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1. hepatitis  (viral, autoimmune, alcoholic, drug induced)
2. hepatotoxic drugs or toxins
3. liver cancer (primary or metastatic)
4. cirrhosis
5. liver abscess
6. steatosis (fatty liver)
7. severe hepatic congestion (due to right heart failure)
8. intrahepatic biliary tract obstruction (cholangitis, cholecystitis, choledocholithiasis)

b) Alanine aminotrasferase serum (ALT, GPT or SGPT)
Is present in large concentration in liver and, in lesser amount, in kidney, heart and skeletal muscle. It's therefore more specific for liver disease than AST.

This test is highly sensitive (transaminases often become elevated before symptoms occur), but it's also very nonspecific, because it detects only that there is a liver damage, giving few information about liver disease that cause it.
ALT levels are generally higher than AST levels when a liver damage is present. When AST are greater than ALT cirrhosis is generally present.
 
 

2) Lactate Dehydrogenase (LDH)
It's an anzyme present in almost all body cells. When cells are damaged release LDH in bloodstream and its blood levels raise.
 

Markers of Cholestasis

1) Alkaline Phosphatase (AP) (normal values 85-240 U/L)

Is a group of enzymes presents in the bile duct cell, intestine, placenta, bone and kidney. It's increase in:

1. bile duct obstruction (gallstone, tumor, primary biliary cirrhosis, sclerosing cholangitis)
2. bone disorders (osteomalacia, extensive bone metastases, Paget's disease)

2) Gamma Glutamyl Transpeptidase (GGT) (normal values 5-40 U/L)
Is an enzyme that transfers C-terminal glutamic acid from a peptide to another.
GGT is present in liver (bile duct cells), kidney and pancreas. It becomes elevated in:

1. bile duct obstruction (intra or extra hepatic) Associated to alkaline phosphatase elevation.
2. liver disease : viral or toxic hepatitis, cirrhosis, cancer (primary or metastasis)
3. acute pancreatitis
4. renal diseases

3) Bilirubin (normal values  total : 0.1-1.2 mg/dl   direct bilirubin : 0.1-0.4 mg/dl    indirect bilirubin : 0.2-0.7 mg/dl )
Is the breakdown product of heme, a molecule, that can bind oxygen, presents in hemoglobin and cytochrome. When red cells are destroyed into spleen, hemoglobin is subdivide into amino acids and heme, that is catabolized to bilirubin. It's bound to albumin (indirect bilirubin) and transported, through the portal vein, to the liver, where bilirubin is conjugated to glucuronides (direct bilirubin) and excreted in bile. Bilirubin reaches intestine where is partially reabsorbed. Therefore bilirubin can be increased in case of:
1) Increased formation of bilirubin

• destruction of red blood cells (hemolysis)

2) Decreased liver metabolism of bilirubin

• liver disease (acute and chronic hepatitis, cirrhosis, liver cancer, drug or toxic)
• Congenital liver enzyme abnormalities
• Gilbert's syndrome (decreased uptake by the liver)
• Dubin-Johnson and Rotor's syndromes (decreased secretion from the liver)
• Crigler-Najjar syndrome (decreased conjugation)

Increased levels of bilirubin is clinically noticeable with:

• jaundice : when levels are greater than 3 mg/dl
• dark urine : when direct bilirubin is increased (it's hydrosoluble)
• pale stools : when there is biliary obstruction (bilirubin don't reach intestine)

4) 5'-Nucleotidase (5'NT) (normal values 2-7 U/L)
It becomes elevated in bile duct diseases.
 

Markers of Synthetic Ability

1) Serum Protein Electrophoresis
This test allows to separate serum proteins by an electric field and to determinate their concentration.

a) Total serum proteins
Serum proteins are subdivided into albumin and globulins. They decrease in:
• advanced liver disease (reduced synthesis)
• malnutrition or malabsorption
• neoplastic diseases
• renal diseases (loss of proteins)
b) Albumin (normal values 3.5-5 g/dl)
Is the most important protein synthesized by liver. It have three main functions :
• maintain the osmotic pressure (it's a force that keep back plasma into blood vessel, opposing to blood (hydrostatic) pressure)
• transport of ions (e.g. calcium), bilirubin, hormones and drugs
• store amino acids
Albumin decrease when production decreases (liver disease, malnutrition) or loss increases (kidney disease).
In more advanced liver disease, when serum albumin is reduced to less than 3.5 mg/dL, plasmatic osmotic pressure become too low to maintain fluids into blood vessels and edema and ascites occur.
c) Globulins
They are subdivided into:
1. alpha globulins : includes acute phase reactants, which are proteins that increase during inflammation.
2. beta globulins
3. gamma globulins : includes antibodies (immunoglobulins). They are increased in:
• chronic liver disease
• chronic inflammatory disease
• multiple myeloma
• Waldenstrom's macroglobulinemia

1. cirrhosis
2. severe acute hepatitis
3. vitamin K deficiency
4. anti-coagulant therapy (warfarin)

4) Triglycerides (normal values 170-250 mg/dl)
Triglycerides are the stored form of fat in body tissue. Serum triglycerides derive from diet and are produced by liver, when there is a surplus of calories or an increased alcohol intake.

5) Glucose (normal values 60-120 mg/dl)
It's a sugar and is used by body cells to produce energy with a chemical process called glycolysis. It derives from diet and is also synthetized by the liver. In many liver diseases glucose blood levels (glicemia) are often low (hypoglicemia)

6) Bilirubin (normal values 0.1-1.2 mg/dl)
Reflect the liver's ability to take up, conjugate and secrete bilirubin into the bile. During liver disease secretion is impaired, so there is increased levels of direct bilirubin.

7) Ammonia (normal value <50 mg/dl)
Transaminases remove amino group from amino acids, producing ammonia. This toxic by-product of protein metabolism is transformed in urea (non toxic) by hepatocytes. In advanced liver diseases there is a build-up of ammonia, due to liver disfunction.
 

Viral Markers

1) Anti-HAV (HAV Ab) (normal value NEGATIVE)
Are antibodies against hepatitis A virus. After infection anti-HAV IgM become positive (diagnosis of acute hepatitis) then, after about 2 months, it switches to IgG class (infection is defeated). HAV Ab IgG persist for years and are protective against a reinfection.

2) HBsAg (Australia Antigen) (normal value NEGATIVE)
Is a group of proteins that composes the outer surface coat (envelope) of HBV. HBsAg appears in the bloodstream after HBV infection and at about 4 weeks before symptoms occur. A positive test for HBsAg indicates current infection with HBV. This marker is generally present for 1-2 months after symptoms occur, then it  disappears and antibodies against it (HBsAb) start to rise. If HBsAg persists for more than 6 months chronic evolution is likely.

3) HBsAb (normal value NEGATIVE)
Are antibodies against HBsAg. They are the last antibodies to appear after infection and are an indicator that infection has been defeated. They neutralize HBV, providing protection against further infection. Therefore they are induced in vaccination by injection of HBsAg.

4) HBcAb (normal value NEGATIVE)
Antibodies against HBcAg (HBcAb) appear at about 8 weeks after infection (they are the first detectable antibodies).
When HBcAb appears in the bloodstream the level of transaminases (AST and ALT) start to rise.
Initial antibodies response is of IgM class then, after about 2 months it switches to IgG class. Therefore we found HBcAb of
IgM class when there is a recent infection (acute phase) and HBcAb of IgG class when infection is resolved.
In chronic infection HBcAb IgM is persistently positive.
These antibodies don't neutralize HBV, but they reveal if there was an infection (they don't appear after vaccination).

5) HBeAg (normal value NEGATIVE)
Is a peptide that is produced and becomes detectable in serum during HBV replication, like HBV DNA and DNA polymerase.
In acute infection HBeAg is transiently present: it's generally detectable at the same time as HBsAg and disappears before
it. Clearance of  HBeAg indicates a favorable prognosis (virus stops its replication and there is no more liver damage).
In chronic infection is positive during viral reactivation.
There are viral mutants of HBV that don't produce HBeAg. This mutants appear to be more aggressive.
Patients HBeAg positive are highly infectious.

6) HBeAb (normal value NEGATIVE)
In acute infection, few weeks later clearance of HBeAg, antibodies against HBeAg (HBeAb) became detectable and transaminases start to drop.
In chronic infection become positive when viral reactivation ends.

7) HBV DNA (PCR) (normal value NEGATIVE)
It's a test that detects HBV viral genome (DNA) in blood.
It becomes positive during viral replication : after infection (in acute hepatitis) and during viral reactivation (in chronic hepatitis).

8) Anti-HCV (HCV Ab) (normal value NEGATIVE)
It's a test that detects antibody produced by immune system against HCV (core and non structural viral proteins).
Positivity for anti-HCV documents previous exposure, not necessarily current infection.
In immunocompromised patients a negative test with acute hepatitis or soon after exposure doesn't exclude HCV infection, because there is a "window period" of some weeks before seroconversion (antibody appearance) occurs.
Test can be performed with:

1. EIA (Enzyme Immune Assay) or ELISA (Enzyme Linked Immuno Sorbent Assay): are suitable for screening (e.g. blood donors) and as an initial test for patients with clinical liver disease.
2. RIBA (Recombinant Immuno Blot Assay or Western blots): is more accurate (but more expensive) than EIA, therefore is used to confirm its findings.

1. First (1989): it was the first commercial test available. It detects antibodies against the C100-3 antigen derived from the non-structural region of HCV (NS3 and NS4). The false positive rate was 5% to 25% and had a "window" period (period between infection and seropositivity) of up to six months.
2. Second (1991): it detects antibodies against other antigens : C22 (core region), C33c (NS3 region) and C200 (from NS3 and NS4). That improved sensitivity and specificity of test and reduce the window period.
3. Third (1995): it incorporates an additional non structural epitope (NS5).

• presence of rheumatoid factor
• high levels of immunoglobulins

9) HCV RNA (PCR and bDNA) (normal value : negative)
It's the most sensitive test to determinate the presence of HCV. In fact viral genome is present in blood in small amount and need to be amplified to become detectable (PCR can amplified it millions of time).
After infection, HCV RNA is the early test to becomes positive, being detectable 2 weeks after viral exposure (diagnosis of acute hepatitis C).
This test is useful to confirm the diagnosis in :

• patients anti-HCV positive, but with normal transaminases
• immunocompromised patients (AIDS, tranplant, chronic renal failure), because don't produce antibodies

10) Viral Load
Is the amount of viruses present in blood. It's a quantitative test performed with the same techniques used to detect viral genome in blood (PCR and bDNA). Viral load is an important predicting factor determining the response to therapy (interferon).
It's assessed with bDNA test or with PCR (more sensitive).

11) Genotypes
PCR, using specific primers to the highly conserved 5'-untraslated region of viral genome, can determinate HCV genotype. There are 6 major HCV genotypes, with different clinical features and response to therapy (genotype 1b seems to be associated with more aggressive liver disease and with less response to therapy).

12) Anti-HDV (HDV Ab) (normal value NEGATIVE)
Is antibody produced by immune system against HDV. It's positive in acute (IgM class) and in chronic (if persists for more than 6 months) hepatitis D. This test is performed only in HBsAg positive patients (HDV is a defective virus than needs HBsAg).
 

Markers of Iron Metabolism

1) Serum Iron Concentration (normal values 50-175 mg/dl)
Is used in evaluation of iron metabolism.
Iron levels are increased in :

• hemochromatosis and hemosiderosis
• hemolytic, pernicious and aplastic anemia
• thalassemia
• viral hepatitis

• malnutrition
• iron deficiency anemia
• kidney diseases (nephrotic syndrome, chronic renal failure)
• hypothyroidism
• cancer

3) Ferritin (normal values 20-250 ng/ml)
Is the iron storage protein. Its blood levels fairly accurately reflect the amount of iron stores in the body.
It increases in diseases associated with excess of iron storage:

• hemochromatosis
• chronic viral hepatitis C
• chronic inflammation (e.g. rheumatoid arthritis)

Markers of Blood Clotting

1) Prothrombin Time (PT) (see above)

2) Platelet Count
Platelets are small cells involved in blood clotting. In liver diseases spleen becomes enlarged, due to portal hypertension, and sequesters platelets, reducing circulating pool (involved in blood clotting).
 

Markers of Autoimmunity

1) Anti Nuclear Antibodies (ANA)  (normal value : titre < 1:32)
Are used in screening for several autoimmune disorders (e.g. Systemic Lupus Erythematosus)
In low titre is also present in liver disease (cirrhosis, chronic viral hepatitis), in autoimmune chronic hepatitis and in other autoimmune disorders.

2) Anti Mitochondrial Antibodies (AMA)
These auto-antibodies are associated with primary biliary cirrhosis (PBC). It's useful to distinguish between PBC (positive) and cholestasis (negative) that have both alkaline phosphatase increased.

3) Anti Smooth Muscle Antibodies (ASMA) (normal value : titre <1:20)
These auto-antibodies are elevated in autoimmune chronic hepatitis (IgG class) and, in lesser amount, in primary biliary cirrhosis (IgM class).

4) LKM

5) Cryoglobulins (normal value : negative or absent)
Are abnormal antibodies, that become insoluble when exposed to a temperature below 37°C (98.6°F) and redissolve when rewarmed. Exposure of skin to low temperature, in patients that have cryoglobulins, leads to formation in blood of precipitates, that can block small vessels causing: skin lesion (ulcers, distal necrosis, purpura, petechiae), arthralgias, Raynaud phenomenon.
Cryoglobulins are usually associated with:

• immunological diseases (systemic lupus erythematosus, rheumatoid arthritis)
• hematological diseases (multiple myeloma, leukemia, lymphoma)
• chronic viral hepatitis (essential mixed cryoglobulinemia)

• qualitative : presence or absence of cryoglobulins (cryoprecipitate)
• quantitative : amount of cryoglobulins (cryocrit)

Tumoral Markers

Are molecules, associated with cancer, that can be detected with blood tests. They are produced by cancer or by organism in response to the cancer presence. Tumor markers are useful for:

1. screening (healthy and high risk people)
2. diagnosis
3. prognosis
4. follow-up of patients during and after therapy

• HCC (useful for screening of high risk patient). Diagnostic if  greater than 200 ng/ml
• testicular germ cell cancer (not in pure seminoma)
• liver diseases : cirrhosis and chronic hepatitis (< 200 ng/ml) and fulminant hepatitis.
• newborn and mother (decrease progressively after delivery)
• pancreatic, gastric and colonic cancer (less specific)

• pancreatic cancer (more specific) It's useful to differentiate benign from malignant pancreatic disease
• gastric cancer
• colon cancer

3) CA 125
Is an antigen associated with ovarian carcinoma (very specific).

4) CEA
Is a glycoprotein associated with some tumors:

• colonic cancer (most specific)
• pancreatic cancer
• gastric cancer
• lung cancer
• breast cancer

References

- Harrison et al. (eds.): "Harrison's Principles of Internal Medicine". 12th edition, McGraw-Hill Inc., New York