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194 Cards in this Set

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What is unconjugated bilirubin?
Also called indirect or trans bilirubin.
Water-insoluble and taken to the liver bound to albumin to be glucorinidated to conjugated bilirubin, which is water-soluble.
What is conjugated bilirubin?
Also called direct or cis bilirubin.
The water-soluble form of bilirubin.
What is bilirubin?
Major metabolite of heme, which is found in hemoglobin, myoglobin, and cytochromes.
How much bilirubin is produced daily?
250-350 mg.
How is bilirubin formed?
In macrophages of the spleen, methemoglobin from red blood cells is split to give free globin chains and heme. The porphyrin ring of heme is oxidized by microsomal heme oxygenase to produce biliverdin, releasing iron. Biliverdin is reduced to bilirubin by the NADPH-dependent enzyme, biliverdin reductase.
Associates with the Y and Z proteins and then binds to ligandin upon entering the hepatocyte. Then transported to the smooth endoplasmic reticulum where glucuronyl transferase catalyzes the esterification of bilirubin to form diglucorinide conjugate.
Conjugated bilirubin is then transported to the canalicular face of the hepatocyte and secreted by an energy-dependent mechanism.
To what is conjugated bilirubin further metabolized by intestinal bacteria?
metabolized by intestinal bacteria to urobilinogen and urobilin, which can be reabsorbed in the gut. Intestinal urobilinogen is further converted to stool pigments such as stercobilin (clay-colored stools are often an early sign of impaired bilirubin metabolism).
Which form of bilirubin never appears in urine, even at extremely high elevations?
Unconjugated bilirubin.
What is delta bilirubin?
Conjugated bilirubin can become covalently bound to albumin that produces delta-bilirubin.
How does the half-life of delta bilirubin compare to that of bilirubin?
Delta bilirubin has a half-life of 17 days whereas bilirubin has a half-life of 24 hours Delta bilirubin is unable to be secreted by the liver and kidneys.
Why does neonatal jaundice develop?
Usually results from build-up of unconjugated bilirubin due to an innate low glucuronyl transferase activity.
What are the clinical features of neonatal jaundice?
Seen between 2-3 days of neonatal life and rarely rises above 5 mg/dL/day.
What are some causes of severe hyperbilirubinemia in the neonate?
Hemolytic disease of the newborn and sepsis.
What causes kernicterus?
Bilirubin can cross the poorly developed blood-brain barrier causing damage to the CNS, which causes yellow staining of the subthalamic nucleus, hippocampus, thalamus, globus pallidus, putamen, cerebellar nuclei, and cranial nerve nuclei.
How is hyperbilirubinemia detected in the newborn before the onset of jaundice?
Transcutaneous bilirubin.
What features suggest that hyperbilirubinemia in a newborn is not due to physiologic jaundice?
Jaundice within first 24 hours of life.
Rising bilirubin beyond 1 week.
Persistence of jaundice past 10 days.
Total bilirubin >12 mg/dL.
Single-day increase of >5 mg/dL.
Direct bilirubin >2 mg/dL.
What does bilirubinuria indicate?
Conjugated hyperbilirubinemia.
When should phototherapy begin in a neonate with jaundice?
Wen bilirubin >10 mg/dL before 12 hours of age, 12 mg/dL before 18 hours of age, and 14 mg/dL before 24 hours of age. (Phototherapy not useful for conjugated hyperbilirubinemia).
When should exchange transfusions begin in a neonate with jaundice?
When bilirubin >20 mg/dL.
What is the differential diagnosis of jaundice in a neonate in the first 24 hours of life?
Erythoblastosis fetalis, concealed hemorrhage, sepsis, or TORCH infection.
What is the differential diagnosis of jaundice in a neonate between the 3rd and 7th days of life?
Bacterial sepsis (particularly urinary tract origin).
What is the differential diagnosis of jaundice in a neonate after the first week of life?
Breast milk jaundice, sepsis, extrahepatic biliary atresia, cystic fibrosis, congenital paucity of bile ducts (Alagille syndrome), neonatal hepatitis, galactosemia, or inherited hemolytic anemia (PK deficiency, G6PD deficiency, hereditary spherocytosis).
What is Gilbert syndrome?
Common (3% of the population) autosomal dominant disorder due to a deficiency in glucoronyl transferase caused by the insertion of two bases into the promoter region of the UGT1A1 gene.
What are the clinical features of Gilbert syndrome?
Characterized by a mild unconjugated hyperbilirubinemia.
Total bilirubin is typically elevated to 2-3 mg/dL and seldom exceeds 5 mg/dL.
Characteristically, bilirubin rises after a 24 hours fast or with acute illness.
Patients may report vague abdominal pain and general fatigue.
What is Crigler-Najjar syndrome?
Extremely rare autosomal recessive unconjugated hyperbilirubinemia caused by a more severe deficiency of glucuronyl transferase than Gilbert’s syndrome.
What are the features of type 1 Crigler-Najjar syndrome?
Uniformly fatal if left untreated due to kernicterus.
Patients have homozygously nonfunctioning proteins.
Associated with neonatal unconjugated hyperbilirubinemia.
Almost complete absence of glucuronyl transferase.
What are the features of type 2 Crigler-Najjar syndrome?
Presents with a lower total bilirubin and response to phenobarbital treatment (induces the expression of glucuronyl transferase).
Severely decreased but not absent glucuronyl transferase.
What is Dubin-Johnson syndrome?
An autosomal recessive conjugated hyperbilirubinemia caused by a blockade of the excretion of bilirubin into the canaliculi due to defective ATP-binding cassette (ABC) anion transporter.
What are the features of Dubin-Johnson syndrome?
Develop nonpruritic jaundice during their teenage years and sometimes nonspecific right upper quadrant pain.
Subclinical cases become apparent during pregnancy and the initiation of oral contraceptions (due to decreased excretion of organic anions).
Characteristically intense dark pigmentation of the liver due to accumulation of lipofuscin pigment.
What is Rotor syndrome?
An autosomal recessive conjugated hyperbilirubinemia characterized by nonpruritic jaundice and NO pigmentation of the liver.
How is Rotor syndrome distinguished from Dubin-Johnson syndrome?
There is no pigmentation of the liver in Rotor syndrome and the gallbladder is able to be radiographically visualized, unlike Dubin-Johnson syndrome.
How is bilirubin measured?
Measured using diazotized sulfanilic acid.
Forms a conjugated azo compound with the porphyrin rings of bilirubin that can be absorbed strongly at 540 nm.
Direct spectrophotometry can determine the bilirubin concentration by measuring absorbance at 455 nm; potential interference by hemoglobin is corrected for by subtracting the absorbace at 575 nm (hemoglobin’s other absorbance peak). This method is only capable of measuring total bilirubin.
Direct bilirubin should be 0-0.1 mg/dL in a normal individual.
What needs to be added to a bilirubin measurement test in order to measure unconjugated bilirubin?
Unconjugated (indirect) bilirubin reacts slowly and needs caffeine or methanol to speed up the reaction to measure total bilirubin, thus, absence of these accelerants only measures direct bilirubin.
What causes hyperammonemia?
Nearly always due to liver failure, but should raise suspicion for urea cycle enzyme deficiencies in children.
What are the sources of ammonia?
Skeletal muscle and bacteria in the gastrointestinal system.
Where is ammonia metabolized and why is it the only organ where ammonia is metabolized?
Ammonia can only be metabolized in the liver because the liver uniquely contains the Krebs-Henseleit or urea cycle.
What is the rate limiting step of the urea cycle?
Ornithin carbamoyltransferase (OCT).
What is the mechanism of ammonia causing neurotoxicity?
Ammonia can cause neurotoxicity by reacting with glutamic acid to form glutamine, thus depleting glutamic acid in the CNS and causing a decrease in gamma-aminobutyric acid (GABA), a neurotransmitter.
What liver disorders cause hyperammonemia?
Reye’s syndrome, fulminant hepatic failure, and cirrhosis, can cause hyperammonemia.
What can be measured to diagnose hepatic encephalopathy?
Cerebrospinal fluid levels of glutamine.
What substance can reduce serum ammonia?
Lactulose, which is metabolized by bacteria to lactate. It is able to trap ammonia as ammonium ion, which cannot be absorbed and is thus excreted.
What is the preferred specimen to meausre ammonia levels?
Arterial blood. If venous blood is used, tourniquets and fist clenching and relaxing should be avoided during collection.
How should a specimen for measurement of ammonia be handled?
Sample should be kept on ice until separation of plasma in order to limit excess generation of ammonia from cell metabolism.
Also, a patient who smokes should abstain for several hours preceding the blood draw.
How is ammonia levels measured?
Measured by enzymatic assays measuring glutamate dehydrogenase, which catalyzes the reaction of alpha-ketoglutarate and ammonia to form glutamate with oxidation of NADPH to NADP as the indicator (decrease in absorbance at 340 nm).
Also measured in a dry slide method using alkaline pH buffers to convert ammonium ions to ammonia gas with bromphenol blue as the indicator.
What lipoprotein abnormalities can be seen with liver dysfunction?
Decrease in HDL (especially HDL3 but not HDL2), decrease in cholesterol acyltransferase (enzyme that esterifies cholesterol), and decrease in lipoprotein lipase (results in triglyceridemia of 250-500). Results in an abnormally migrating beta-lipoprotein typical of Type III hyperlipoproteinemia.
What lipoprotein abnormalities are caused by alcohol ingestion?
increased apoA-I protein. HDL3 is elevated if alcohol ingestion continues.
What lipoprotein abnormalities are caused by cirrhosis?
ApoA-I protein decreases
What lipoprotein abnormalities are caused by cholestasis?
biliary regurgitation causes build-up of lipoprotein X.
What bile salt abnormalities are caused by cirrhosis?
Primary bile salts (cholate, chenodeoxycholate) are produced in the liver, excreted in bile, and turned into secondary bile salts (lithocholate, deoxycholate, ursodeoxycholate) by intestinal bacteria.
In cirrhosis there is a disproportionate decrease in cholic acid and decreased ratio of primary to secondary bile salts due to decreased conjugation of bile salts to taurine and sulfates. Bile salts are not formed with cholestasis, and so the ratio of primary to secondary bile salts is greatly increased.
How is bile salt analysis performed?
Must be done on serum from fasting state patients because food causes increased bile acid levels. High-performance liquid chromatography is used to allow separation of bile salts.
How can the inability of the damaged liver to metabolize drugs be used to diagnose liver disease?
Radiolabeled drug (13C-labeled) can be used with the amount of 13CO2 measured.
Caffeine and diazepam are metabolized independent of blood flow to the liver. Caffeine metabolism is decreased with age and increased by smoking.
Methacetin, phenacetin, and erythromycin depend on hepatic blood flow for metabolism on top of cytochrome P450.
Less than normal levels of 13CO2 will be exhaled with vitamin B12 deficiency simply due to low vitamin B12 levels.
What protein produced by the liver has the shortest half-life?
Factor VII has the shortest half-life at 4-6 hours. Transthyretine and transferrin also have short half-lives.
What is the half-life of albumin?
20 days.
How are serum protein levels determined?
Serum protein levels are determined by the biuret method, which is based on the ability of C=O groups to form color complexes with copper that absorb at 540 nm.
Total serum protein has a reference range of 6-7.8 g/dL, and at least 60% should be albumin (3.5-5 g/dL).
What is the serum protein profile for a patient with cirrhosis?
There is a DECREASE in albumin and the alpha-1, alpha-2, and beta bands. However, there is an INCREASE in immunoglobulins, producing the beta-gamma “bridging” pattern.
What is the serum protein profile for a patient with autoimmune hepatitis?
Polyclonal increase in IgG.
What is the serum protein profile for a patient with primary biliary cirrhosis?
Polyclonal increase in IgM.
What are the features of alpha-1-antitrypsin?
An important protease inhibitor in plasma.
Coded for by the Pi gene on chromosome 14.
Adults with PIZZ are prone to emphysema early in life due to uninhibited trypsin activity on alveolar wall elastin. Also accumulate Z protein in the cytoplasm of periportal hepatocytes, which causes neonatal hepatitis.
What is ceruloplasmin?
A copper-containing protein that is a ferroxidase responsible for converting iron to a ferric state so that it can bind to transferrin.
Ceruloplasmin in the liver promotes copper secretion into plasma and the biliary tract.
What condition is associated with low ceruloplasmin?
Wilson disease has a low level of ceruloplasmin. Caused by a mutation in the cellular adenosine triphosphatase (ATPase) protein coded by chromosome 13.
What are the features of Wilson disease?
Excess copper is deposited into lysozymes of hepatocytes and induce lipid peroxidation and membrane instability, causing chronic active hepatitis. Copper is also deposited in the lenticular nucleus of the basal ganglia and the iris (Keyser-Fleischer rings).
What is the only clotting factor not produced by the liver?
Von Willebrand factor.
What is the most commonly seen coagulopathy in liver failure?
DIC, which is characterized by increased consumption of clotting factors and platelets with an increase in PT and PTT times. Diagnosis of DIC is confirmed by elevated D-dimer. Sequestration of platelets in the spleen combined with elevated PT and PTT can mimic DIC.
What affect does cholestasis have on clotting factors?
Absorption of fat soluble vitamin K is low with decreased bile salts due to cholestasis. Factors II, VII, IX, and X depend on vitamin K, so coagulation abnormalities result.
What is the MELD?
Model for end-stage liver disease (MELD) score in evaluating priority for liver transplantation. This value is based upon bilirubin, INR, and creatinine.
What is des-gamma-carboxy prothrombin (DCP)?
DCP is the unmodified precursor of prothrombin that can be elevated in patients with hepatocellular carcinoma.
Vitamin K-dependent coagulation factors require post-translational modification prior to secretion into blood.
How is des-gamma-carboxy prothrombin (DCP) measured?
Measured using 19B7 and MU-3 monoclonal antibodies.
What is aspartate aminotransferase (AST)?
Previously called serum glutamate oxaloacetate transaminase (SGOT).
Found in cardiac muscle, liver, skeletal muscle, kidney, brain, lung, pancreas (in decreasing order of concentration). Found within cytoplasm (about 20%) and mitochondria (about 80%).
Often used to monitor therapy with potentially hepatotoxic drugs.
What is the half-life of aspartate aminotransferase (AST)?
17 hours.
What is the activity of AST compared to that of ALT?
AST activity is slightly higher than ALT in children with this pattern reversing by age 20.
What is the required cofactor of aspartate aminotransferase (AST)?
Pyridoxal phosphate (vitamin B6).
AST can be low in alcoholics even with hepatic injury due to deficiency of vitamin B6.
What is the affect of alcohol ingestion on AST and ALT?
Alcohol induces mitochondrial damage, resulting in AST elevation that is disproportionate to ALT (ALT/AST quotient is called the DeRitis ratio).
What is the upper limit of normal for aspartate aminotrasnferase (AST)?
Upper limit of normal is 40 IU/L.
Levels of aspratate aminotrasnferase (AST) are higher in which individuals?
Levels are higher in adult males than adult females and African-Americans.
How is aspartate aminotrasnferase measured?
Aspartate is added to the assay to force the reaction to produce glutamate. Glutamate production is coupled to glutamate dehydrogenase to yield alpha-ketoglutarate in the indicator reaction. NAD is converted to NADH, which causes increased absorbance at 340 nm.
Another assay is to couple oxaloacetate (forms from aspartate in the above stated reaction) to malate dehydrogenase, which converts oxaloacetate to malate with NADH conversion to NAD and thus decreased absorbance at 340 nm.
How do the levels of AST in a patient on heparin compare to normal levels?
Elevated around 3 x baseline.
How do the levels of AST in a patient with renal failure compare to normal levels?
Significantly lower in patients with renal failure than in healthy individuals.
What is alanine aminotransferase?
Previously called serum glutamate pyruvate transaminase(SGPT).
Located entirely within the cytoplasm.
More specific for liver, confined mainly to liver and kidney.
What is the required cofactor of alanine aminotransferase?
Pyridoxal phosphate (vitamin B6).
ALT can be low in alcoholics even with hepatic injury due to deficiency of vitamin B6.
What is the half-life of alanine aminotransferase?
47 hours.
For which patients is ALT more specific than AST for detecting hepatocyte injury?
Nonalcoholic patients.
Also hepatitis C.
How do AST and ALT compare in a patient with chronic hepatocytic injury?
ALT is more commonly elevated than AST in chronic hepatocytic injury. However, AST is often higher than ALT as fibrosis progresses.
What is the upper limit of normal for alanine aminotransferase (ALT)?
40 IU/L.
What substance lowers alanine aminotransferase (ALT) levels?
Ursodeoxycholic acid.
How is alanine aminotransferase (ALT) measured?
Alanine is added to the assay to force the reaction to yield glutamate. Glutamate production is coupled to glutamate dehydrogenase to yield alpha-ketoglutarate in the indicator reaction. NAD is converted to NADH, which causes increased absorbance at 340 nm.
Conversion of alanine to pyruvate allows coupling to pyruvate dehydrogenase which converts pyruvate to acetyl coenzyme A that converts NAD to NADH, causing increased absorbance at 340 nm.
Must be evaluated over a short time period because alpha-ketoglutarate is regenerated by the indicator reaction.
In which patients is alanine aminotransferase (ALT) elevated?
Higher in adult males than adult females and African-Americans.
Is intra-individual variation more significant for AST or ALT?
Intra-individual variation is more significant for ALT than AST, with marked diurnal variation (highest in the afternoon) and day-to-day variation of up to 30%.
What are the features of LD1 and LD2?
Fastest-moving isozymes of lactate dehydrogenase by electrophoresis.
Predominately found in cardiac muscle, kidney, and erythrocytes with a significantly greater proportion of LD1 than LD2.
What are the features of LD4 and LD5?
Slowest-moving isozymes.
Predominately found in liver and skeletal muscle.
What are the features of LD3?
Predominately found in lung, spleen, lymphocytes, and pancreas.
What are the features of LD6?
Sometimes seen migrating cathodal to LD5.
Thought to be a dire finding indicative of hepatic vascular insufficiency (usually in the setting of cardiovascular collapse).
What are the normal comparative concentrations of lactate dehydrogenase in serum?
LD2>LD1>LD3>LD4>LD5.
What conditions could be associated with elevated LD1, particularly with a "flipped LD" ratio (LD1 > LD2)?
Acute myocardial infarction, hemolysis, and renal infarction.
What does elevated LD4 and LD5 suggest?
Liver damage, but other possibilities include skeletal muscle insults.
How can elevated LD1 and LD5 be explained?
Acute myocardial infarction which has been complicated by liver congestion
Chronic alcoholism that has been complicated by liver damage and megaloblastic anemia.
What are the normal comparative concentrations of lactate dehydrogenase in CSF?
LD1>LD2>LD3>LD4>LD5.
What is the upper limit of normal for lactate dehydrogenase?
150 IU/L.
What laboratory values suggest a space-occupying lesion of the liver?
LD levels >500 IU/L combined with alkaline phosphatase >250 IU/L in the absence of elevated AST and ALT suggests space-occupying lesions of the liver.
Does LDH become elevated in patients with hepatitis?
LD levels become elevated in hepatitis but return to normal levels by the time of clinical presentation.
What is alkaline phosphatase?
Two types of phosphatases:
Acid (pH optimum is 5) phosphatases (ACP) are found in greatest concentrations in prostate, red cells, and bone. Red cell acid phosphatase is distinguished from other ACPs by its susceptibility to inhibition by 2% formaldehyde and resistance to inhibition by tartrate.
Alkaline phosphatases (pH optimum is 9).

Present in liver, bone, placenta, intestine, and kidney.
In what conditions can elevated alkaline phosphatases be seen?
Biliary disease, bone disease, bone growth (children), and pregnancy.
What is the half-life of alkaline phosphatase?
3 days.
What conditions are associated with decreased alkaline phosphatase?
Hypophosphatasia (an inborn deficiency) and malnutrition.
What is high-molecular-weight alkaline phosphatse?
High-molecular-weight ALP seen in cholestasis that consists of ALP attached to fragments of canalicular membrane. Another high-molecular-weight ALP has been seen in malignant liver disease.
What is the relationship between bilirubin and alkaline phosphatase in patients with obstructive cholestasis?
Elevated twice the upper limit of normal in obstructive cholestasis and rises parallel to bilirubin elevation.
Elevated out of proportion to bilirubin elevation in partial obstruction.
ALP falls back to normal levels slower than bilirubin does after cholestasis is relieved.
How can the different types of alkaline phosphatase be differentiated?
Electrophoresis can separate alkaline phosphatase into 4 isoenzymes, each of which displays characteristic degrees of inactivation with heating, urea incubation, and 1-phenylalanine. Sensitivity to urea incubation parallels heating.
What is the most sensitive alkaline phosphatase marker of hepatic metastases?
Biliary alkaline phosphatase.
What is the significance of bone alkaline phosphatase?
Bone alkaline phosphatase is produced by osteoblasts and reflects bone-forming activity. Some of the highest alkaline phosphatase levels are seen in Paget disease of bone. A specific immunoassay for bone alkaline phosphatase is available.
What is the Regan isoenzyme?
The Regan isoenzyme is observed in 5% of individuals with carcinoma. It appears to be identical to placental alkaline phosphatase.
What is the significance of intestinal alkaline phosphatase?
Intestinal alkaline phosphatase can be the cause of factitious elevations in nonfasting individuals, particularly in Lewis positive type B or O secretors. Ingesting a meal can elevate the alkaline phosphatase by 30% for 2-12 hours. A repeat fasting alkaline phosphatase may be indicated.
In which patients are the alkaline phosphatase levels elevated?
Alkaline phosphatase is usually a little higher in men than women and higher in African-American women than in white women. If it is minimally elevated on 2 separate occasions >6 months apart, further studies must be done.
What conditions are associated with elevated alkaline phosphatase?
Unrecognized pregnancy, CHF, hyperthyroidism, and exposure to certain drugs (ibuprofen, acetaminophen).
What are the characteristics of biliary alkaline phosphatase?
Mildly inhibited by heat/urea.
Not inhibited by L-phenylalanine.
Has an anodal mobility of 1.
What are the characteristics of bone alkaline phosphatase?
Severely inhibited by heat/urea ("bone burns").
Not inhibited by L-phenylalanine.
Has an anodal mobility of 2.
What are the characteristics of placenta alkaline phosphatase?
Not inhibited by heat/urea.
Severely inhibited by L-phenylalanine.
Has an anodal mobility of 3.
What are the characteristics of intestinal alkaline phosphatase?
Mildly inhibited by heat/urea.
Severely inhibited by L-phenylalanine.
Has an anodal mobility of 4.
What are the characteristics of Regan alkaline phosphatase?
Not inhibited by heat/urea.
Severely inhibited by L-phenylalanine.
Has an anodal mobility of 3.
Which alkaline phosphatases are inhibited by heat/urea?
Bone, intestinal.
Which alkaline phosphatases are inhibited by L-phenylalanine?
Placenta, intestinal, Regan.
Which variants of alkaline phosphatase have similar characteristics?
Placenta and Regan.
What is gamma-glutamyl transferase (GGT)?
Found in the biliary epithelial cell, particularly those that line the small interlobular bile ducts and bile ductules. Also present within the smooth endoplasmic reticulum of hepatocytes, so can be followed as a marker of alcohol consumption and other liver injury.
What is the half-life of gamma-glutamyl transferase (GGT)?
10 days but can be as long as 28 days in recovering alcoholics.
What conditions are associated with elevated gamma-glutamyl transferase (GGT)?
Liver disorders, steatosis, diabetes, hyperthyroidism, rheumatoid arthritis, acute myocardial infarction, and chronic obstructive pulmonary disease.
Is gamma-glutamyl transferase higher in patients with obstructive and space-occupying lesions or patients with hepatocytic injury?
Higher in obstructive disorders and space-occupying lesions than hepatocytic injury.
What laboratory findings can be seen with cholestasis of pregnancy?
GGT remains normal in cholestasis of pregnancy whereas ALP is increased.
What drugs raise gamma-glutamyl transferase (GGT)?
Phenytoin, carbamazepine, and acetaminophen all raise GGT (possibly due to GGT being used to restore glutathione that is used to metabolize these drugs).
How is gamma-glutamyl transferase (GGT) measured?
GGT utilizes gamma-glutamyl-p-nitroanilide. p-nitroaniline is liberated and produces a colored product that can be measured.
What are the features of 5'-nucleotidase?
It is produced in the biliary epithelium, and levels are highest in cholestatic diseases. Hardly ever elevated in patients with bone disease, so its elevation can confirm elevated alkaline phosphatase caused by hepatobiliary disease.
Where is alpha-feta protein produced?
Produced by embryonic hepatocytes and fetal yolk sac cells.
What are the features of alpha-feta protein?
Elevated in fetal neural tube defects.
Vary with gestational age.
Rises after hepatic injury (100-200 ng/dL) from regenerating hepatocytes.
Marker of hepatocellular carcinoma.
What level of alpha-feta protein indicates a high probability of hepatocellular carcinoma?
>400 ng/dL.
Upon what does the level of alpha-feta protein depend in patients with hepatocellular carcinoma?
Degree of differentiation of tumor and age of patient.
What is antimitochondrial antibody?
It is an antibody seen in primary biliary cirrhosis, which is seen primarily in women in the fifth decade that also have other autoimmune disorders, particularly Sjögren’s syndrome. Causes fibrosis of bile canaliculi and portal triads.
How is antimitochondrial antibody detected?
ELISA detects antibodies in 90% of patients directed against the inner mitochondrial membrane (M2) that is dihydrolipoamide acetyltransferase. Anti-M2 is 100% specific for primary biliary cirrhosis.
What antimitochondrial antibody is associated with syphilis?
Anti-M1.
What antimitochondrial antibody is associated with collagen vascular disease?
Anti-M5.
What antimitochondrial antibody is associated with iproniazide-induced hepatitis?
Anti-M6.
What antimitochondrial antibody is associated with cardiomyopathies?
Anti-M7.
What antibodies are associated with primary sclerosing cholangitis?
Perinuclear antineutrophil cytoplasmic antibodies (pANCAs) are found in 2/3 of patients with primary sclerosing cholangitis. 75% of patients also have antinuclear antibodies (ANAs) or anti-smooth muscle antibodies (ASMAs).
What antibodies are associated with type 1 autoimmune hepatitis?
Type 1 autoimmune hepatitis (most common autoimmune hepatitis in the US) is associated with antinuclear antibodies (ANAs) and anti-actin antibodies (ASMAs). Titers >1:80 suggests autoimmune hepatitis.
What antibodies are associated with type 2 autoimmune hepatitis?
Type 2 autoimmune hepatitis usually affects children and is more common in Europe. ANAs and ASMAs are negative, but antibodies to liver-kidney microsomal antigens (anti-LKM1) are positive.
What antibodies are low in patients with hepatitis C?
ANAs and ASMAs.
What are the features of hepatitis A?
Member of the picornavirus family of RNA viruses.
Transmitted fecal-orally with an incubation period of 15-50 days.
Self-limited.
Which hepatitis is part of the picornivirus family of RNA viruses?
Hepatitis A.
What is the initial immune response to hepatitis A and how long does it take to develop?
Initially immune response is IgM anti-HAV, which develops 2-3 weeks after infection. AST and ALT become elevated after antibody development.
How long does it take for IgG to develop against hepatitis A?
IgG is produced within 1-2 weeks of IgM production.
How is hepatitis A infection diagnosed?
Total anti-HAV measures IgM and IgG antibodies.
PCR should not be used for routine diagnosis.
What are the features of hepatitis B?
DNA virus of the hepadnavirus family.
Transmitted by body fluid, sex, and mother to baby.
Which hepatitis is part of the hepadnivirus family of DNA viruses?
Hepatitis B.
What antigens are important for the diagnosis of hepatitis B infection?
Core antigen (HBcAg), surface antigen (HBsAg), and e antigen (HBeAg).
What antigens are seen in acute HBV hepatitis?
HBsAg, IgM anti-HBc.
What antigens are seen in chronic HBV hepatitis?
HBsAg, IgG anti-HBc, IgG anti-HBs.
What antigens are seen in the core window of hepatitis B infection?
IgG anti-HBe, IgM anti-HBc, IgG anti-HBc.
Which antigen is the last marker of recovery from hepatitis B infection?
Development of anti-HBs.
What is associated with e antigen seen in HBV infection?
Circulating viral particles.
What test is used to monitor therapeutic response in patients with hepatitis B infection?
HBV DNA PCR.
What are the features of hepatitis C?
RNA virus of flavivirus family.
85% of patients with HCV have chronic infection.
Which hepatitis is part of the flavivirus family of RNA viruses?
Hepatitis C.
What tests are used to diagnose hepatitis C infection?
Third-generation HCV assay detects antibody 7-9 weeks after infection.
HCV recombinant immunoassay (RIBA-1) uses recombinant HCV proteins to confirm positivity. Presence of 2 out of 4 HCV antigens is a positive, presence of 0 out of 4 is a negative, and presence of 1 out of 4 is indeterminate.
What test is used to confirm persistence of hepatitis C infection?
HCV RNA.
What is the most common genotype of hepatitis C in the United States?
Genotype 1.
What genotype of hepatitis C is most responsive to treatment?
Genotypes 2 and 3.
What are the features of hepatitis D?
RNA virus that needs HBsAg to replicate.
Also called the delta-agent.
As it pertains to hepatitis, what is coinfection?
Infection of hepatitis B and hepatitis D occur at the same time.
Infection is more severe and can cause fulminant hepatitis.
Higher fatality rate than hepatitis B alone.
Diagnosed by presence of anti-HBc and anti-HDV.
As it pertains to hepatitis, what is superinfection?
HDV infection on top of persistent hepatitis B infection.
Faster progression of disease.
Diagnosed by presence of anti-HDV and absence of anti-HBc.
What are the features of hepatitis E?
RNA virus caused by fecal-oral infection.
Increased fatality rate of 20% in pregnant women.
What antibody is associated with recent hepatitis E infection?
Anti-HEV IgM detects recent or current infection.
What antibody is associated with past hepatitis E infection?
Anti-HEV IgG detects current or past infection.
What test provides the definitive diagnosis of hepatitis E?
PCR using serum, plasma, bile, or feces is available and is the definitive indicator of disease. However, it has a window of detection between 2-7 weeks after infection.
What are the features of hepatitis G?
A virus that is suspected to cause post-transfusion hepatitis but does not seem to cause liver disease.
No routine testing recommended.
What are the clinical features of hepatitis?
Presents clinically with fatigue and anorexia.
Damage is caused by virus as well as immune response to infection.
Can have jaundice.
What laboratory findings are found in patients with hepatitis infection?
Principal change in hepatitis is elevations of aminotransferases >200 IU/L and sometimes >500 IU/L. However, hepatitis C has mild elevations of ALT but usually normal AST.
Lactate dehydrogenase is mildly elevated to 300-500 IU/L, and alkaline phosphatase can be elevated to 200-350 IU/L due to canalicular damage.
What is chronic passive congestion?
Usually secondary to CHF as a result of back pressure from the right heart.
Back pressure is transported to the hepatic sinusoids via the inferior vena cava and hepatic veins.
What laboratory findings are seen in patients with chronic passive congestion?
Chronic passive congestions results in mild increase in aminotransferases and bilirubin.
What is hemochromatosis?
Iron deposits in tissues including liver where it is hepatotoxic and predisposes to cirrhosis.
Results from single amino acid substitution (C282Y) in protein product of HFE gene on chromosome 6.
How is hemochromatosis diagnosed?
Diagnosed by serum iron-binding saturation (>45% in patients with hemochromatosis).
What disorders can cause cirrhosis?
Alcohol, hemochromatosis, Wilson disease, alpha-1-antitrypsin deficiency.
What clinical sequelae are associated with hepatic encephalopathy?
Ranges from asterixis to lethargia to obtundation to frank coma.
What does the PGA index include?
PT and serum levels of gamma-glutamyl transferase and apolipoprotein A1.
Higher PGA scores correlate with degree of hepatic fibrosis and severity of cirrhosis.
What are the features of the Fibrotest and Actitest?
Fibrotest and Actitest index includes levels of apolipoprotein A1, haptoglobin, total bilirubin, GGT, ALT, and alpha-2 macroglobulin as well as patient age and gender.
F0: No fibrosis.
F1: Portal fibrosis.
F2: Bridging fibrosis with few septae.
F3: Bridging fibrosis with many septae.
F4: Frank cirrhosis.
A0: No necroinflammatory activity.
A1: Minimal necroinflammatory activity.
A2: Moderate necroinflammatory activity.
A3: Severe necroinflammatory activity.
What is a Fibrotest index of F0?
No fibrosis.
What is a Fibrotest index of F1?
Portal fibrosis.
What is a Fibrotest index of F2?
Bridging fibrosis with few septae.
What is a Fibrotest index of F3?
Bridging fibrosis with many septae.
What is a Fibrotest index of F4?
Frank cirrhosis.
What is an Actitest index of A0?
No necroinflammatory activity.
What is an Actitest index of A1?
Minimal necroinflammatory activity.
What is an Actitest index of A2?
Moderate necroinflammatory activity.
What is an Actitest index of A3?
Severe necroinflammatory activity.
What is posthepatic biliary obstruction?
Posthepatic biliary obstruction is blockage of the intrahepatic and extrahepatic bile ducts, which causes backflow of bile into the hepatocyte.
What are the most common causes of posthepatic biliary obstruction?
Most common cause is cholelithiasis, but can be caused by primary biliary cirrhosis, primary sclerosing cholangitis, and ascending cholangitis.
What drug can cause posthepatic biliary obstruction?
Chlorpromazine, a neuroleptic, can cause cholestatic jaundice.
What are the laboratory findings of posthepatic biliary obstruction?
Elevated bilirubin, GGT, and ALP.
What laboratory findings are found in space-occupying lesions of the liver?
Represented by isolated elevation of lactate dehydrogenase (500-1000 IU/L) and alkaline phosphatase (>500 IU/L).
Mild transaminase elevation can occur if the malignant lesion spreads widely.
Can have hyperbilirubinemia, low protein, and low albumin with extensive disease, but low protein and albumin is usually caused by generalized cachexia associated with tumor spread.
What cellular organelle conjugates bilirubin in the liver?
Smooth endoplasmic reticulum.