Transcript Liver Enzyme Alteration - Patologos de Puerto Rico

Liver Enzyme Alteration
ANGELISA B. FRANCESCHINI, MD
CHAIRWOMAN DEPARTMENT OF PATHOLOGY
UNIVERSIDAD CENTRAL DEL CARIBE, SCHOOL OF MEDICINE
MEDICAL DIRECTOR LABORATORIOS BORINQUEN, INC
Biochemical markers of liver
damage
 Isolated alterations in healthy patients
 Guidelines ?
 Classify: hepatocellular vs. cholestatic
 Initial investigation
Liver enzyme levels
 Liver damage vs. alteration in bile flow?
 Patient with symptoms or signs?
 Sudden isolated unexpected finding while screening for a non-hepatic
condition?
 Challenge
 Expensive testing
 Consultation
 Aim of this presentation:
Provide you, pathologists, with a guide to help general physicians
in the interpretation of liver enzyme alterations.
This is the external surface of a normal liver. The color is brown and the surface is smooth. A normal liver
is about 1200 to 1600 grams. Central role carbohydrate, protein and fat metabolism. Waste products of
metabolism are detoxified- amino acid deamination….urea.
 Maintains a stable blood level of glucose:
Glycogenosis
 Glycogenolysis
 Gluconeogenesis
 Synthesis and secretion of bile
 Synthesis of lipoproteins and plasma protein, including coagulation
factors.
 Microscopy: acinus-(primary functional unit)
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Three zones: on the basis of the distance from the supplying vessels.
 Example: zone 3 - least oxygen perfusion, most mitochondria.
***Edoardo G. Giannini, MD
Normal Ranges: How to apply reference ranges?
 Performance characteristics (reproducibility, bias, total error).
 Definition: a value exceeding the upper reference limit is abnormal.
 Low levels has no significance
except: serum albumin.
Use your own laboratory ranges…
Remember there are patients with subclinical liver disease included.
2.5% of “normal” patients have “abnormal” - AST or ALT
Some patients with chronic hepatitis C- 16%, non-alcoholic fatty liver13%....with histological findings.
Age and sex limits
Activity- exercise: ↑ALT & ↑AST
Hospital patients- diet? And ↓exercise restriction- ↓
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Fig. 1: Schematic representation of an approach to liver enzyme alteration. Specific
modalities of enzyme
alteration (how) and their relation with peculiar characteristics of the patient and locality (where
and when) should be thoroughly assessed before the definitive diagnostic work-up is begun.
Where, When and How
 Always ask questions…Traveling…Ethnicity
 Where? Who is your patient?
 Example: Bayamón, P.R. – 50%- ↑ALT (genetics?)
 Wales- 60% - ↑ AST (due to ischemic or toxic liver disease).
 Far East- orofecal transmittable hepatitis viruses (60%) are the
major causes of sporadic acute and fulminant hepatitis.⁵
 Primary Biliary Cirrhosis 2% in Australia; .424 per 100,000 in Asia.
 Homozygosity for the C282Y mutation in the HFE gene can be found
in about 5/1000 people of Northern European descent but
.0001/100 people of African American ethnicity.
When?
 Timing in relation to age of the patient
 Example: Wilson’s disease – early in life
 Comorbid conditions should be explore
 Ingestion of medications.
 Date it started with relation to alterations.
 Almost any medication can liver enzymes.
 Herbal remedies are overlooked.
 Over the counter meds.
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How?
 First piece of evidence: Pattern.
 Disease: Common causes have typical patterns…
 Careful examinationPredominant pattern- (hepatocellular vs. cholestatic)
 Magnitude of alteration (<5 time, 5-10 times or >10 times); mild,
moderate or marked.
 Rate of change (increase or decrease over time)
 The nature of the course of alteration (mild fluctuations vs.
progressive)
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Serum aminotransferace levels in various liver disease
Hepatocellular predominant and cholestatic predominant
 Fundamental to narrowing down the differential diagnosis.
 Certain liver diseases may display a mixed biochemical picture
↑AST and ↑ALT with mild abnormalities of alkaline phosphatase
(ALP) and gamma- glutamyl transpeptidase (GGT) levels-
Hepatocellular predominant
 AST and ALT increased:
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are enzymes that catalyze the transfer of α-amino groups from aspartate and
alanine to the α-keto group of ketoglutaric acid to generate oxalacetic and
pyruvic acids respectively, which are important contributors to the citric acid
cycle. Both enzymes require pyridoxal-5’-phosphate (vitamin B6) in order
to carry out this reaction, although the effect of pyridoxal-5’-phosphate
deficiency is greater on ALT activity than on that of AST.
 This has clinical relevance in patients with alcoholic liver disease,
in whom pyridoxal-5’-phosphate deficiency may decrease ALT
serum activity and contribute to the increase in the AST/ALT
ratio that is observed in these patients.
Hepatocellular predominance
 Both aminotransferases are highly concentrated in the liver.
 AST is also diffusely represented in the heart, skeletal muscle, kidneys,
brain and red blood cells, and ALT has low concentrations in skeletal
muscle and kidney.
 An increase in ALT serum levels is, therefore, more specific
for liver damage
Marked and moderate aminotransferace increase
 > 10 times the upper reference limit: acute hepatic injury.
 Data suggest that the most sensitive and specific aminotransferase
threshold is within the moderate range (5-10 at 200 IU/L for AST and
300 IU/L for ALT).
 The academic attribution of cause and “severity” of acute
damage on the basis of magnitude of enzyme elevation
may be misleading since there can be a gray areas in
which a range of causes overlap.
 IMP: When the enzymes were tested?
Schematic representation of the rate of change of aminotransferace and bilirubin
levels in a patient with acute ischemic hepatitis (green and yellow) and acute viral
hepatitis.(blue and orange) figure 3
Acute viral hepatitis:
 Aminotransferase peak before jaundice appears. Greater
increase in serum bilirubin.
 Jaundice 70% of acute hepatitis A
 Jaundice in 33-50% of acute hepatitis B infection.
 Jaundice in 20-33% of cases of hepatitis C infection. LDH is
altered in 50% of cases, slightly above the limits.
Ischemic or hypoxic liver injury
 Very high levels of aminotranferase > 75x the upper limit, bilirubin is lower than 34
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µmol/L and LDH very high (ALT/LDH < 1). High bilirubin and Pt prolonged- risk of failure.
 Less common in acute viral hepatitis
AST peaks before ALT because of peculiar intralobular distribution. Zone 3 is more
vulnerable.
It is more likely in patients with concomitant sepsis or low flow hemodinamics.
Acetaminophen induced hepatic damage 54%-16% of acute failure in UK and the
USA respectively.
Alcohol induced damage- GGT/ALP ratio > 2.5: jaundice in > 60% pts.
Cohen and Kaplan - ↑AST was < 6-7 times in 98% of Pts.
AST/ALT > than 1 in 92% and > 2 in 70% of cases.
Physical signs may help distinguish…acute vs. chronic.
 Rapidly decrease of Aminotransferase after peaking, does not have prognostic value.
(Figure 3)
Fig. 4: Schematic, initial diagnostic algorithm for a patient presenting with mild
aminotransferase abnormality. HCV = hepatitis
 C virus, HBsAG = hepatitis B surface antigen, ANA =
antinuclear antibodies, ASMA = anti-smooth body antibodies,
LKM =liver–kidney microsomes.
 Alcohol abuse and, to a lesser extent, drug-induced liver
injury are frequently associated with mild aminotransferase
abnormality, and their causality should be ruled out on a
clinical basis.
 In the western world, chronic viral hepatitis, autoimmune
hepatitis and hereditary hemochromatosis are the most
common causes of mild aminotransferase alteration for which
specific serological tests are available.
 Although nonalcoholic fatty liver disease (NAFLD) or
steatohepatitis is frequently encountered in clinical practice, it
remains a diagnosis of exclusion.
•Mild increase in aminotransferase levels
A minimal or mild increase in aminotransferase level is
the most common biochemical alteration encountered in
everyday clinical practice.
 Nonalcoholic fatty liver disease is the most common cause of mild
alteration of liver enzyme levels in the western world, and, according to
the National Health and Nutritional Survey, point-prevalence is about
23% among American adults.
 The biochemical picture includes mildly raised aminotransferase
levels, and GGT levels can be elevated up to 3 times the upper reference
value in nearly half of patients in the absence of ethanol consumption.
 As with chronic viral hepatitis, an AST/ALT ratio greater than 1, which
is observed in 61% of patients with advanced fibrosis
and 24% of patients with no or initial fibrosis, is highly
suggestive of advanced liver disease
Mild increase in aminotransferase
Suspicion of nonalcoholic fatty liver disease is
increased by the presence of conditions linked to the
metabolic syndrome and insulin resistance
(increased body mass index, diabetes, hyperlipemia,
hypertension), although the disease may occur in
patients without these associated factors.
• All
patients presenting with mild increases in aminotransferase
levels should be questioned about risk factors for hepatitis B or C
infection (intravenous drug use, exposure to nonsterile needles or
sexual exposure to an infected person).
• However, since these 2 diseases have a high prevalence worldwide
and infected people may lack or underreport specific risk factors for
infection, testing for HCV antibodies and hepatitis B surface antigens
is advisable for all patients presenting with a mild increase in
aminotransferase levels.
•If the patient tests positive for HCV antibodies, then qualitative HCV
RNA testing should follow.
Cholestatic predominance
 Presentation of liver injury with a prevalent
cholestatic pattern is less frequently encountered in
clinical practice than the pattern of hepatocellular
damage.
 ALP and bilirubin levels are routinely assessed, and
the level of GGT is often measured as an additional
aid toward diagnosis in particular situations because
of its high sensitivity but low specificity. (Dosage of
AlP isoenzymes is a more complicated technique and
expensive , so GGT is preferred)
Alkaline Phosphatase
 Drug-induced liver injury may present with a cholestatic pattern
(preferential increase in ALP or ALT/ALP ratio < 2), although the
degree of ALP alteration is variable and may be accompanied by
hyperbilirubinemia.
 Commonly used drugs such as antihypertensives
(e.g., angiotensin converting enzyme inhibitors) or hormones (e.g.,
estrogen) may cause cholestasis and can be overlooked.
Liver ultrasound in these patients is often unremarkable.
 Varying degrees of ALP alteration in patients with inflammatory bowel
disease (most commonly ulcerative colitis) suggest the presence of
primary sclerosing cholangitis, since about 70% of these cases are
associated with inflammatory bowel disease.
 The same biochemical abnormality observed in middle-aged women
with a history of itching and autoimmune disease raises the suspicion
of primary biliary cirrhosis.
ALP
•Abnormal ALP levels may also be a sign of metastatic
cancer of the liver, lymphoma or infiltrative diseases such
as sarcoidosis.
•In some of these situations ALP levels may be markedly
elevated and the only sign of liver involvement.
•Liver ultrasound examination is extremely important
when the patient history is not suggestive of disease.
•Patients may require liver biopsy in order to obtain a
definitive diagnosis.
γ-Glutamyl transpeptidase
 GGT is an enzyme that is present in hepatocytes and biliary
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epithelial cells, renal tubules, the pancreas and intestine.
The mechanisms of alteration are similar to those described
for alkaline phosphatase.
GGT is a microsomal enzyme, and its activity can be induced
by several drugs, such as anticonvulsants and oral
contraceptives.
Elevated GGT levels can be observed in a variety of
nonhepatic diseases, including chronic obstructive pulmonary
disease (COPD) and renal failure.
May be present for weeks after an acute myocardial infarction.
GGT
 Lack of specificity but high sensitivity for liver
disease, GGT can be useful for identifying causes of
altered ALP levels, or elevated levels, together with
other biochemical abnormalities…
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AST/ALT ratio > 2 may support the diagnosis of alcoholic
liver disease.
Gilbert’s syndrome
 Gilbert’s syndrome is determined by a variety of genetic
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defects in UDP-glucuronyltransferase that affect about
5% of the population.
In these subjects serum indirect bilirubin usually does
not exceed 68 μmol/L, and the remainder of liver
chemistry tests and
Liver ultrasound is unremarkable.
This condition is usually diagnosed on a clinical basis
alone.
The patient should be reassured of the benign nature of
this enzymatic alteration.
Albumin and prothrombin time assessment:
Are we really testing liver function?
 Determining serum albumin levels and assessing prothrombin
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time are often considered “tests of liver function.”
…because hepatic synthesis of albumin tends to decrease in endstage liver disease
Increase in prothrombin time depends on the decreased synthesis
of liver-derived coagulation factors.,
In fact, Albumin is produced by hepatocytes, and prothrombin time
depends on the activity of clotting factors I, II, V, VII and X,
which are produced in the liver.
Neither test is specific for liver disease, since albumin serum levels
may decrease in patients with nephrotic syndrome, malabsorption
or protein-losing enteropathy, or malnutrition, and prothrombin
time may be prolonged by warfarin treatment, deficiency in vitamin
K (which is needed to activate clotting factors II, VII and X) and
consumptive coagulopathy.
Conclusions
 Alterations in liver enzyme levels are one of the most
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common problems encountered in everyday clinical practice.
Finding the way through the multiple diagnostic
pathways can challenge even the experienced clinician.
Knowledge of the pathophysiology of liver enzymes is an
essential guide to understanding their alteration.
The pattern of enzyme abnormality, interpreted in the context of
the patient’s characteristics, can aid in directing the subsequent
diagnostic work-up.
Awareness of the prevalence of determined liver disease in specific
populations and of possible hepatic involvement during systemic
illnesses or drug therapies may help the clinician identify the cause
of alterations
efficiently.