Alkaline phosphatase (ALP) (40-130 IU/L)
Refers to a group of isoenzymes that are widely distributed throughout the body. In adults, the most clinically significant ALP isoenzymes come from the liver and bones, as these organs are the main sources of ALP in the blood. Other sources include the placenta, small intestine, and kidneys. In the liver, ALP is located on the canalicular membranes of hepatocytes and cholangiocytes (therefore there are more amount of this ALP in this cells along the biliary tree- from bile canaliculi to larger ducts.
Its exact function is not well understood. ALP has a half-life in the blood of about 7 days, but its breakdown locations are unclear, and its clearance from the bloodstream is not dependent on bile flow or liver function. Liver and bile duct diseases increase ALP levels in the blood due to the enzyme’s increased production and leakage, a process influenced by bile acids.
Several physiological factors can influence ALP levels. For instance, individuals with blood types O and B may experience elevated ALP levels after a fatty meal due to the release of intestinal ALP, prompting some experts to recommend fasting before testing ALP levels. Additionally, benign familial elevations in ALP are linked to an increase in intestinal ALP. ALP levels also vary by age. Adolescents typically have ALP levels twice as high as adults, which is related to bone growth, as the increase is primarily in bone ALP. After age 30, ALP levels gradually rise in both men and women, with the increase being more pronounced in women. By age 65, a healthy woman’s ALP level can be 50% higher than that of a healthy 30-year-old woman, though the cause of this difference is unclear. Low ALP levels may be observed in patients with Wilson disease, particularly those with severe hepatitis and hemolysis, potentially due to decreased enzyme activity caused by copper displacing zinc, an essential cofactor for ALP.
GGT (8-60 U/L)
Gamma-glutamyl transpeptidase (GGT) is found in various organs, including the kidneys, pancreas, spleen, heart, brain, and seminal vesicles, and is present in the blood of healthy individuals. Serum GGT levels are similar between men and women and do not increase during pregnancy. While elevated GGT levels are highly sensitive to detecting liver and bile duct diseases, their lack of specificity limits their clinical usefulness. The primary role of measuring GGTP levels is to help identify the source of isolated alkaline phosphatase (ALP) elevation, as GGTP is not increased in bone disease.
GGT levels can also rise in patients taking certain medications, such as phenytoin, barbiturates, and some drugs used in HIV therapy, including non-nucleoside reverse transcriptase inhibitors and the protease inhibitor abacavir. Additionally, GGT is elevated in individuals who consume alcohol, however, the sensitivity of GGT for detecting alcohol use ranges from 52% to 94%, and its low specificity limits its effectiveness for this purpose.
GGT has a negative predictive value of 97.9%—higher than ALP, total bilirubin, ALT, and AST—for identifying bile duct stones in patients undergoing laparoscopic cholecystectomy. Elevated GGT has also been associated with higher mortality risk, as well as conditions like metabolic syndrome, diabetes, and cardiovascular disease.
Bilirubin (<1.2 mg/dl or <20ummol)
Bilirubin is NOT synthesized in liver. It is a byproduct of heme breakdown, with around 4 mg/kg produced daily, primarily from the breakdown of hemoglobin in aging red blood cells . The remainder comes from the turnover of other heme-containing proteins like myoglobin and cytochromes. Bilirubin metabolism starts in reticuloendothelial cells, mainly in the spleen, where heme is converted to biliverdin by the enzyme heme oxygenase. Biliverdin is then reduced to bilirubin by biliverdin reductase. This form unconjugated or indirect bilirubin.
Unconjugated bilirubin is lipid-soluble and water-insoluble, requiring transport by binding to albumin in the blood. This complex travels to the liver, where bilirubin dissociates from albumin and enters hepatocytes. Inside the liver cells, bilirubin binds to proteins, preventing its return to the bloodstream. It is then conjugated (direct) to glucuronic acid by the enzyme UDP glucuronyl transferase, making it water-soluble. The conjugated bilirubin is excreted into bile via a protein called MRP2 in an ATP-dependent process.
In the distal ileum and colon, bacteria break down conjugated bilirubin into unconjugated bilirubin using β-glucuronidases. This unconjugated bilirubin is then reduced to colorless urobilinogen by the same bacteria. Urobilinogen can be excreted as is, oxidized into urobilin (which gives urine its orange color), or reabsorbed into the portal system. Most reabsorbed urobilinogen is re-excreted by the liver, while a small amount is filtered by the kidneys and excreted in urine. Unconjugated bilirubin is never found in urine since it binds to albumin and can’t pass through the kidneys. The presence of bilirubin in urine suggests conjugated hyperbilirubinemia and liver disease.
The level of hiperbilirubinemia that can be see as conjuntival icterus is >3mg/dl or 50 ummol.
To differentiate conjugated or unconjugated, usually depends on the fraction between direct and indirect. If direct is >15% (Often >50%, we assume direct or mixed, whereas if <15% is direct, we assume unconjugated hyperbilirubinaemia.
Gilbert’s syndrome is common, affecting 6% to 12% of people. It results from a mutation in the promoter region of the UDP glucuronyl transferase gene, reducing enzyme activity to about one-third of normal. This leads to mildly elevated levels of indirect bilirubin, can appear under conditions of exertion, stress, fasting, and infections, but the condition is otherwise usually asymptomatic. In contrast, Crigler-Najjar syndrome types I and II are rare and result in much lower UDP glucuronyl transferase activity, causing significantly higher levels of unconjugated bilirubin and an increased risk of kernicterus.
When hyperbilirubinemia has a conjugated fraction over 15%, and typically over 50%, it points to either Dubin-Johnson syndrome or Rotor’s syndrome. Dubin-Johnson syndrome is caused by a defect in the MRP2 gene, while Rotor’s syndrome is linked to deficiencies in organic anion transport proteins OATP1B1 and OATP1B3. Both syndromes result in reduced excretion of conjugated bilirubin but are clinically benign and not associated with harmful outcomes.
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In summary , when either biliary obstruction cause backflow of bile and inflammation of the adjacent hepatic cells (very rich in ALP and GGT) as well as filtration of conjugated bilirubin back into the bloodstream- or some hepatic injury to liver cells adjacent to biliary cannaliculi , ie drug induced cholestasis- we call this pattern of raised ALP, GGT and sometimes Bilirubin as cholestatic pattern