (times)
2-3 to 20 2-3 to 20 1.5-2 to 5 2-3 to 10

Marked (times)
>20 >20 >5 >10

Initial Approach
history and physical examination algorithm approach useful mainly when no clinical clues
history patients symptoms risk factors for liver disease concomitant conditions medications occupational exposure to hepatotoxins physical examination body habitus splenomegaly ascites cutaneous stigmata of chronic liver disease

Albumin
depend on nutrition, volume status, vascular integrity, catabolism, hormone, malabsorption, proteinuria not specific for liver disease T1/2 19-21 D
not reliable indicator of acute liver disease

Globulin
produced by stimulated B lymphocyte elevation in chronic liver disease chronic inflammation and malignant disease

Prothrombin time
liver synthesize coagulation factor except FVIII most present in excess, clotting abnormal occur only when substantial impairment in ability of liver to synthesis PT : FI, II, V, VII, IX and X T1/2 FVII 6 hrs. (shortest) prognosis : acute, chronic hepatocellular disease

Prothrombin time
prolonged : vitamin K deficiency (malnutrition, malabsorption, antibiotics) massive transfusion congenital disease liver disease warfarin DIC

Prothrombin time
in vit K deficiency, vit K 10 mg SC decrease prolong PT >30% within 24 hrs.

most frequent used markers of hepatocellular necrosis, but not correlate with eventual outcome decrease : recovery or poor prognosis
poor prognosis : rapid fall with rising of bilirubin and PT

AST and ALT

AST catalyze transfer amino groups to form pyruvate cytosol (20%) and mitochondria (80%) T1/2 17 hr. (cytosol) 87 hr. (mitochondria) liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leucocytes, and RBC

ALT catalyze transfer amino groups to form oxaloacetate cytosol T1/2 47 hr. low concentration in other tissues

AST, ALT
level of transminase elevation predominant AST elevation rate of transaminase declination

ALT and AST >15 times : acute hepatic injury

5-15 times : less useful <5 times : chronic hepatic injury improved acute hepatic injury

AST/ALT ratio
< 1 : majority of liver disease >2
extrahepatic source alcoholic hepatitis ischemic and toxin acute Wilsons disease : hemolysis cirrhosis

>4 : fulminant Wilsons disease

Rate of Transaminase Declination

rapid ischemic short half life drug acute biliary tract obstruction fulminant hepatitis

slow acute viral hepatitis long half life drug AIH metabolic disease

Risk factor of chronic viral hepatitis

injection drug use birth to mother with HBV blood transfusion prior to 1992 needle stick from a donor subsequently testing positive for HBV or HCV chronic hemodialysis unvaccinated health care workers homosexual body piercing or tattooing

ALT and AST < 5 times

discontinue all nonessential medications if mild elevation and essential medications must be continued
if liver enzyme elevations continue to rise, suspect medication should be stopped long-term effects of chronic, medication induced hepatotoxicity are lacking for many drugs

Mild Transaminitis
AST/ALT < 5 times upper limit of normal Etiologies
Hepatic: ALT-predominant Chronic Hep C Hemochromatosis Chronic Hep B Medications/Toxins Acute viral hep Autoimmune Hep Steatosis Alpha1 Antitrypsin Def Wilsons Disease Celiac Disease

Mild Transaminitis
Hepatic: AST predominant
Alcohol Steatosis Cirrhosis

Non-hepatic
Hemolysis Myopathy Thyroid disease Strenuous exercise

Gamma-GT hepatocytes and biliary epithelial cells,

pancreas, renal tubules and intestine Very sensitive but Non-specific Raised in ANY liver discease hepatocellular or cholestatic Usefulness limited Confirm hepatic source for a raised ALP Alcohol Isolated increase does not require any further evaluation, suggest watch and rpt 3/12 only if other LFTs become abnormal then investigate

Markers of Cholestasis

ALP liver and bone (placenta, kidneys, intestines or

WCC) Hepatic ALP present on surface of bile duct epithelia and accumulating bile salts increase its release from cell surface. Takes time for induction of enzyme levels so may not be first enzyme to rise and half-life is 1 week. ALP isoenzymes, 5-NT or gamma GT may be necessary to evaluate the origin of ALP

Bilirubin, Albumin and Prothrombin time (INR)

Useful indicators of liver synthetic function In primary care when associated with liver disease abnormalities should raise concern Thrombocytopaenia is a sensitive indicator of liver fibrosis

Patterns of liver enzyme alteration

Hepatic vs cholestatic Magnitude of enzyme alteration (ALT >10x vs minor abnormalities)

Rate of change
Nature of the course of the abnormality (mild fluctuation vs progressive increase)

Patterns of liver enzyme alteration

Acute hepatitis transaminase > 10x ULN Cholestatic

Mild rise in ALT

Acute hepatitis (ALT>10xULN)

Viral Ischaemic Toxins Autoimmune Early phase of acute obstruction

Acute hepatitis (ALT>10xULN)

Viral Hep A, B, C, E, CMV, EBV ALT levels usually peak before jaundice appears. Jaundice occurs in 70% Hep A, 35% acute Hep B, 25% Hep C Check for exposure Check Hep A IgM, Hep B core IgM and HepBsAg, Hep C IgG or Hep C RNA

Acute hepatitis (ALT>10xULN)

Ischaemic- sepsis, hypotension ?most common cause in-patients Often extremely high >50x Decrease rapidly LDH raised 80% Rarely jaundiced

Acute hepatitis (ALT>10xULN)

Toxins - paracetamol (up to 50% of all cases of Acute Liver Failure) Ecstasy ( 2nd most common cause in the young <35) Any drug herbal remedies Alcohol almost never, AST <7xULN in 98% AST/ALT ratio > 1 in 92%, >2 in 70%

Acute hepatitis (ALT>10xULN)

Autoimmune Rarely presents with acute hepatitis Usually jaundiced and progressive liver failure Raised IgG and autoantibodies (anti-SM, -LKM, SLA) Liver biopsy Steroids and azathioprine

Acute hepatitis (ALT>10xULN)

Early phase- extrahepatic obstruction/cholangitis Usually have history of pain USS dilated CBD ? ERCP or lap chole

Cholestasis

Isolated ALP 3rd trimester, adolescents Bone exclude by raised GGT, 5-NT or isoenzymes May suggest biliary obstruction, chronic liver disease or hepatic mass/tumour Liver USS/CT most important investigationdilated ducts Ca pancreas, CBD stones, cholangioca or liver mets

Cholestasis non-dilated ducts

Cholestatic jaundice Drugs- Antibiotics, Nsaids, Hormones, ACEI PBC anti- mitochondrial Ab, M2 fraction, IgM Chronic liver disease Cholangiocarcinoma beware fluctuating levels Primary or Metastatic cancer, lymphoma Infiltrative sarcoid, inflammatory-PMR, IBD Liver biopsy often required

COMMON CAUSES OF ABNORMAL LFTS

Transient mild

abnormalities which are simply impossible to explain Drugs eg Statins Alcohol excess Hepatitis C Non-Alcoholic Fatty Liver Disease (NAFLD)

Bilirubin
Product of hemoglobin breakdown 2 Forms
Unconjugated (indirect)- insoluble in hemolysis, Gilbert syndrome, meds Conjugated (direct)- soluble in obstruction, cholestasis, cirrhosis, hepatitis, primary biliary cirrhosis, etc. No elevation until loss of > 50% capacity

Elevated Bilirubin
Unconjugated bili; Normal alk phos, ALT, AST Conjugated bili; Abnormal alk phos, ALT, AST

RUQ u/s to assess ductal dilatation

Hemolysis studies, review meds

+
ERCP or MRCP

ALT eval, review meds, AMA, ERCP or MRCP, liver bx

Abnormal LFTs - Conclusions

Many

abnormal LFTs will return to normal spontaneously An important minority of patients with abnormal LFTs will have important diagnoses, including communicable and potentially life threatening diseases Investigation requires clinical assessment and should be timely and pragmatic

VIRAL HEPATITIS
All exam questions rely on you understanding that acute infection has IgM antibodies and chronic has IgG

Viral Hepatitis
HAV
Incubation Onset
Transmission
4 weeks Acute

HBV
4 12 weeks
Acute / insidious

HCV
7 weeks Insidious

HDV
4 12 weeks
Acute / insidious

HEV
6 weeks Acute

Fecal oral

Parenteral +++ Perinatal +++ Sexual ++

+++
variable +

+++ + ++

Fecal - oral

Clinical
Fulminant Progression to chronicity

0.1 % None

0.1 1 % Neonates 90% Adults 1-10%

0.1 % Infect 80-90% Hepatitis 70%

5 20 % Common

1 2% None

HCCancer Prophylaxis
Immune globulin Inactivated vacc

+
Immune globulin Recombinan vacc

+
NONE

+
HBV vaccine NONE

Therapy

NONE

IFN Lamivudine

Interferon Ribavirin

Interferon +

None

HEPATITIS A
RNA Virus Fecal-oral Incubation 15-50 days Anti -Hepatitis A IgM present during acute illness. TX/Prevention: Vaccine, Immune serum globulin for contacts Px: Good doesnt 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 bodys reaction to the virus rather than due to the virus itself Therefore patients who have a severe illness from hep B are more likely to clear the virus. SEROLOGY:
Remember Acute infection has IgM chronic has IgG Anti Core IgM is present during acute phase Anti Core IgG indicates chronic infection. Patients with Hep B e Ag have continued active replication Immunized 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

Question
A 48 yo woman plans to travel to Mexico with her husband and 11 year old child. The family have no known history of liver disease or hepatitis and no members of the family have had immunizations for hepatitis. What immunizations would you recommend: Hepatitis A vaccination for both parents and child Hepatitis A Vaccination for parents and child and Hepatitis B vaccination for the child Hepatitis A and Hepatitis B vaccination for both parents and the child Screen parents for previous Hep A infection, and recommend Hep A vaccination for the child Screen all members of the family for Hep A and B exposure.

A. B. C. D. E.

ANSWER B
All children should now get Hep B. vaccination as babies, if they miss this they should have catch up vaccination as 11-12 year olds Previous Hep A infection is unlikely in children and adults not in high risk populations therefore it is safe to vaccinate without antibody testing.

QUESTION
A 40 yo married man with two children was recently evaluated for fatigue and elevations of liver function tests and was found to have chronic Hep B. Physical examination reveals a few spider angiomata on his chest and upper extremities. Labs: HBsAg Pos HBeAg Pos HBV DNA 90 (low) ALT 156 U/L Albumin 3.8 INR 1.5 A liver biopsy is performed and shows cirrhosis with moderate inflammatory activity The most appropriate recommendation for this patient is A. He should receive the Hepatitis A Vaccine B. His Wife and Childern should receive the Hepatitis B Vaccine C. He should be treated with Interferon Alpha D. All of the above

ANSWER: D
All patients with Liver disease should have the Hepatitis A vaccine as they have decreased hepatic reserve and the mortality of Hepatitis A in a patient with Hepatitis B is considerably increased Household contacts of patients with Hepatitis B should be vaccinated Patients with HBeAg are candidates for Interferon therapy, this is most likely to benefit patients with HBV DNA <200 and evidence of ongoing immune mediated liver cell damage on biopsy.

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 tarda

Management 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.

Other issues re. Hep C

Once 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.

A. B. C. D.

A 38 yo woman was found to be Hep C positive 6 months ago after evaluation for raised AST. The infection was attributed to blood transfusions received during a car accident 15 years ago. She was pleased to learn last month that she is pregnant with her first child. The physical examination is within normal limits She would like further information concerning her prognosis and the risk of transmission of HCV to her husband and her child. All of the following statements about HCV infection are true except: The chance of transmission of HCV to the newborn is low in the 5% range. Barrier precautions including safe sex are recommended for all couples in a monogamous relationship because of high risk of transmission to the partner Low level transmission of Hep C is recognized within households (5-10%), and the risk for such transmission should be minimized by practices that avoid blood-blood exposure such as sharing dental implements and razors In patients with Hep C the chance of developing cirrhosis over several decades is 20-35%

Question

Answer B
Maternal-fetal HCV transmission is approx 5%, however if mother is co-infected with HIV then risk increases to 30% Risk of sexual transmission between monogamous spouses is also low approx 5% Transmission can occur between non-sexual household contacts therefore should be told to avoid sharing razors etc. 20-35% of patients with Hep C develop cirrhosis

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 disease

Primary 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.

Primary Sclerosing Cholangitis

Seen in patients with UC and HIV Inflammation, fibrosis and strictures of biliary tree causing Beaded biliary tree on ERCP Chronic biliary obstruction leads to cirrhosis Presentation: Asymptomatic high Alk Phos, Jaundice, pruritis abdo pain and fatigue Dx: High bilirubin and Alk phos but NEGATIVE antimitochondrial Ab (Cf. primary biliary cirrhosis) Mgt: Steroids, Cholestyramine or ursodeoxycholic acid to treat the pruritis and cholestasis but does not affect disease process Liver transplant for endstage disease but 20% recur. NB. PSC is independent of activity of UC.