Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2754_Библиотеки_им_академика_М_И_Перельмана
.pdf
316 BASIC SKILLS IN INTERPRETING LABORATORY DATA
https://t.me/med1917
FIGURE 15-1. Basic structure of a liver lobule, including the lymph ow system comprised of the spaces of Disse
and interlobular lymphatics. Source: Reproduced with permission from Guyton AC. Medical Physiology. 5th ed.
Philadelphia, PA: WB Saunders; 1976.
With its double blood supply, large size, and critical role in
regulating body metabolic pathways, the liver is aected by
many systemic diseases. Although numerous illnesses aect the
liver, it has tremendous reserve capacity and can oen maintain
its function despite signicant disease. Furthermore, the liver is
one of the few human organs capable of regeneration.
Pancreas
e pancreas is an elongated gland located in the retroperitoneum. Its head lies in close proximity to the duodenum, and
the pancreatic ducts empty into the duodenum. e pancreas
has both exocrine glands (which secrete digestive enzymes into
the duodenum) and endocrine glands (which secrete hormones
directly into the circulation).
e pancreatic exocrine glands produce enzymes that aid in
digestion of proteins, fats, and carbohydrates (including trypsin,
chymotrypsin, lipase, and amylase). Insucient enzyme production (ie, pancreatic exocrine insuciency) is associated with
malabsorption of nutrients, leading to progressive weight loss
and severe diarrhea. e glands also produce many hormones,
including insulin and glucagon. Insucient insulin production
leads to diabetes mellitus. us, the pancreas plays an important
role in digestion and absorption of food as well as metabolism
of sugar. Like the liver, the pancreas has a tremendous reserve
capacity; >90% glandular destruction is required before diabetes
or pancreatic insuciency develops.
INTRODUCTION TO LIVER TESTS AND
THE LIVER FUNCTION TEST PANEL
Investigation of liver disease oen begins with obtaining a panel
of liver tests, generally referred to as the LFT panel or liver func-
tion tests (LFTs).1 is panel may vary slightly between hospitals
and laboratories but generally includes the aminotransferases
TABLE 15-1. Categories of Liver Tests
MOST CLOSELY RELATED
PROCESS
Protein synthesis Albumin
Excretion into the bile
ducts and drainage into the
duodenum (impairment of
this process is dened as
cholestasis)
Hepatocellular injury Aminotransferases:
Detoxication
(previously referred to as transaminases), including aspartate
aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline phosphatase (ALP), and albumin. LFT is a misnomer because not all tests actually measure liver function
(specically, aminotransferases reect liver injury).
Additionally, the liver has multiple functions, and dierent
tests reect these dierent functions. Tab l e 15-1 divides liver
tests into rough categories. Although there is considerable overlap between these categories, these divisions may provide an
initial framework for understanding the LFT panel.
is grouping of tests mirrors a division of liver diseases into
two broad categories: cholestatic and hepatocellular. In cholestatic disease, there is an abnormality in the excretory function
TESTS
Prealbumin
PT/INR (clotting factors)
Bilirubin
ALP
5′- nucleotidase
GGT
AST
ALT
Ammonia (NH
+)
3
CHAPTER 15 • LivER And GAsTRoEnTERoLoGy TEsTs 317
https://t.me/med1917
of the liver (ie, namely secretion of bile by hepatocytes and passage of bile through the liver and bile ducts into the duodenum).
In hepatocellular disease, there is primary inammation and
damage to the hepatocytes themselves (eg, due to viral infection
of the hepatocytes). ese two categories may overlap because
disease of the hepatocytes (hepatocellular processes), if severe
enough, will also lead to derangement of bile secretion. However, the distinction between primarily cholestatic and primarily hepatocellular diseases and, in turn, LFT patterns, remains
useful and fundamental. Further confusing is the fact that liver
test results may be abnormal in patients with diseases that do
not aect the liver.
e range of normal laboratory values used here is taken
from Harrison’s Principles of Internal Medicine, 19th edition.2
Reference ranges may vary slightly between dierent laboratories, and most laboratories list their reference ranges along
with laboratory results. Listed normal ranges are for adult
patients; normal ranges for pediatric patients oen have
dierent values.
TESTS OF SYNTHETIC LIVER
FUNCTION
As discussed previously, one of the functions of the liver is to
synthesize proteins that circulate in the blood, including albumin and clotting proteins. Measurement of the levels of these
proteins in the blood provides a reection of the ability of the
liver to synthesize them. e liver has an enormous reserve
function so that it may synthesize normal amounts of proteins
despite signicant liver damage. erefore, tests of synthetic
function are not sensitive to low levels of liver damage or dysfunction. Inadequate protein synthetic function is mainly limited to hepatic cirrhosis, which is scarring of the liver that can
result from years of alcohol abuse, inammation, or massive
liver damage (eg, due to alcoholic liver disease, severe acute viral
hepatitis, autoimmune hepatitis, unrecognized and untreated
chronic hepatitis, or potentially lethal toxin ingestion). In these
situations, measuring synthetic function may be useful in determining prognosis by reecting the degree of hepatic failure. e
most commonly used tests of protein synthetic function are
albumin, prothrombin time (PT), and International Normalized Ratio (INR). An example of this is the Model for End- stage
Liver Disease score, which uses the prothrombin time/INR (PT/
INR) to help assess the severity of a patient’s liver disease and
has been used to prioritize patients awaiting liver transplants.
Albumin
Normal range: 4 to 5 g/dL (40 to 50 g/L)
Albumin is a major plasma protein that is involved in maintaining
plasma oncotic pressure and the binding and transport of numerous hormones, anions, drugs, and fatty acids. e normal serum
half- life of albumin is about 20 days, with about 4% degraded
dai ly.3 Because of albumin’s long half- life, serum albumin measurements are slow to fall aer the onset of hepatic dysfunction (eg,
complete cessation of albumin production results in only a 25%
decrease in serum concentrations aer 8 days). For this reason,
levels are oen normal in acute viral hepatitis or drug- related hepatotoxicity. Alternatively, albumin is commonly reduced in patients
with chronic synthetic dysfunction caused by cirrhosis.
Albumin levels may be low due to a variety of other abnormalities in protein synthesis, distribution, and excretion, in
addition to liver dysfunction. ese abnormalities include malnutrition/malabsorption; protein loss from the gut, kidney, or
skin (as in nephrotic syndrome, protein- losing enteropathy,
or severe burns, respectively); or increased blood volume (eg,
following administration of large volumes of intravenous [IV]
uids). Albumin is a negative acute phase reactant, meaning
that in the setting of systemic inammation (eg, due to infection or malignancy), the liver produces less albumin, and there
is a shiing of albumin out of the intravascular compartment.
Severely ill, hospitalized patients commonly have low albumin levels due to a combination of poor nutrition, systemic
inammation, and IV uid administration. In these patients,
extremely low albumin concentrations carry a poor prognosis
regardless of any particular liver disease. Although hypoalbuminemia is common in these patients, there is little evidence
to support replacement simply for a low albumin concentration. Given the numerous causes of a low albumin level, it is
important to interpret it within the context of each patient.
For example, in a patient with metastatic cancer and no known
liver disease, a low albumin level suggests decreased nutritional intake and advanced malignancy with systemic inammation. Alternatively, in a patient with known cirrhosis, a low
albumin level suggests severe chronic liver failure. While a
low albumin level is commonly found in elderly patients with
suboptimal nutrition, it may also suggest the presence of signicant disease and requires further consideration and oen
investigation.
Hypoalbuminemia itself is usually not associated with specic symptoms or ndings until concentrations become quite
low. At very low concentrations (<2 to 2.5 g/dL), patients can
develop peripheral edema, ascites, or pulmonary edema. Albumin normally generates oncotic pressure, which holds uid in
the vasculature. Under conditions of low albumin, uid leaks
from the vasculature into the interstitial spaces of subcutaneous tissues or into the body cavities. Calcium is bound to albumin, so a decrease in serum albumin may be associated with
a decrease in total calcium concentrations, but the ionized
(ie, free) calcium concentration usually does not change. In the
presence of hypoalbuminemia, measuring an ionized calcium
level helps sort this out. Finally, in the presence of low albumin
concentration, the percentage of nonprotein bound medication
in the bloodstream is increased for highly protein- bound agents
(eg, phenytoin, warfarin, and salicylates). is could result in
increased pharmacologic eects or adverse eects from usual
doses of these medications.
Hyperalbuminemia is seen in patients with marked dehydra
tion (which concentrates their plasma), in which it is associated
with concurrent elevations in blood urea nitrogen (BUN) and
hematocrit. Patients taking anabolic steroids may demonstrate
truly increased albumin concentrations, but those on heparin or ampicillin may have falsely elevated results with some
assays. Perhaps the most common cause of hyperalbuminemia
-
318 BASIC SKILLS IN INTERPRETING LABORATORY DATA
https://t.me/med1917
is iatrogenic, overzealous use of parenteral albumin, which may
be associated with uid overload. Otherwise, hyperalbuminemia
is not associated with any symptoms.
Prealbumin (Transthyretin)
Normal range: 17 to 34 mg/dL (170 to 340 mg/L)
Prealbumin is similar to albumin in several respects: it is synthe-
sized primarily by the liver, involved in the binding and transport of various solutes (thyroxin and retinol), and aected by
similar factors that aect albumin levels. e primary dierence
between the two proteins is that prealbumin has a short half- life
(2 days, compared with 20 days for albumin) and a smaller body
pool than albumin, making the former more rapidly responsive
than albumin.4 Additionally, due to its high percentage of tryptophan and essential amino acids, prealbumin is more sensitive
to protein nutrition than albumin and is less aected by liver
disease or hydration status than albumin.5 In practice, prealbumin is generally used to assess protein calorie nutrition, which
is discussed in more detail in Chapter12.
6
International Normalized Ratio and
Prothrombin Time
Normal range: INR 0.9 to 1.1; PT 12.7 to 15.4 seconds
For an introduction to INR and PT, please see Chapter17. ese
two tests measure the speed of a set of reactions in the extrinsic pathway of the coagulation cascade. Decreased synthesis or
impaired activation of clotting factors correlates with prolonged
reaction times and increased values of INR and PT. Both PT and
INR are two dierent measures of the same set of reactions, with
the INR being a derived index that takes into account variations
between test reagents used in dierent laboratories. As such,
INR is more precise and easily interpretable and replaces the
use of the PT.
e liver is required for the synthesis of clotting factors (with
the exception of factor VIII), many of which require a vitamin K
cofactor for their activation. erefore, either hepatic impairment or vitamin K deciency may lead to a deciency in activated clotting factors with subsequent prolongation of PT/INR.
Both synthetic failure and vitamin K deciency may also cause
prolongation of activated partial thromboplastin time, which
measures a dierent set of coagulation reactions in the intrinsic
coagulation cascade, but to a much lesser degree than PT/INR.
e prolongation of PT/INR alone is not specic for liver
disease. It can be seen in many situations, most of which interfere with the use of vitamin K, a cofactor required for the proper
posttranslational activation of clotting factors II, VII, IX, and X.
Because vitamin K is a fat- soluble vitamin, inadequate vitamin K in the diet or fat malabsorption as caused by cholestasis
may cause hypovitaminosis. Many broad- spectrum antibiotics,
including tetracyclines, may reduce vitamin K–producing ora
in the gut. e anticoagulant agent warfarin interferes directly
with vitamin K–dependent activation of clotting factors.
If the etiology of elevated PT/INR remains unclear despite
obtaining additional coagulation tests, then the clinical approach
is to provide parenteral vitamin K.7 Although commonly given
as a subcutaneous injection, vitamin K (10 mg) can be given
by slow IV infusion in patients with prolonged PT/INR with
FIGURE 15-2. Evaluation of a prolonged PT/INR.
serious bleeding. If the PT/INR is prolonged due to malabsorption, warfarin, perturbed gut ora, or the absence of vitamin K
in the diet, the PT/INR usually corrects by at least 30% within
24 hours. Alternatively, failure of PT/INR to normalize despite
parenteral vitamin K suggests impaired synthetic liver function
(Figure15-2). Other factors that may cause a prolonged PT/INR
that does not respond to parenteral vitamin K include inherited
clotting factor deciencies.
Because clotting factors are produced in excess of need and
because the liver has tremendous synthetic reserves, only substantial hepatic impairment (>80% loss of synthetic capability)
leads to decreased synthesis of these factors and subsequent
clotting abnormalities. us, PT/INR, albumin, and prealbumin levels lack sensitivity and may remain normal in the face of
substantial liver damage. However, they have considerable prognostic value if liver damage is sucient to aect them. Unlike
albumin (which responds slowly to hepatic insult), PT/INR
responds within 24 hours to changes in hepatic status because of
the short half- life of certain clotting proteins (ie, factor VII has
a half- life of <6 hours). us, the PT/INR may become elevated
days before other manifestations of liver failure and, likewise,
may normalize before other evidence of clinical improvement.
One use for determining PT/INR in liver disease is to provide
prognostic data, generally in situations in which the cause of
the elevated PT/INR is known; for example, with an acute acetaminophen overdose leading to hepatic failure.
In addition to serving as an LFT, PT/INR has direct clinical
relevance in accessing a patient’s tendency to bleed spontaneously or as a result of surgical or diagnostic procedures. Bleeding is a dramatic complication of hepatic failure. When the PT/
INR is signicantly elevated, bleeding may be controlled or at
least diminished by coagulation factors or fresh frozen plasma,
which contains the needed activated clotting factors and oen
corrects the PT/INR temporarily.
CHOLESTATIC LIVER DISEASE
Cholestasis is a deciency of the excretory function of the liver.
As described previously, bile is normally secreted by hepatocytes into bile canaliculi, where it ows into larger bile ducts
and eventually empties into the duodenum. Excretion of bile
from the liver serves multiple purposes. Certain large lipophilic
CHAPTER 15 • LivER And GAsTRoEnTERoLoGy TEsTs 319
https://t.me/med1917
toxins, drugs, and endogenous substances are eliminated by
secretion into the bile with eventual elimination in the feces.
Bile salts also play an important role in dissolving and absorbing dietary fat- soluble vitamins and nutrients within the small
intestine.
Failure of the excretory functions of the liver leads to a predictable set of consequences. Substances normally secreted
in the bile accumulate, resulting in jaundice (from bilirubin),
pruritus (from bile salts), or xanthomas (from lipid deposits in
skin). Absence of bile salts to dissolve fat- soluble nutrients can
lead to deciencies of fat- soluble vitamins A, D, E, and K, which
may result in osteoporosis (lack of vitamin D) and PT/INR elevation (lack of vitamin K).
Cholestatic syndromes may be subclassied as either disorders of hepatocytes and microscopic bile ducts (intrahepatic cho-
lestasis) or anatomic obstruction of the macroscopic bile ducts
(extrahepatic cholestasis).8 e approach to a patient with cholestasis generally begins with a radiographic study, oen a right
upper- quadrant ultrasound, to look for dilation of bile ducts
within or outside of the liver. Dilation of the bile ducts indicates
extrahepatic cholestasis; otherwise, extrahepatic cholestasis is
largely excluded, and the next step is to investigate for various
causes of intrahepatic cholestasis.
Intrahepatic Cholestasis
Intrahepatic cholestasis includes a variety of processes that interfere with hepatocyte secretion of bile as well as diseases of the
microscopic and macroscopic bile ducts within the liver. Etiologies involving impaired hepatocyte secretion of bile overlap to
some extent with hepatocellular diseases as noted previously;
such processes include viral hepatitis (especially type A), alcoholic hepatitis, and even cirrhosis. Processes that cause a cholestatic pattern include a variety of drugs (Tabl e 15-2), pregnancy,
severe infection (cholestasis of sepsis), and certain nonhepatic
neoplasms, especially renal cell carcinoma. Inltrative processes
of the liver produce a primarily cholestatic pattern, and these
include granulomatous diseases and amyloidosis. PBC causes
inammatory scarring of the microscopic bile ducts, whereas
sclerosing cholangitis is a similar process that may affect
TABLE 15-2. Classication of Liver Disease
HEPATOCELLULAR CHOLESTATIC
Viral hepatitis
Autoimmune hepatitis
Impaired blood ow
Hypotension (shock liver)
Congestive heart failure
Metabolic diseases
Hemochromatosis
Wilson disease
Alcoholic hepatitis
NAFLD
Intrahepatic
Systemic illness (ie, sepsis,
CHF)
Extrahepatic neoplasms
(ie, renal cell)
Cholestasis of pregnancy
Inltrative liver diseases
Granulomatous (sarcoid, TB)
Lymphoma
Metastatic carcinoma
a
TABLE 15-2. Classication of Liver Diseasea, cont’d
HEPATOCELLULAR CHOLESTATIC
Drugs include
Acetaminophen
ACE inhibitors
Allopurinol
Amiodarone
Antiepileptic agents
Carbamazepine
Phenytoin
Valproic acid
Antimicrobial agents
Amoxicillin– clavulanate
Azole antifungals
Dapsone
Fluoroquinolones
INH
Nitrofurantoin
Protease inhibitors
Sulfonamides
Azathioprine
Cisplatin
Glyburide
Heparin
Labetalol
Methotrexate
Methyldopa
Niacin
NSAIDs
Phenothiazines
Trazodone
Statin medications
Herbal medications
Nutritional supplements
Illicit drugs
Toxins
ACE = angiotensin- converting enzyme; INH = isoniazid; NAFLD =
nonalcoholic fatty liver disease; TPN = total parenteral nutrition.
a
Note that listings of drugs contain more commonly used
agents and are not exhaustive. For any particular patient,
potentially causative drugs should be specically researched
in the appropriate databases to determine any hepatotoxic
effects, such as the National Library of Medicine database,
LiverTox: Livertox.nih.gov/.
Inammatory diseases of
bile ducts
PBC
PSC
AIDS Cholangiopathy
IgG4 associated disease
Benign postoperative
jaundice.
Drugs include
Allopurinol
Antibiotics
Erythromycin
β- lactams
Rifampin
Cardiovascular
Amiodarone
Captopril
Diltiazem
Quinidine
Carbamazepine
Hormonal agents
Estrogens
Methyltestosterone
Anabolic steroids
Niacin
NSAIDs
Penicillamine
Phenothiazines
Sulfa drugs
TPN (hyperalimentation)
Extrahepatic
Biliary stricture
Gallstone-
obstructing bile
duct
Tumors
Pancreatic cancer
Cholangiocarcinoma of
bile duct
PSC
AIDS cholangiopathy
320 BASIC SKILLS IN INTERPRETING LABORATORY DATA
https://t.me/med1917
microscopic or macroscopic bile ducts. Masses within the liver,
including tumors or abscesses, may block the ow of bile as well.
Extrahepatic Cholestasis
Extrahepatic cholestasis involves obstruction of the larger bile
ducts both inside and outside the liver. e most common
cause is stones in the common bile duct; other causes include
obstruction by strictures (aer surgery), tumors (of the pancreas, ampulla of Vater, duodenum, or bile ducts), chronic pancreatitis with scarring of the ducts as they pass through the
pancreas, and parasitic infections of the ducts. Another cause
is primary sclerosing cholangitis (PSC), a disease- causing diffuse inammation of the bile ducts, oen both intrahepatic and
extrahepatic. Of note is that PSC is associated with inammatory bowel disease, especially involving the colon. Some patients
with human immunodeciency virus (HIV) can develop a picture similar to sclerosing cholangitis, referred to as AIDS cholan-
giopathy. Although previously referred to as surgical cholestasis,
extrahepatic cholestasis can oen be treated or at least palliated using endoscopic means (eg, dilation of strictures with or
without stent placement). Another entity is immunoglobulin G
(IgG) 4–related sclerosing cholangitis. is is an autoimmune
disease, a variant of autoimmune hepatitis, oen with elevated
autoimmune markers (antinuclear antibody, abnormal serum
protein electrophoresis). It can present with a picture of sclerosing cholangitis or even one mimicking cholangiocarcinoma,
but the elevated autoimmune markers, especially elevated levels
of IgG4, help make this distinction. Tissue biopsy reveals IgG4,
plasma cell inltrates, and interstitial brosis. Patients characteristically respond to glucocorticoids.
Tests Associated with Excretory Liver Function
and Cholestasis
Laboratory tests do not distinguish between intrahepatic and
extrahepatic cholestasis. is distinction is usually made radiographically. In most instances of extrahepatic cholestasis, a
damming eect causes dilation of bile ducts above the obstruction, which can be visualized via computed tomography (CT),
magnetic resonance imaging (MRI), or ultrasound. Laboratory
abnormalities primarily associated with cholestasis include
elevation of ALP, 5′- nucleotidase, γ- glutamyl transpeptidase
(GGT), and bilirubin.
Alkaline Phosphatase
Normal range: 33 to 96 units/L (0.56 to 1.63 µkat/L)
Alkaline phosphatase (ALP) refers to a group of isoenzymes
whose exact function remains unknown. ese enzymes are
found in many body tissues, including the liver, bone, small
intestine, kidneys, placenta, and leukocytes. In the liver, they
are found primarily in the bile canalicular membranes of the
liver cells. In adults, most serum ALP comes from the liver and
bone (∼80%), with the remainder mostly contributed by the
small intestine.
Normal ALP concentrations vary primarily with age. In children and adolescents, elevated ALP concentrations result from
bone growth, which may be associated with elevations as high
as three times the adult normal range. Similarly, increase during late pregnancy is due to placental ALP.9 In the third trimester, concentrations oen double and may remain elevated for
3weeks postpartum.
e mechanism of hepatic ALP release into the circulation
in patients with cholestatic disease remains unclear. Bile accumulation appears to increase hepatocyte synthesis of ALP, which
eventually leaks into the bloodstream. ALP concentrations persist until the obstruction is removed and then normalize within
2 to 4 weeks.
Clinically, ALP elevation is associated with cholestatic disorders and, as mentioned previously, does not help to distinguish
between intrahepatic and extrahepatic disorders. ALP concentrations more than four times normal suggest a cholestatic disorder, and 75% of patients with primarily cholestatic disorders
have ALP concentrations in this range (Table15-3). Concentrations of three times normal or less are nonspecic and can occur
in all types of liver disease. Mild elevations, usually <1.5 times
normal, can be seen in healthy patients and are less signicant.
When faced with an elevated ALP concentration, a clinician must determine whether it is derived from the liver. One
approach is to fractionate the ALP isoenzymes using electrophoresis, but this method is expensive and oen unavailable.
us, the approach usually taken is to measure other indicators of cholestatic disease, 5′- nucleotidase, or GGT. If ALP is
elevated, an elevated 5′- nucleotidase or GGT indicates that at
least part of the elevated ALP is of hepatic origin. Alternatively,
a normal 5′- nucleotidase or GGT suggests a nonhepatic cause
(Table15-3).
TABLE 15-3. Initial Evaluation of Elevated ALP Concentrations in Context of Other Test Results
AMINOTRANSFERASES
ALP GGT, 5′ NUCLEOTIDASE
(ALT AND AST) DIFFERENTIAL DIAGNOSIS
Mildly elevated Within normal limits Within normal limits Pregnancy; nonhepatic causes (Table 15-4)
Moderately elevated
Markedly elevated Within normal limits or
Cholestatic syndromes
a
minimally elevated
Mildly elevated
a
Usually more than four times normal limit.
b
Usually less than four times normal limit.
b
Mildly elevated Markedly elevated Hepatocellular disease
CHAPTER 15 • LivER And GAsTRoEnTERoLoGy TEsTs 321
https://t.me/med1917
TABLE 15-4. Some Nonhepatic Illnesses
Associated with Elevated ALP
OTHER DISORDERS AND
BONE DISORDERS
Healing fractures
Osteomalacia
Paget disease
Rickets
Tumors
Nonhepatic causes of elevated ALP include bone disorders
(eg, healing fractures, osteomalacia, Paget’s disease, rickets,
tumors, osteoporosis, hypervitaminosis D, or vitamin D deciency as caused by celiac sprue), hyperthyroidism, hyperparathyroidism, sepsis, diabetes mellitus, renal failure, and neoplasms
(which may synthesize ALP ectopically, outside tissues that normally contain ALP) (Tab l e15-4). Some families have inherited
elevated concentrations (two to four times normal), usually as
an autosomal dominant trait.10 Markedly elevated concentrations (more than four times normal) are generally seen only in
cholestasis, Paget’s disease, or inltrative diseases of the liver.
Because of an increase in intestinal ALP, serum ALP concentrations can be falsely elevated in patients with blood type O or B
whose blood is drawn 2 to 4 hours aer a fatty meal.11 Alkaline
phosphatase concentrations can be lowered by several conditions, including hypothyroidism, hypophosphatemia, pernicious
anemia, and zinc or magnesium deciency. Also, ALP may be
confounded by a variety of drugs.
5′-Nucleotidase
Normal range: 0 to 11 units/L (0 to 0.19 µkat/L)
Although 5′- nucleotidase is found in many tissues (including
liver, brain, heart, and blood vessels), serum 5′- nucleotidase
is elevated most oen in patients with hepatic diseases. It has
a response prole parallel to ALP and similar utility in dierentiating between hepatocellular and cholestatic liver disease.
Because it is only elevated in the face of liver disease, the presence of an elevated ALP together with a normal 5′- nucleotidase
(or GGTP, see below) suggests that the ALP is elevated secondary to nonhepatic causes.
γ-Glutamyl Transpeptidase
Normal range: 9 to 58 units/L (0.15 to 0.99 µkat/L)
γ- glutamyl transpeptidase (GGT, also GGTP), a biliary excretory
enzyme, can also help determine whether an elevated ALP is of
hepatic etiology. Similar to 5′- nucleotidase, it is not elevated in
DRUGS
Acromegaly
Anticonvulsant drugs (eg,
phenytoin and phenobarbital)
Hyperthyroidism/
hyperparathyroidism
Lithium (bone isoenzymes)
Neoplasia
Oral contraceptives
Renal failure
Small bowel obstruction
Pregnancy (third trimester)
Sepsis
bone disorders, adolescence, or pregnancy. It is rarely elevated
in conditions other than liver disease.
Generally, GGT parallels ALP and 5′- nucleotidase levels
in liver disease. Additionally, GGT concentrations are usually
elevated in patients who abuse alcohol or have alcoholic liver
disease. erefore, this test is potentially useful in dierential
diagnosis, with a GGT/ALP ratio >2.5 being highly indicative
of alcohol abuse.12 With abstinence, GGT concentrations oen
decrease by 50% within 2 weeks.
Although it is oen regarded as the most sensitive test for
cholestatic disorders, GGT is unlike 5′- nucleotidase in that GGT
lacks specicity. Not all GGT elevations are of hepatic origin.
GGT is found in the liver, kidneys, pancreas, spleen, heart,
brain, and seminal vesicles. Elevations may occur in pancreatic diseases, myocardial infarction, severe chronic obstructive
pulmonary diseases, some renal diseases, systemic lupus erythematosus, hyperthyroidism, certain cancers, rheumatoid arthritis,
and diabetes mellitus. GGT may be confounded in patients on a
variety of medications, some of which overlap with the medications that confound ALP test results. us, elevated GGT (even
with concomitant elevated ALP) does not necessarily imply
liver injury when 5′- nucleotidase is normal, but rather both
elevations in GGT and ALP may be caused by a common confounding medication (eg, phenytoin, barbiturates) or medical
condition (eg, myocardial infarction).
Bilirubin
Total bilirubin: 0.3 to 1.3 mg/dL (5.1 to 22 µmol/L)
Indirect (unconjugated, insoluble) bilirubin: 0.2 to 0.9 mg/dL
(3.4 to 15.2 µmol/L)
Direct (conjugated, water soluble) bilirubin: 0.1 to 0.4 mg/dL
(1.7 to 6.8 µmol/L)
Understanding the various laboratory studies of bilirubin
requires knowledge of the biochemical pathways for bilirubin
production and excretion (Figure15-3). Bilirubin is a breakdown product of heme pigments, which are large, insoluble
organic compounds. Most of the body’s heme pigments are
located in erythrocytes (red blood cells), in which they are a
component of hemoglobin. Breakdown of erythrocytes releases
hemoglobin into the circulation (which is converted to bilirubin,
predominantly in the spleen), where it is initially a large lipophilic molecule bound to albumin.
e liver plays a central role in excretion of bilirubin, similar to its role in the metabolism and excretion of a wide variety
of lipophilic substances. Prior to excretion, bilirubin must be
converted into a form that is water soluble. e liver achieves
this by covalently linking it to a water- soluble sugar molecule
(glucuronic acid) using an enzyme glucuronyl transferase. e
conjugate of bilirubin linked to glucuronic acid is water soluble, so it may then be excreted into the bile and eventually
eliminated in the feces. Incidentally, bilirubin and some of its
breakdown products are responsible for coloring feces brown
(such that with complete obstruction of the bile ducts or cessation of bile synthesis by the liver, the stool takes on a pale
color). With progressive cholestasis, there is increased renal
excretion of the water- soluble bilirubin, coloring the urine
dark brown.
322 BASIC SKILLS IN INTERPRETING LABORATORY DATA
https://t.me/med1917
FIGURE 15-3. Overview of bilirubin production
and metabolism. Most bilirubin is produced by the
breakdown of heme pigments in erythrocytes (red
blood cells) and, to a lesser extent, other tissues. The
indirect bilirubin is carried in the circulation to the
liver, where it is conjugated and becomes direct or
conjugated bilirubin. In healthy individuals, conjugated
bilirubin is largely excreted via the biliary system into
the gut. In individuals with disease, it will “back up”
into the circulation, causing elevated levels of direct/
conjugated bilirubin and, ultimately, jaundice. (Courtesy
of Esta Farkas.)
Indirect Versus Direct Bilirubin
e total amount of bilirubin in the serum can be divided into
direct and indirect fractions. Bilirubin conjugated to glucuronic
acid (water- soluble bilirubin) reacts quickly in the van der Bergh
reaction and is thus called direct- reacting or direct bilirubin.
Alternatively, unconjugated bilirubin, because it is water insoluble, requires the presence of dissolving agents to be detected
by this assay and is thus called indirect- reacting or indirect bili-
rubin. Although this nomenclature system is slightly awkward, it
is the standard terminology used in clinical practice today. Labs
generally measure the total bilirubin and the direct bilirubin.
Indirect bilirubin may be determined by subtracting the direct
from the total bilirubin. Only the water- soluble direct bilirubin
can be excreted in the urine; therefore, urine dipsticks only will
measure this fraction. In fact, urine dipsticks may be more sensitive than most serum tests for detecting a slight elevation of
direct bilirubin.
Elevated bilirubin causes abnormal yellow coloration of the
skin and sclera of the eyes (collectively, these symptoms are
referred to as jaundice or icterus). Excess carotenes (eg, due
to large amounts of carrot consumption) may cause a similar
eect on the skin but spare the eyes. Icterus usually becomes
visible when total bilirubin concentrations exceed 2 to 4 mg/dL.
In infants, extremely elevated concentrations of bilirubin (for
example, >20 mg/dL) may have neurotoxic eects on the
developing brain, but in adults a direct toxic eect of bilirubin
is quite rare.
e rst step in evaluating an elevated serum bilirubin is to
determine if only the indirect fraction is elevated or if there is
involvement of the direct fraction. Given the sequential location
of these two molecules within the pathway of bilirubin metabo
lism, elevated levels of the molecules may have markedly dierent signicance (Tab l e15-5).
Indirect Hyperbilirubinemia (Unconjugated, Insoluble)
Indirect bilirubin is mostly produced by the breakdown of erythrocytes and is removed from the circulation by conversion to
direct bilirubin by glucuronyl transferase in the liver. erefore, elevated levels may result from increased breakdown of
red blood cells (hemolysis) or reduced hepatic conversion to
direct bilirubin. Patients with primarily unconjugated hyperbili-
rubinemia (>70% indirect) generally do not have serious liver
disease. e most common causes of elevated indirect bilirubin
are hemolysis, Gilbert syndrome, Crigler-Najjar syndrome, and
various drugs, including probenecid and rifampin. In infants,
this can be physiologic (neonatal jaundice), although very high
levels may require medical intervention.
Hemolysis refers to increased destruction of erythrocytes,
which increases the production of indirect bilirubin and may
overwhelm the liver’s ability for conjugation and excretion.
However, the liver’s processing mechanisms are intact so that
serum bilirubin generally does not rise dramatically (rarely
>5 mg/dL). Hemolysis may result from a wide variety of hematologic processes, including sickle cell anemia, spherocytosis,
hematomas, mismatched blood transfusions, and intravascular
fragmentation of blood cells. Evaluation includes various hematologic tests, as described in further detail in Chapter16.
Gilbert syndrome is an inherited, benign trait present in
3% to 5% of the population. It is due to reduced production of
hepatic glucuronyl transferase enzymes, resulting in intermittent
elevation of indirect bilirubin and mild jaundice (increased with
fasting, stress, or illness). e primary signicance is that it may
cause elevation of bilirubin when there is in fact no signicant
hepatic or hematologic disease. Bilirubin elevation is generally
mild, with values <5 mg/dL.
Direct Hyperbilirubinemia (Conjugated, Soluble)
Conjugated hyperbilirubinemia is dened as bilirubinemia with
>50% in the direct fraction (although absolute levels of unconjugated bilirubin may also be elevated). In the normal course of
-
CHAPTER 15 • LivER And GAsTRoEnTERoLoGy TEsTs 323
https://t.me/med1917
TABLE 15-5. Evaluation of Elevated Bilirubin Concentrations in Context of Other Test Results
TOTAL
BILIRUBIN
Moderately
elevated
Moderately
elevated
Mildly elevated Mildly elevated Moderately
a
Usually indirect bilirubin is <4 mg/dL but may increase to 18 mg/dL.
b
Usually indirect bilirubin is >12 mg/dL but may go as high as 45 mg/dL.
c
These syndromes are distinguished in the laboratory by liver biopsy.
d
Usually direct bilirubin is 3 to 10 mg/dL.
DIRECT
BILIRUBIN
Within normal
limits or low
Moderately
elevated
INDIRECT
BILIRUBIN ALT, AST, GGT DIFFERENTIAL DIAGNOSIS
Moderately
elevated
Within normal
limits
Within normal
limits
Within normal
limits
Moderately
elevated
elevated
bilirubin metabolism, direct bilirubin is synthesized in hepatocytes by conjugating indirect bilirubin and secreted into bile.
erefore, elevated direct bilirubin implies hepatic or biliary
tract disease that interferes with secretion of bilirubin from the
hepatocytes or clearance of bile from the liver.
Direct hyperbilirubinemia is generally classied as a positive
cholestatic liver test, although as discussed earlier, it may be
elevated to some extent in hepatocellular processes as well. In
cholestatic disease, elevated bilirubin is primarily conjugated,
whereas in hepatocellular processes signicant increases in both
conjugated and unconjugated bilirubin may result. e most
reliable method of determining the cause of hyperbilirubinemia considers the magnitude and pattern of abnormalities in
the entire liver function panel. It should be noted that direct
bilirubin is generally readily cleared by the kidney, such that its
levels rarely rise very high, even in severe cholestatic disease if
a patient has normal renal function. Very rarely, congenital disorders (eg, Dubin-Johnson and Rotor syndromes) may cause
elevations of primarily conjugated bilirubin.
It should be noted that a gray area exists between indirect
and direct hyperbilirubinemia. Most authors agree that >50%
direct bilirubin indicates direct hyperbilirubinemia whereas
<30% direct fraction indicates indirect hyperbilirubinemia. For
cases in which the fraction falls between 30% and 50%, other
liver tests and hematologic tests may be required to determine
the etiology.
Patients with elevated direct bilirubin levels may have some
binding of bilirubin to albumin, referred to as d bilirubin. is
explains delayed resolution of jaundice during recovery from
acute hepatobiliary diseases; while the “free” bilirubin is rapidly
metabolized, the bilirubin linked to albumin is metabolized at
a much slower rate. Δ bilirubin has a half- life of 14 to 21 days,
which is similar to albumin.
13
HEPATOCELLULAR INJURY
As discussed earlier, the liver is a large organ with diverse
biochemical roles, which require its cells to be in close communication with the bloodstream. ese properties place the
Hemolysis,
a
Gilbert syndrome,a Crigler-
Najjar syndrome,b neonatal jaundice
c
Congenital syndromes
: Dubin-Johnsond and
Rotor
Hepatobiliary disease
hepatocytes at risk for injury due to a variety of processes. Toxin
and drug metabolism produce cascades of metabolic byproducts, some of which may damage hepatocytes. Likewise, the liver
plays a central role in the body’s biochemical homeostasis, so
metabolic disorders tend to involve the liver. Finally, the close
relationship of hepatocytes to the blood supply places them at
risk for a variety of infectious agents.
Hepatitis is a term that technically refers to a histologic pattern of inammation of hepatocytes. It may also be used to refer
to a clinical syndrome caused by diuse liver inammation. e
laboratory reection of hepatitis is a hepatocellular injury pattern, which is marked primarily by elevated aminotransferases.
ere are multiple causes of hepatitis. One common type
is viral hepatitis, which is classied A, B, C, D (δ hepatitis), or
E based on the causative virus. ese viruses, and the tests for
them, are discussed in detail in the Viral Hepatitis section. Less
common viral hepatitis may be caused by the Epstein-Barr virus,
herpes virus, or cytomegalovirus.
Hepatitis may also be caused by various medications, and
drug- induced hepatitis can be either acute or chronic. Some
drugs commonly implicated in cellular hepatotoxicity are listed
in Tabl e 15-2. In addition, elevation of aminotransferases has
been reported in patients receiving heparin.14 ALT is elevated
in up to 60% of these patients, with a mean maximal value of
3.6 times the baseline. A vast number of drugs can cause hepatic
injury, especially drugs that are extensively metabolized by the
liver. Although numerous drugs may result in aminotransferase
elevations, such elevations are usually minor, transient, not associated with symptoms, and of no clinical consequence.
Perhaps the most common cause of abnormal aminotransferases in ambulatory patients is fatty liver.15 Estimates are 30%
to 46% of adults in the United States have fatty liver, which can
vary from hepatic steatosis (fat in the liver) to nonalcoholic steatohepatitis (NASH), in which the extra fat in the liver is associated with inammation. It is potentially serious because up to
one- fourth of these patients can progress to having cirrhosis.
Fatty liver and NASH are mostly related to increased body mass
index, but they can also be associated with rapid weight loss
or drugs such as tamoxifen, amiodarone, diltiazem, nifedipine,
324 BASIC SKILLS IN INTERPRETING LABORATORY DATA
https://t.me/med1917
corticosteroids, and petrochemicals. Fatty liver/NASH can be
seen in patients with hepatitis C and patients on total parenteral
nutrition, and it is associated with hypothyroidism and short
bowel syndrome.
It is important to note that although mild hepatic inammation is oen of minimal signicance, it may signal the presence
of a chronic and serious disease process. Some other causes of
hepatic inammation and injury are listed in Table15-2.
It is oen dicult to determine the exact etiology of hepatic
inammation or hepatitis. A careful history— especially for
exposure to drugs, alcohol, or toxins— and detailed physical examination are crucial. Additional laboratory studies are
usually necessary to distinguish one form of hepatitis from
another (Figure15-4). Radiologic testing or liver biopsy may be
indicated, not only to determine the etiology of the liver disease
but also to help determine the indications for (and results of)
therapy and prognosis.
Aminotransferases: Aspartate Aminotransferase
and Alanine Aminotransferase
AST: 12 to 38 units/L (0.2 to 0.65 µkat/L); ALT: 7 to 41 units/L
(0.12 to 0.70 µkat/L) (normal values for either test vary
from laboratory to laboratory but tend to be in the range of
<30 units/L for men and <20 units/L for women)
e aminotransferases (also known as transaminases) are
used to assess hepatocellular injury and include AST (formerly
serum glutamic- oxaloacetic transaminase) and ALT (formerly
FIGURE 15-4. Algorithm for differential diagnosis of suspected hepatitis.
CHAPTER 15 • LivER And GAsTRoEnTERoLoGy TEsTs 325
https://t.me/med1917
serum glutamic- pyruvic transaminase). ese enzymes are primarily located inside hepatocytes, where they assist with various metabolic pathways. ey are released into the serum in
greater quantities when there is hepatocyte damage, are very
sensitive, and may be elevated even with minor levels of hepatocyte damage. However, this renders them relatively nonspecic,
and slightly elevated levels may not be clinically signicant (particularly in an ill, hospitalized patient who is on many medications and has a variety of active medical problems).
Aminotransferases are oen slightly increased in cholestatic
liver diseases, but in this situation, they are generally overshadowed by a greater elevation of cholestatic liver tests (ie, ALP and
total bilirubin to produce a predominantly cholestatic pattern
of liver tests). If both aminotransferases and cholestatic tests are
elevated in a similar pattern, it suggests a severe hepatocellular
process, which interferes with bile secretion at the level of the
hepatocytes. Finally, it should be noted that aminotransferases
may rise into the thousands within 24 to 48 hours aer common
bile duct obstruction, aer which they decline rapidly. is is
one instance in which a cholestatic process may transiently cause
a hepatocellular injury LFT prole.
Both AST and ALT have half- lives of 17 and 47 hours, respectively, so they reect active hepatocyte damage and not, for
example, damage to hepatocytes that occurred weeks, months,
or years previously. is may lead to some counterintuitive relationships between aminotransferase levels and the overall state
of the liver. For example, a drop in aminotransferase levels in the
setting of acute massive (fulminant) hepatitis may reect a depletion of viable hepatocytes with poor prognosis. Extremely high
concentrations (>1,000 units/L) are usually associated with acute
viral hepatitis, severe drug or toxic reactions, or ischemic hepatitis (inadequate blood ow to the liver). Lesser elevations are
caused by a vast number of hepatic insults and are less specic.
e ratio of AST to ALT may be of value in diagnosing alcoholic hepatitis, in which the AST is generally at least twice the
ALT, and the AST is rarely >300 units/L. In alcoholic liver disease, this is due, in part to a deciency of pyridoxal 5′- phosphate,
which favors production of ALT over AST.16 Alcoholic liver
disease is also suggested by an elevation in GGT, as previously
reviewed.
AST is not solely located in hepatocytes but rather is also
found in cardiac muscle, skeletal muscle, kidneys, brain, lungs,
intestines, and erythrocytes. Consequently, AST may be elevated
due to a variety of situations, including musculoskeletal diseases
(eg, muscular dystrophy, dermatomyositis, heavy exercise, trichinosis, gangrene, and muscle damage secondary to hypothyroidism), myocardial infarction, renal infarction or failure, brain
trauma or cerebral infarction, hemolysis, pulmonary embolism,
necrotic tumors, burns, and celiac sprue. ALT is more localized
to the liver than AST, so it is more specic to liver injury. Elevation of AST without elevation of the ALT or other liver test
abnormality suggests cardiac or muscle disease. A muscular origin of aminotransferases may also be indicated by increases in
aminotransferases >300 International Units/L with concomitant
increases in serum creatine kinase activity.
Measurement of AST may be aected by a bewildering variety of medications. Almost any prescription drug (as well as
various herbal compounds and illegal drugs) can cause an elevation of aminotransferases, and the signicance of these elevations is oen unclear. Furthermore, the in vitro assay may be
confounded by a variety of factors, including uremia, hyperlipidemia, and hemolysis.17 False elevations in the in vitro test may
also be seen in patients on acetaminophen, levodopa, methyldopa, tolbutamide, para- aminosalicylic acid, or erythromycin.
Other factors may interfere with the test’s accuracy. Levels may be elevated to two to three times normal by vigorous
exercise in male patients and decreased to about half following dialysis. Complexing of AST with immunoglobulin (known
as macro-AST) may occasionally produce a clinically irrelevant
elevation of AST.18 Testing for macro-AST is not a clinical laboratory test used in practice. Given the array of factors that can
cause an abnormal result, unexplained false- positive results
oen occur. In healthy individuals, an isolated elevated ALT
returns to normal in repeat studies one- half to one- third of the
time. For this reason, prior to an evaluation of mildly elevated
aminotransferases in low- risk healthy patients, a practitioner
should check for an elevation of more than one test (ie, both
AST and ALT) or repeated elevations of a single test.
TESTS ASSOCIATED WITH
DETOXIFICATION
Hepatic Encephalopathy
Hepatic encephalopathy refers to a potentially reversible diuse
metabolic dysfunction of the brain that may occur in acute or
chronic liver failure.19 Clinically, it ranges from subtle changes in
personality to coma and death. e etiology of hepatic encephalopathy remains controversial. Many theories ascribe a major
role to ammonia. Most ammonia enters the portal circulation
from the intestines, where it is formed by bacterial catabolism
of protein within the gut lumen as well as conversion of serum
glutamine into ammonia by enterocytes of the small intestine.
Normally, the liver removes >90% of this ammonia via rst- pass
metabolism before it can enter the systemic circulation.20 In liver
failure, ammonia, along with possibly other toxic substances,
may avoid this rst- pass metabolism and gain immediate access
to the brain, where it has a variety of toxic eects. While the
exact role of ammonia in terms of hepatic encephalopathy is
not clear, it is of interest that current treatment seems focused
on lowering serum ammonia levels.
Ammonia
Normal range: 19 to 60 mcg/dL (11 to 35 µmol/L)
Ammonia levels do not correlate well with hepatic encepha-
lopathy in the setting of chronic liver failure (ie, patients with
cirrhosis). is is likely because hepatic encephalopathy also
involves an increase in the permeability of the blood–brain barrier to ammonia. ere is a large overlap between ammonia levels in patients with and without hepatic encephalopathy among
patients with chronic liver disease, making it a poor test in this situation.21 Although a very high ammonia level (ie, >250 mcg/dL)
is suggestive of hepatic encephalopathy, most patients with
Соседние файлы в папке Библиотека им академика М.И. Перельмана