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Lab Data Interpretation - Liver Function Tests - Additional Notes
Lab Data Interpretation - Liver Function Tests - Additional Notes
4
LFT……introduction
• The term "liver function tests" (LFTs)
• is commonly used
• is imprecise since many of the tests reflecting the
health of the liver are not direct measures of its
function
• Furthermore, the commonly used liver function
tests may be abnormal even in patients with a
healthy liver
• In addition, these tests may be normal in patients
who have advanced liver disease
5
Introduction……Cont’d…….
• Despite their limitations, LFTs have many applications in
patient care :
• Provide a noninvasive method to screen for the presence
of liver disease
• Used to measure the safety/ efficacy of treatments for
liver disease
• such as immunosuppressant agents for autoimmune
hepatitis)
• Used to monitor the progression of a disease such as viral or alcoholic
hepatitis
• Reflect the severity of liver disease, particularly in patients who have
cirrhosis.
• As an example, the Child-Pugh score, which incorporates the
prothrombin time and serum bilirubin and albumin6 concentrations, can
predict survival
• The most common laboratory measures classified as
LFTs include
• Enzyme tests (serum aminotransferases, alkaline
phosphatase, and gamma glutamyl transpeptidase)
• Tests of synthetic function (serum albumin
concentration and prothrombin time), and
• The serum bilirubin, which measures the liver's ability
to detoxify metabolites and transport organic anions
into bile
7
Introduction…..cont’d…
• LFTs can be categorized as follows:
• Tests that detect injury to hepatocytes :
• tests measure the activity of hepatic enzymes in the
circulation.
• enzymes are released when hepatocytes are injured
• Tests of the liver's capacity to transport organic anions
and metabolize drugs :
• tests measure the liver's ability to clear endogenous or
exogenous substances from the circulation.
• The best studied include serum measurements of
bilirubin, bile acids, etc
8
Introduction…cont’d…..
• Tests of the liver's biosynthetic capacity —
• tests to assess the biosynthetic capacity of the liver
• the serum albumin and the prothrombin time
• Other tests which have been use are the serum
concentrations of lipoproteins,…etc
• Tests that detect chronic inflammation in the liver, altered
immunoregulation, or viral hepatitis —
• tests include the immunoglobulins, hepatitis serologies, and
specific autoantibodies
• Most of these substances are proteins made by B
lymphocytes, not by hepatocytes.
• However, some are quite specific for certain liver diseases,
such as antimitochondrial antibodies in primary
9
biliary
cirrhosis
Introduction…. Cont’d…..
• The liver contains thousands of enzymes.
• Elevation of an enzyme activity in the serum
primarily reflects release from damaged liver cells.
• Elevation of serum enzyme tests can be grouped
into two categories:
• Enzymes that reflect generalized damage to
hepatocytes
• Enzymes that reflect cholestasis
10
Liver Diseases Tests
• Two types:
• (1) Lactate Dehydrogenase (LDH) and
• (2) Aminotransferases
• Intracellular enzymes
• No role in the blood (present at low level)
• Elevates in cell damage only
11
Facts….LFTs
• The extent of liver cell necrosis correlates poorly with
the magnitude of serum aminotransferase elevation
• The absolute elevation in serum aminotransferases is
of little prognostic value since the liver can recover
from most forms of acute injury
• A rapid decrease in serum aminotransferases is
usually a sign of recovery from disease
• But may also reflect the massive destruction of viable
hepatocytes in patients with fulminant hepatitis,
signaling a poor prognosis.
12
Liver Diseases Tests
Serum concentration does not correlate with degree of
inflammation or prognosis
13
Liver Diseases
• Classification
• Cholestatic – primary interference with metabolism or
secretion of bile
• Failure of bile to reach GI (decrease synthesis or
secretion)
• Hepatocellular – damage to the liver (viral or drug-
induced hepatitis)
14
Cholestatic - Classification
• Intrahepatic
• infiltration of malignant cells, primary biliary cirrhosis
etc.
• conjugated bilirubin 1-10mg/dL, ALP 2-3x reference
range
• Extrahepatic
• gallstones obstructing, carcinoma
• conjugated bilirubin >20mg/dL, ALP 10x reference
range
15
Liver Function Tests……Enzymes
• Aminotrasnferase (formerly called transaminase)
• ALT; AST
• Gamma Glutamyl Transferase (GGT)
• Often used to monitor patients recovering from hepatitis and
cirrhosis
• Lactate Dehydrogenase (LD)
• Increased in liver disease and following heart attacks
• Markedly elevated level > 1000 IU/L is usually associated
with acute diseases
16
Liver function tests that detect injury to
hepatocytes
• SERUM AMINOTRANSFERASES
• are sensitive indicators of liver cell injury
• commonly measured are
• alanine aminotransferase (ALT, serum glutamic-pyruvic
transaminase [SGPT]) and
• aspartate aminotransferase (AST, serum glutamic-oxaloacetic
transaminase [SGOT])
• The serum ALT and AST concentrations are normally less than 30 to 40
IU/L
• ALT is present in highest concentration in the liver
• AST is found, in decreasing order of concentration, in the liver, cardiac
muscle, skeletal muscle, kidneys, brain, the pancreas, lungs,
leukocytes, and erythrocytes
17
Medications Vs aminotransferases
• The first step in approaching elevated aminotransferases
should be to:
• identify medications and supplements that can cause
elevation of the serum aminotransferases, to assess for
alcohol use, and to test for viral hepatitis B and C, and
fatty liver
• Medications —
• Almost any medication can cause an elevation of liver
enzymes
• Common causes include non-steroidal anti-inflammatory
drugs, antibiotics, statins, antiepileptic drugs, and anti-
tuberculous drugs. In addition, herbal preparations
18
and
illicit drug use may also be the cause
Alanine Aminotransferase (ALT)
(3-40 IU/L)
• Serum ALT results, which are useful for identifying
inflammation and necrosis of the liver
• The enzyme has its highest concentration in the
liver with lesser amounts in the kidney and
skeletal muscle
• ALT is located in the microsomal portion of the
hepatic cell in contrast to AST, which is found in
hepatic cell mitochondria
• ALT - found exclusively in the cytosol, while AST
occurs in the cytosol and mitochondria
19
ALT (interpretation)
ALT is more specific for liver disease than AST
ALT results greater than 20 times the upper limit
of the reference range usually indicate hepatic
injury
Match
1. Alcoholic hepatitis a. ALT exceeds
AST
2. Acute viral hepatitis b. AST exceeds ALT
22
Clinical significance : ALT & AST tests
• Serum aminotransferases are elevated in most liver
diseases
• High serum ALT concentrations are indicative of
hepatocellular disease
• Elevations greater than three times the upper limit of
normal are considered significant
• The highest elevations occur in disorders associated
with extensive hepatocellular injury, such as acute
viral hepatitis, and acute drug- or toxin-induced liver
injury (e.g., acetaminophen intoxication)
23
Clinical significance : cont’d……
• Elevated ALT may be caused by a no. of medications,
including
• HMG-CoA reductase inhibitors, niacin, phenytoin,
and valporic acid
• In alcoholic liver disease, the ratio of AST to ALT is
usually greater than 2:1
• Elevations of AST may also be seen with drug
toxicity.
• Acetaminophen, erythromycin, levodopa,
methyldopa, and tolbutamide may falsely elevate AST
by interfering with the assay 24
Issues in interpretation….
• Four important clinical issues related to the
interpretation of serum aminotransferase levels:
• Marked elevation in aminotransferase levels
• The AST-to-ALT ratio
• High aminotransferase levels in the absence of hepatic
disease
• Normal aminotransferase levels in the presence of
hepatic disease
• N.B. a rapid decrease in plasma AST and ALT levels,
together with a rise in the plasma bilirubin
concentration and prolongation of the prothrombin
time, is indicative of a poor prognosis in patients with
acute fulminant hepatitis. 25
Others………
• SERUM CONCENTRATIONS OF OTHER HEPATIC
ENZYMES —
• A variety of other hepatic enzymes have been
measured but none is as useful as the
aminotransferases for the diagnosis of hepatic disease
• Lactate dehydrogenase
• Glutamate dehydrogenase
26
Alkaline Phosphatase (AP)
• Normal range: 30 – 120 U/L
• No known function – found in many body
tissues (80% in liver and bones) AP is useful for
diagnosing hepatobiliary and bone disease
• Physiologic elevations
of AP occur with bone
growth and during
pregnancy owing to
AP that is derived
from the placenta
29
AP interpretation
• The increased serum AP level associated with liver
disease results from regurgitation of AP into the
circulation through the sinusoids
30
AP interpretation (3)
Lactated Dehdrogenase (LDH)
(100 – 225 IU)
• Has 5 isoenzymes (LDH 1-5)
• LDH1 – Cardiac
• LDH5 more specific to liver (less sensitive than AST/ALT)
• ALT/ADH ratio >1.5
• LDH1 - Mostly used in cardiac disease (MI)
32
Tests of the liver's capacity to
transport organic anions and
metabolize drugs
• These tests measure the liver's ability to clear
endogenous or exogenous substances from
the circulation
• The best studied include serum measurements
of bilirubin, bile acids
• Bilirubin [ normal range]
• Total bili. : 0.1–1.0 mg/dL
• Indirect Billi.: 0.2– 0.7 mg/dL
• Direct : 0–0.2 mg/dL
33
Bilirubin (bili)
• is a breakdown product of hemoglobin.
• The bilirubin produced from hemoglobin metabolism
is referred to as unconjugated or indirect bilirubin
• Unconjugated bilirubin is converted to conjugated or
direct bilirubin by the liver through the process of
glucuronidation
• Elevated direct bilirubin may be associated with
hepatocellular disease and cholestasis.
• Increased levels of indirect bilirubin may result from
hemolysis, pernicious anemia, large hematomas
34
Total Bilirubin
(0.1– 1 mg/dl)
36
Bilirubin
RBC destruction Iron
Protein Urine
HEME 1-4mg of urobilinogen
excreted in the urine per day
Unconjugated bilirubin
Systemic circulation
A small portion of urobilinogen formed
Liver reaches the circulation and is excreted
Unconjugated bilirubin is conjugated through the kidney into the urine
with glucuronic acid by the action of
glucuronyl transferase to form conjugated bilirubin Enterohepatic circulation
20% of urobilnogen formed in the GI
tract will be absorbed and recirculated to
Intestine the liver and reexcreted in the feces
Conjugated bilirubin is reduced by
Feces
50-250mg of urobilinogen
excreted per day 37
Bilirubin (interpretation)
Bilirubin Metabolism
39
Bilirubin Metabolism
40
Bilirubin Metabolism
Heme Metabolism
Bili Lights
Bili Lights
44
Bili Lights
45
Jaundice
Jaundice
Jaundice baby
Bilirubin in the urine
Bilirubin crystals from the urinary sediment of a patient with
hepatitis. Bilirubin crystals are yellowish brown in the shape of
small needle-like crystals, and often are phagocytized by white
blood cells. Unstained, X400
Tests of the liver's biosynthetic
capacity
• (eg, albumin, coagulation factors, prothrombin time)
• SERUM PROTEINS —
• The liver is the major site where serum proteins are
synthesized. These include albumin and the coagulation
factors
• Albumin — Albumin is quantitatively the most
important plasma protein
• The serum albumin concentration reflects the rate of
synthesis, the degradation, and the volume of
distribution
• Coagulation factors — 51
Albumin
(3.5 – 5 g/dL)
• Albumin, the most abundant protein in blood, is synthesized
almost entirely by the liver
• Low means the liver’s ability to produce albumin and other
proteins is diminished
• Low serum albumin in the absence of liver disease is seen in malnutrition,
renal or intestinal albumin loss, severe infections, and severe burns
• Low albumin leads to peripheral edema, ascities, pulmonary edema
• Low albumin can affect concentration of drugs; phenytoin,
salicylates, and calcium
58
Cirrhosis
• Cirrhosis can be caused by alcohol, viral agents,
biliary obstruction, or ischemic or by a
combination of these causative factors
• The major laboratory abnormality in cirrhosis is a
decrease in albumin related to hepatic cell
synthesis
• If the etiologic factor is persistent, other results,
such as those for AST, ALT, AP, unconjugated, and
conjugated bilirubin, remain elevated
59
Amylase
(20 – 128 IU/L), varies with type of assay
• Breaks starch into glucose
• Secreted by pancrease and salivary gland
• Used in the diagnosis of pancreatitis
• Serum t ½ = 1- 2 hours
• Acute Pancreatitis – increase amylase concentration in 2-3 hr (up to 25
times the upper limit)
• Peaks after 12-30 hrs and returns to normal within 3-5 days.
• Has low specificity/sensitivity (normal in 20% of patients with
acute pancreatitis)
61
Hyperbilirubinemia
A value of 5 suggests absence of liver impairment, whereas 15 would indicate severe liver
failure. Child-Pugh class A = 5 to 6 points, class B = 7 to 9 points, and class C = 10 to 15 points.
The original Child-Turcotte classification consisted of grades A, B, and C, with grade C being the
most severe liver disease. Similar to the Pugh modification, the Child-Turcotte
64 classification
includes albumin, bilirubin, and ascites, plus assessment of nutrition and neurological disorder
Dose adjustment : based on Child-
Pugh score
• Reduce the maintenance dose by 25% for a drug that is
primarily dependent on the liver for elimination (>/= 65% to
70%) in a patient with a score of 8 to 9.
• A dose reduction of at least 50% would be prudent for a
patient with a score of 10.
• Likewise, Child-Pugh B and C classifications could result in
similar 50% and 75% reductions, respectively, of the daily
maintenance dose
• For both classification systems, depending on the severity of
the liver dysfunction and clinical judgment, extension of the
dosing interval should also be considered
65
Endocrine Tests
66
Signs and Symptoms of
Hypoglycemia
• 5 Causes: Too much insulin, not enough food,
increased physical activity, illness, and injury
• Faster onset than DKA
• Early signs: Headache, Hunger, Mild agitation
• Blood sugar below 50-70 mg/dL
– hallucinations or nervousness or outright hostility
– cold sweat and tachycardia common but not required
• Blood sugar blow 20 -50 mg/dL
– convulsions and loss of consciousness
– as sugar drops the convulsions stop but coma persists
67
Treatment of Hypoglycemia
68
Hyperglycemic Syndromes
• Diabetic ketoacidosis (DKA)
• Hyperglycemic hyperosmolar state (HHS)
• Manifestations – dehydration, polyuria/
polydipsia, altered mental status, nausea, emesis,
abdominal pain
69
Drugs that Affect Blood Glucose
• Beta blockers
• Phenytoin
• Diuretics
• Contraceptives
70
Glucose – Lab assessment
Initial diagnosis and short-term monitoring
• Fasting BG
• Two hrs Post Prandial
• Oral Glucose Tolerance Test (OGTT)
Long-term monitoring
• Glycosylated hemoglobin (A1C)
• Fructosamine
71
Sample Collection & Storage
Why separate RBC & WBC from the serum before
measuring blood glucose?
72
Fasting Plasma Glucose (FPG)
(70 – 100 mg/dl)
• Prediabtes (impaired fasting glucose)
• 100 < FPG < 126 mg/dl
• Diagnosis of DM – FPG > 126 mg/dl (at two
occasions)
• FPG done after 8 hr of fasting (before BF)
• ADA recommend q3 years screening above 45 year-
old (>30 yrs of age if have risk factors)
73
Oral Glucose Tolerance (OGTT)
(< 140 mg/dl)
• Prediabetes
• 2-hr post prandial glucose: 140 – 200 mg/dl
• Commonly used to diagnosis gestational DM
(pregnancy)
• 75 G glucose solution given over 5 min following
overnight fasting and blood drown at 0, 0-2 hr, and
at 2 hrs.
• No alcohol 3 days before the test, Coffee and tea, not
permitted during the test.
74
Hemoglobin (Hb) A1C
< 7%
• Bound glucose to RBC irreversibly (over 120 days life span) is
measured
• Subfraction A1a, A1b, and A1c – A1c is more susceptible to non-
glucose in the blood of patients with opiate addiction, lead
poisoning, uremia, and alcoholism
• HbA1c can be measured without any special patient preparation
(e.g., fasting) and generally is not subject to acute changes in
insulin dosing, exercise, or diet
75
Fructosamine
(<285)
• Measures glycosylated protein not RBC
• Not commonly used; affected by several factors
76
Hyperglycemic Syndromes – Treatment
• Identify and treat precipitating factors
• Restore fluid/electrolyte balance
• Insulin – iv bolus and infusion
• Add glucose to infusion when glucose <250-300 mg/dL
(13.9-16.7 mmol/L)
• Treat electrolyte changes (K, PO4)
• NaHCO3 rarely needed
77
Thyroid Function Tests
Thyroid Stimulating Hormone (TSH) has
Inverse or Direct
relationship to thyroid function?
78
TFT’s….
• Thyroid-Stimulating Hormone
• 0.3–5 µU/mL
• Total Thyroxine
• 4–12 µg/dL
• Free Thyroxine
• 0.8–2.7 ng/dL
• Total Triiodothyronine
• 80–200 ng/dL
79
Thyroid Storm
• Exaggerated manifestations of
hyperthyroidism
• Supportive measures
• Specific measures
– Propylthiouracil or methimazole
– Propranolol
– Potassium or sodium iodide
– Dexamethasone, sodium ipodate 80
Thyroid Storm (Thyrotoxicosis)
81
ENDOCRINE TESTS: ADRENAL GLAND
• Cortisol [Normal range]
• Morning 6-25 μg/dL
• Evening 3-16 μg/dL
• Overnight Dexamethasone Suppression Test
• Normal Range: Cortisol less than 5 μg/dL at 8:00 AM.
• Adrenocorticotropic Hormone [ Normal range]
• < 60 pg/mL
82
Question??
• Which of the following laboratory values would
suggest the need for a change in pharmacotherapy
to better achieve patient outcomes?
A. An AST of 35 U/L in a patient taking an HMG-CoA
reductase inhibitor
B. A fasting glucose of 195 in a patient with
diabetes
C. An LDL level of 79 mg/dL in a patient with a
history of CHD
D. A uric acid level of 5.0 mg/dL in a patient with a
history of gout 83