Evaluating the Patient With Abnormal Liver Tests-1

פרופ' צבי אקרמן מבית חולים הדסה הר הצופים

צורות של פרזנטציה בקליניקה של רופא המשפחה

• A 20 years old women with severe hepatitis[an aspartate (AST ,GOT)or alanine aminotransferase (ALT ,GPT) levels of >x 10ULN.

• A 42-year-old asymptomatic man with AST or GPT levels of x 2-5ULN.

• A 35-year-old woman with itching and an alkaline phosphatase level of x 2-4ULN.

• A obese woman with right-upper-quadrant pain and minimal aminotransferase elevation.

1שכיחות ההפרעות באנזימי כבד-

• Abnormal liver test results are a common problem in clinical practice.

• Patients with abnormal liver tests pose clinical challenges in diagnosis.

• Aminotransferase elevation occurs in approximately 8% of Americans, with men (9.3%) more likely to have abnormalities than women (6.6%).

• Not all who have abnormal liver test results will be found to significant acute or chronic liver diseases.

Upper Limit of Normal ALT Levels• Updated upper limits

– Males: 30 U/L (-25% from previous ULN)

– Females: 19 U/L (-37% from previous ULN)

• Based on retrospective cohort study

– 6835 first time blood donors 1995-1999

• Anti-HCV negative and no contraindication to donation

• ALT activity independently related to

– BMI

– Abnormal lipid or carbohydrate metabolism

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2008;6:1315-1341. Prati D, et al. Ann Intern Med. 2002;137:1-9.

2שכיחות ההפרעות באנזימי כבד-

• Men are also more likely to have underlying chronic liver disease, including:

• Nonalcoholic fatty liver disease (NAFLD).• Hepatitis B.• Hepatitis C with or without alcoholic liver disease.• Alcoholic liver disease.

• NAFLD is often the most likely diagnosis when abnormal liver tests are encountered in adults in the absence of overt signs of advanced liver disease.

1 הגישה ההתחלתית להפרעות באנזימי כבד-

• The presence of elevated aminotransferase and gamma glutamyltranspeptidase (GGT) serum levels can indicate a greater likelihood of finding a cause for the liver injury.

• Additional factors that may cause abnormal liver tests in adults in the absence of overt signs of advanced liver disease are:

• Ethanol.• Medications.

2 הגישה ההתחלתית להפרעות באנזימי כבד-

• If there are no physical signs of chronic liver disease in patients with mild increases of aminotransferase or alkaline phosphatase, it may be best to simply retest the patient in 3-5 months.

• If more than 1 liver test result is abnormal or test values are moderately or markedly elevated, the patient should be evaluated immediately.

• A careful history and physical examination coupled with a thoughtful laboratory and radiologic evaluation will often provide a likely diagnosis.

1אנמנזה-• The symptoms of liver disease are nonspecific.

• Anorexia, nausea and vomiting, fever and chills, right-upper-quadrant pain, dark urine and light-colored stools, or alteration of taste for cigarettes (suggesting acute hepatitis) may be present.

• Dry mouth and dry eyes are associated with autoimmune disorders such as primary biliary cirrhosis.

• Pruritus develops with intrahepatic cholestasis or extrahepatic biliary blockage.

2אנמנזה-

• In advanced liver disease, symptoms of confusion and disorientation may indicate hepatic encephalopathy.

• A history of illicit or prescribed medications, ethanol use, tattoos (especially self-administered), multiple sexual partners, and travel to endemic areas can raise questions of drug-induced or chronic viral hepatitis.

• The presence of type 2 diabetes mellitus, hypertension, or hyperlipidemia can suggest NAFLD

Signs of Liver Disease and Related Conditions

Examination

Obesity, increased waist circumference-NAFLD

Cirrhosis, Pregnancy -Spider Angiomata

Spider Angiomata

Jaundice,

Palmar Erythema

Dupuytren's contractures-Alcoholism

White nails, clubbing-Cirrhosis

Finger Clubbing

Parotid enlargement-Alcoholism

Gynecomastia, testicular atrophy-Cirrhosis

Caput Medusae

Itching in Primary Biliary Cirrhosis

Xanthomata, xanthelasma-Primary biliary cirrhosis

Kayser-Fleischer corneal rings -Wilson's disease

Das SK and Ray K (2006) Wilson's disease: an updateNat Clin Pract Neurol 2: 482–493 10.1038/ncpneuro0291

Figure 2 The Kayser–Fleischer ring around the periphery of the cornea caused by deposition of copper in Descemet's membrane

From Atlas on Clinical Ophthalmology. Published with permission fromJaypee Brothers Medical Publishers (P) Ltd

Signs of congestive heart failure: jugular venous distention, right pleural -effusion, S3 gallop- Cardiac

cirrhosis

Arterial bruit heard over the liver- Hepatocellular carcinoma, alcoholic hepatitis, arteriovenous malformation (rare)

1גיל ומחלת כבד-

• Chronic liver disorders tend to group within specific age ranges.

• In the teenage years, Wilson's disease and autoimmune hepatitis are the most prevalent chronic liver diseases.

• During the twenties, Wilson's disease continues to present as liver disease up to the age of 25 years, and autoimmune hepatitis and chronic viral hepatitis also occur.

• In the 30-year age group, chronic viral hepatitis and primary biliary cirrhosis (90% are women) are likely.

2גיל ומחלת כבד- • During the forties and fifties, primary biliary cirrhosis remains

prevalent in women and alcoholic hepatitis, chronic viral hepatitis occur in men.

• Drug-induced liver disease can be found at any age, although it is more common in older adults.

• Primary sclerosing cholangitis may also occur at any age, although it tends to occur in men in their twenties and thirties.

• NAFLD coupled with metabolic syndrome occurs at any age.

Common Liver Tests and Associated Conditions

Abnormal Liver Test Results-1

• Most laboratory liver tests are not actual tests of liver function, although hepatic function can be inferred from:

• Prothrombin times (international normalized ratio). • Albumin levels.• Bilirubin levels.

INR-international normalized ratio

• Impaired synthesis of vitamin K-dependent coagulation factors

Albumin

• Cirrhosis, severe hepatocellular injury.

• Other causes for low albumin?

Bilirubin

• Any acute or chronic liver disease.• Congenital disorders of bilirubin metabolism.

Causes for Hyperbilirubinemia:

1.1. Increased bilirubin Increased bilirubin production production

2.2. Reduced bilirubin Reduced bilirubin uptake by hepatic cellsuptake by hepatic cells

3.3. Disrupted intracellular Disrupted intracellular conjugationconjugation

4.4. Disrupted secretion of Disrupted secretion of bilirubin into bile bilirubin into bile canaliculicanaliculi

5.5. Intra/extra-hepatic bile Intra/extra-hepatic bile duct obstructionduct obstruction

Lead to increase in Lead to increase in free (free (unconjunconj.) .) bilirubinbilirubin

Result in rise in Result in rise in conj.conj. bilirubin levels bilirubin levels

DISRUPTED INTRACELLULAR CONJUGATION (unconj. Hyperbilirubinemia)

Gilbert’s SyndromeGilbert’s Syndrome : : glucuronosyl transferase activity glucuronosyl transferase activity reduced to 10-30% of normal; also reduced to 10-30% of normal; also accompanied by defective accompanied by defective

bilirubin uptake bilirubin uptake mechanismmechanism

Bile

MRP2

BB + +GSTGST

CBCB

Plasma Hepatic cellAlb

BB

Alb :GSTBB

sER

BB +UDPGAUGT1A1

Additional points -Hyperbilirubinemia

• In acute and chronic liver diseases every point in the metabolism of bilirubin may be defected.

Abnormal Liver Test Results• Aminotransferases, alkaline phosphatase, and GGT are enzymes that are

released during injury to liver cells or bile ducts.

Aminotransferases (AST, ALT)• Hepatocellular injury Acute or Chronic :• Ethanol.• Drug-induced hepatitis.• Hepatitis A or B or C.• Ischemic injury.• Chronic liver disease.• NAFLD.• Acute biliary obstruction.• Hyperthyroidism (rarely ).• Celiac disease.• skeletal muscle disease.

Aminotransferases-Height of enzymes

• Marked elevations of aminotransferases occur from viral infection, ischemic liver injury, and drug-induced liver disease.

• Moderate elevations occur in patients with autoimmune hepatitis and some patients with cirrhosis.

• Minimal elevations of aminotransferases are more frequent in NAFLD, chronic viral hepatitis, alcoholism, nonspecific viral injury, and cholestatic liver disease.

Aminotransferases

• The ratio of AST to ALT may indicate alcoholic liver disease when greater than 2:1.

Alkaline phosphatase

• Cholestasis (Canalicular injury ,intrahepatic and extra

hepatic bile duct obstruction).• Hepatocellular damage.• Children during bone growth.• Bone disease.• Pregnancy (placenta origin).

GGT - gamma glutamyltransferase

• Cholestasis (Canalicular injury ,intrahepatic and

extra hepatic bile duct obstruction).

• Medications.

• Ethanol

Abnormal Liver Test Results-1

• Liver tests can be used to:• Screen for liver disease.• Confirm suspected liver disease. • Assist in differential diagnosis of liver disease.• Monitor the progression of liver disease.• Monitor the progress of specific therapies.

Lactate dehydrogenase

• Lactate dehydrogenase (LDH) is not a reliable liver test but can be significantly elevated during:

• Ischemic injury.• Liver disease associated with hemolysis.• Solid tumors or rapidly growing lymphomas.

MCV

• Alcohol consumption, folic acid and B12 deficiency

ADDITIONAL HEMATOLOGICAL PARAMETERS MAY BE HELPFUL IN LIVER PATEINT EVALUATION

• Leukopenia.• Thrombocytopenia .

• These may result from hypersplenism associated with portal hypertension.

Cholestasis• Laboratory tests for cholestasis include GGT and alkaline

phosphatase. • These enzymes are elevated in hepatobiliary diseases, including abnormalities of

either the canaliculus or the intrahepatic and extrahepatic bile ducts and in replacement disease from hepatic tumors or granulomas.

• Hepatobiliary diseases include:• partial biliary tract obstruction from stones.• pancreatitis.• parasitic disease.• acute cholecystitis.• papillary dysfunction.

• With biliary disorders, the tests may fluctuate in value, suggesting intermittent or partial blockage.

Cholestasis- additional points1

• Acute biliary tract obstruction from stones can be associated with aminotransferase levels > 500 U/L with normal or mildly elevated alkaline phosphatase levels.

• Medications such as ethanol, phenytoin, anabolic steroids, and major tranquilizers can also increase GGT and alkaline phosphatase levels due to hepatocellular enzyme induction or canalicular injury and cholestasis.

• Other considerations include primary biliary cirrhosis, sclerosing cholangitis, alcoholic liver disease, ductopenic syndromes.

• GGT may also be elevated in patients with NAFLD with obesity and diabetes mellitus.

additional points 2-Cholestasis• Isolated GGT elevations occur, and if other liver test results are normal and no ethanol or

medication use is evident, additional workup can generally be delayed.

• Isolated alkaline phosphatase elevation occurs from bone disease, bone growth in children, and the placenta during pregnancy. GGT levels should be normal in these conditions.

• Additional evaluation of patients suspected of having cholestasis should include a:

• Careful history and physical examination.• Ultrasonography of the biliary tree.• Magnetic resonance cholangiography(MRCP).• Eendoscopic retrograde cholangiography(ERCP).• Liver biopsy(when needed) .

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