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cholelithiasis - gallstones in gallbladder
choledocholithiasis - gallstone in common bile duct
cholecystitis - inflammation of gallbladder
cholangitis - infection of biliary tract
cholangiocarcinoma - adenocarcinoma of bile ducts
Klatskin's tumor - cholangiocarcinoma of bile duct at the junction of the right and left hepatic ducts
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Cholangiocarcinoma is an adenocarcinoma of the biliary duct system. It is a relatively rare cancer with an incidence of 1-2:100,000 in the Western world. Its risk factors may include environmental exposures such as polyvinyl chloride or Thorotrast (thorium dioxide); however, this is controversial. It is also associated with the parasite opisthorchis viverrini and clonorchiasis - liver fluke. Other risk factors include hepatolithiasis, congenital liver disorders, thorotrast and ulcerative colitis. A third of patients with primary sclerosing cholangitis will develop cholangiocarcinoma, so careful clinical, laboratory (liver function tests and cancer markers such as CA-19-9), and radiologic follow-up of these patients is warranted. It is NOT associated with hepatitis B or liver cirrhosis. Mutations at the INK4a/ARF locus have been detected in cholangiocarcinomas.
[edit] Treatment
Cholangiocarcinoma is considered curable only by surgical resection, and very often the disease is discovered too late for successful surgery. Chemotherapy has traditionally been seen as largely ineffective, but the chemotherapy agent gemcitabine (Gemzar) is often prescribed. Recently, there has been some success with the GFLIP protocol (Gemzar, 5-FU, leucovorin, irinotecan, and cisplatin or oxaliplatin), a protocol first developed and shown to be useful for pancreatic cancer.
[edit] Prognosis
Less than 10% of patients are considered suitable for surgical resection. Even following resection with negative margins, five year survival rates are are less than 20%.
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Adenocarcinoma is a form of carcinoma that originates in glandular tissue. To be classified as adenocarcinoma, the cells do not necessarily need to be part of a gland, as long as they have secretory properties. This form of carcinoma can occur in some higher mammals, including humans.[1]
The term adenocarcinoma is derived from 'adeno' meaining 'pertaining to a gland' and 'carcinoma', which describes a cancer that has developed in the epithelial cells.
It can first present as an adenoma (a glandular tumor that is benign).
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Liver function tests (LFTs or LFs), which include liver enzymes, are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. Most liver diseases cause only mild symptoms initially, while it is vital that these diseases be detected early. Hepatic involvement in some diseases can be of crucial importance. This testing is performed by a Medical technologist on a patient's serum or plasma which is collected by a phlebotomist.
[edit] Total Protein (TP)
The liver produces most of the plasma proteins in the body making a measure of the amount of protein in the blood useful. Reference range (60-80 g/L).
[edit] Albumin (Alb)
Albumin is a protein made specifically by the liver, and can be measured cheaply and easily. It is the main constituent of total protein; the remaining fraction is called globulin (including e.g. the immunoglobulins). Albumin levels are decreased in chronic liver disease, such as cirrhosis. It is also decreased in nephrotic syndrome, where it is lost through the urine. Poor nutrition or states of protein catabolism may also lead to hypoalbuminaemia. The half-life of albumin is approximately 20 days. Albumin is not considered to be an especially useful marker of liver synthetic function, coagulation factors (see below) are much more sensitive. The reference range is 30-50 g/L. (3.0-5.0 g/dL)
[edit] Alanine transaminase (ALT)
Alanine transaminase (ALT), also called Serum Glutamic Pyruvic Transaminase (SGPT) or Alanine aminotransferase (ALAT) is an enzyme present in hepatocytes (liver cells). When a cell is damaged, it leaks this enzyme into the blood, where it is measured. ALT rises dramatically in acute liver damage, such as viral hepatitis or paracetamol (acetaminophen) overdose. Elevations are often measured in multiples of the upper limit of normal (ULN). The reference range is 15-45 U/L in most laboratories.
[edit] Aspartate transaminase (AST)
Aspartate transaminase (AST) also called Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartate aminotransferase (ASAT) is similar to ALT in that it is another enzyme associated with liver parenchymal cells. It is raised in acute liver damage, but is also present in red cells, and cardiac and skeletal muscle and is therefore not specific to the liver. The ratio of AST to ALT is sometimes useful in differentiating between causes of liver damage:
ALT>AST: acute viral hepatitis, drug-induced hepatitis or Non-alcoholic fatty liver disease
ALT
In resource-poor settings, the AST is more frequently available than the ALT, because it is a cheaper assay.
[edit] Alkaline phosphatase (ALP)
Alkaline phosphatase (ALP) is an enzyme in the cells lining the biliary ducts of the liver. ALP levels in plasma will rise with large bile duct obstruction, intrahepatic cholestasis or infiltrative diseases of the liver. ALP is also present in bone and placental tissue, so it is higher in growing children (as their bones are being remodelled). The reference range is usually 30-120 U/L.
[edit] Total bilirubin (TBIL)
Bilirubin is a breakdown product of heme (a part of haemoglobin in red blood cells). The liver is responsible for clearing the blood of bilirubin. It does this by the following mechanism: bilirubin is taken up into hepatocytes, conjugated (modified to make it water-soluble), and secreted into the bile, which is excreted into the intestine.
Liver function tests typically measure Total bilirubin (TBIL) and Direct bilirubin (a.k.a. conjugated bilirubin, CB). Indirect bilirubin (a.k.a. unconjugated bilirubin, UCB) is obtained by subtracting direct bilirubin from total bilirubin.
Increased total bilirubin causes jaundice, and can signal a number of problems:
1. Increased bilirubin production. This can be due to a number of causes, including hemolytic anemias and internal hemorrhage.
2. Problems with the liver, which are reflected as deficiencies in bilirubin metabolism (e.g. reduced hepatocyte uptake, impaired conjugation of bilirubin, and reduced hepatocyte secretion of bilirubin). Some examples would be cirrhosis and viral hepatitis.
3. Obstruction of the bile ducts, reflected as deficiencies in bilirubin excretion. (Obstruction can be located either within the liver or outside the liver.)
The diagnosis is narrowed down further by looking at the levels of direct bilirubin. If direct (i.e. conjugated) bilirubin is normal, then the problem is an excess of unconjugated bilirubin, and the location of the problem is upstream of bilirubin excretion. Anemia, viral hepatitis, or cirrhosis can be suspected. If direct bilirubin is elevated, then the liver is conjugating bilirubin normally, but is not able to excrete it. Bile duct obstruction by gallstones or cancer should be suspected.
[edit] Other tests commonly requested alongside LFTs:
[edit] Gamma glutamyl transpeptidase (GGT)
Although reasonably specific to the liver and a more sensitive marker for cholestatic damage than ALP, Gamma glutamyl transpeptidase (GGT) may be elevated with even minor, sub-clinical levels of liver dysfunction. It can also be helpful in identifying the cause of an isolated elevation in ALP. GGT is raised in alcohol toxicity (acute and chronic).
[edit] 5' nucleotidase (5'NTD)
5'NTD is another test specific for cholestasis or damage to the intra or extrahepatic biliary system, and in some laboratories, is used as a substitute for GGT for ascertaining whether an elevated ALP is of biliary or extra-biliary origin.
[edit] Coagulation tests (e.g. INR)
The liver is responsible for the production of coagulation factors. The international normalized ratio (INR) measures the speed of a particular pathway of coagulation, comparing it to normal. If the INR is increased, it means it is taking longer than usual for blood to clot. The INR will only be increased if the liver is so damaged that synthesis of vitamin K-dependent coagulation factors has been impaired: it is not a sensitive measure of liver function.
It is very important to normalize the INR before operating on people with liver problems (usually by transfusion with blood plasma containing the deficient factors) as they could bleed excessively.
[edit] Serum glucose (BG, Glu)
The liver's ability to produce glucose (gluconeogenesis) is usually the last function to be lost in the setting of fulminant liver failure.
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Jaundice
At what level of serum total bilirubin does one start to get jaundiced?
Greater than 2.5
With good renal function, how high can the serum total bilirubin go?
Very rarely, greater than 20
What are the signs and symptoms of obstructive jaundice?
Jaundice, dark urine, clay-colored stools (acholic stools), pruritus (itching), loss of appetite, nausea
What causes the itching in obstructive jaundice?
Bile salts in the dermis (ot bilirubin)
Jaundice, also known as icterus (attributive adjective: "icteric"), is a yellowing of the skin, conjunctiva (clear covering over the sclera, or whites of the eyes) and mucous membranes caused by increased levels of bilirubin in the human body (or the body of another red blooded animal). Usually the concentration of bilirubin in the blood must exceed 2–3 mg/dL for the coloration to be easily visible. Jaundice comes from the French word jaune, meaning yellow. Jaundice typically appears in a 'top to bottom' progression (starting with the face, progressing toward the feet), and resolves in a 'bottom to top' manner.
[edit] Causes of jaundice
When red blood cells die, the heme in their hemoglobin is converted to bilirubin in the spleen and in the hepatocytes in the liver. The bilirubin is processed by the liver, enters bile and is eventually excreted through feces.
Consequently, there are three different classes of causes for jaundice. Pre-hepatic or hemolytic causes, where too many red blood cells are broken down, hepatic causes where the processing of bilirubin in the liver does not function correctly, and post-hepatic or extrahepatic causes, where the removal of bile is disturbed.
[edit] Pre-hepatic
Pre-hepatic (or hemolytic) jaundice is caused by anything which causes an increased rate of hemolysis (breakdown of red blood cells). In tropical countries, malaria can cause jaundice in this manner. Certain genetic diseases, such as sickle cell anemia and glucose 6-phosphate dehydrogenase deficiency can lead to increased red cell lysis and therefore hemolytic jaundice. Defects in bilirubin metabolism also present as jaundice. Jaundice usually comes with high fevers.
The laboratory findings include
Urine: no bilirubin present, urobilirubin > 2 units (except in infants where gut flora has not developed).
Serum: increased unconjugated bilirubin.
[edit] Hepatic
Hepatic causes include acute hepatitis, hepatotoxicity and alcoholic liver disease, whereby cell necrosis reduces the liver's ability to metabolise and excrete bilirubin leading to a build up in the blood. Less common causes include primary biliary cirrhosis, Gilbert's syndrome (a genetic disorder of bilirubin metabolism which can result in mild jaundice, which is found in about 5% of the population) and metastatic carcinoma. Jaundice seen in the newborn, known as neonatal jaundice, is common, occurring in almost every newborn as hepatic machinery for the conjugation and excretion of bilirubin does not fully mature until approximately two weeks of age.
Laboratory Findings: Urine: bilirubin present, Urobilirubin > 2 units but variable (Except in children)
[edit] Post-hepatic
Post-hepatic (or obstructive) jaundice, also called cholestasis, is caused by an interruption to the drainage of bile in the biliary system. The most common causes are gallstones in the common bile duct, and pancreatic cancer in the head of the pancreas. Also, a group of parasites known as "liver flukes" live in the common bile duct, causing obstructive jaundice. Other causes include strictures of the common bile duct, ductal carcinoma, pancreatitis and pancreatic pseudocysts. A rare cause of obstructive jaundice is Mirizzi's syndrome.
The presence of pale stools and dark urine suggests an obstructive or post-hepatic cause as normal faeces get their colour from bile pigments. Patients sometimes also complain of itching.
[edit] Neonatal jaundice
See Neonatal jaundice for details.
Neonatal jaundice is usually harmless: this condition is often seen in infants around the second day after birth, lasting till day 8 in normal births, or to around day 14 in premature births. Serum bilirubin normally drops to a low level without any intervention required: the jaundice is presumably a consequence of metabolic and physiological adjustments after birth.
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Obstructive Jaundice
What is it?
Jaundice(hyperbilirubinemia > 2.5) from obstruction of bile flow to the duodenum
What lab results are associated with obstructive jaundice?
Elevated alkaline phosphatase, elevated bilirubin with or without elevated LFTs
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Bilirubin is a yellow breakdown product of normal heme catabolism. Its levels are elevated in certain diseases and it is responsible for the yellow color of bruises and the brown color of feces. Bilirubin reduction in the gut leads to a product called urobilinogen, which is excreted in urine.
Metabolism
Erythrocytes (red blood cells) are destroyed when they get old or damaged, in the spleen and bone marrow. This releases haemoglobin. This is broken down to heme, as the globin parts are turned into amino acids. The heme is then turned into unconjugated bilirubin in the macrophages of the spleen and bone marrow. It is then bound to albumin and sent to the liver.
In the liver it is conjugated with glucuronic acid, making it water soluble. Much of it goes into the bile and thus out into the small intestine. Some of the conjugated bilirubin remains in the large intestine and is oxidised to urobilin and then stercobilin, which gives feces its color.
Some is reabsorbed, and excreted in the urine as urobilinogen. If the liver’s function is impaired, or biliary drainage blocked, some of the conjugated bilirubin appears in the urine, turning it dark.
[edit] Bilirubin toxicity
Unconjugated hyperbilirubinaemia in the neonate can lead to accumulation of bilirubin in certain brain regions, a phenomenon known as kernicterus, with consequent irreversible damage to these areas manifesting as various neurological deficits, seizures, abnormal reflexes and eye movements. Aside from specific chronic medical conditions that may lead to hyperbilirubinaemia, neonates in general are at increased risk since they lack the intestinal bacteria that facilitate the breakdown and excretion of conjugated bilirubin in the feces (this is largely why the feces of a neonate are paler than those of an adult). Instead the conjugated bilirubin is converted back into the unconjugated form by the enzyme b-glucoronidase and a large proportion is reabsorbed through the enterohepatic circulation.
[edit] Bilirubin benefits
Reasonable levels of bilirubin can be beneficial to the organism. Evidence is accumulating that suggests bilirubin can protect tissues against oxidative damage caused by free radicals and other reactive oxygen species. Statistical analysis of people with high normal or slightly elevated bilirubin levels in blood shows that they have a lower risk of developing cardiovascular diseases.
[edit] Bilirubin blood tests
Bilirubin is either in the insoluble form, unconjugated bilirubin (also indirect bilirubin), or bound to glucuronic acid to form the so called conjugated bilirubin (also direct bilirubin). The indirect form is insoluble and it is transformed into a soluble or direct form, in the liver. Total and direct bilirubin levels can be measured from the blood, but indirect bilirubin is calculated from the total and direct bilirubin.The terms "direct" and "indirect" reflect the way the two types of bilirubin react to certain dyes. Conjugated bilirubin is water-soluble and reacts directly when dyes are added to the blood specimen. The non-water soluble, free bilirubin does not react to the reagents until alcohol is added to the solution. Therefore, the measurement of this type of bilirubin is indirect. Test results may be listed as "BU" for unconjugated bilirubin and "BC" for conjugated bilirubin. Total bilirubin measures both BU and BC. To further elucidate the causes of jaundice or increased bilirubin, it is usually simpler to look at other liver function tests (especially the enzymes ALT, AST, GGT, Alk Phos), blood film examination (hemolysis, etc.) or evidence of infective hepatitis (e.g., Hepatitis A, B, C, delta E, etc).
Bilirubin is an excretion product, and the body does not control levels. Bilirubin levels reflect the balance between production and excretion. Thus, there is no "normal" level of bilirubin.
Bilirubin is broken down by light, and blood collection tubes (especially serum tubes) should therefore be protected from such exposure.
[edit] Interpretation
The reference range for total bilirubin is 2 - 14 μmol/L or 0.3 - 1.9 mg/dL. For direct bilirubin, it is 0 - 4 μmol/L or 0 - 0.3 mg/dL.
Mild rises in bilirubin may be caused by
Hemolysis or increased breakdown of red blood cells.
Gilbert's syndrome - a genetic disorder of bilirubin metabolism which can result in mild jaundice, found in about 5% of the population.
Moderate rise in bilirubin may be caused by
Drugs (especially anti-psychotic, some sex hormones, and a wide range of other drugs).
Hepatitis (levels may be moderate or high).
Very high levels of bilirubin may be caused by
Neonatal hyperbilirubinaemia, where the newborn's liver is not able to properly conjugate the bilirubin (see jaundice).
Unusually large bile duct obstruction, eg stone in common bile duct, tumour obstructing common bile duct etc.
Severe liver failure with cirrhosis.
Severe hepatitis.
Crigler-Najjar syndrome
Dubin-Johnson syndrome
Cirrhosis may cause normal, moderately high or high levels of bilirubin, depending on exact features of the cirrhosis
[edit] Jaundice
Jaundice may be noticeable in the sclera (white) of the eyes at levels above about 30-50 μmol/l, and in the skin at higher levels. Jaundice is classified depending upon whether the bilirubin is free or conjugated to glucuronic acid into:
Conjugated jaundice
Unconjugated jaundice
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Secretin is a peptide hormone produced in the S cells of the duodenum in the crypts of Lieberkühn. Its primary effect is to regulate the pH of the duodenal contents via the control of gastric acid secretion and buffering with bicarbonate.
[edit] Stimulus
Secretin is secreted in response to low duodenal pH due to chyme, which contains hydrochloric acid, entering from the stomach.
[edit] Function
Secretin stimulates the secretion of bicarbonate (base) from the liver, pancreas, and duodenal Brunner's glands in order to buffer the incoming protons of the acidic chyme. It also enhances the effects of cholecystokinin. It is known to promote the normal growth and maintenance of the pancreas.
It also reduces acid secretion from the stomach by inhibiting gastrin release from G cells. This helps neutralize the pH of the digestive products entering the duodenum from the stomach, as digestive enzymes from the pancreas (eg, pancreatic amylase and pancreatic lipase) function optimally at neutral pH.
The crypts of Lieberkühn (or intestinal glands) are glands found in the epithelial lining of the small intestine and colon. Named after the 18th-century German anatomist Johann Nathanael Lieberkühn, the crypts secrete various enzymes, including sucrase and maltase. Loss of proliferation control in the crypts is thought to lead to colorectal cancer.
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Cholecystokinin (CCK; from Greek chole, "bile"; cysto, "sac"; kinin, "move"; hence, move the bile-sac (gallbladder)) is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, previously called pancreozymin, is secreted by the duodenum, the first segment of the small intestine, and causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively. It also acts as a hunger suppresant. Recent evidence has suggested that it also plays a major role in inducing drug tolerance to opioids like morphine and heroin, and is partly implicated in experiences of pain hypersensitivity during opioid withdrawal.
CCK mediates a number of physiological processes, including digestion and satiety.
[edit] Digestion
CCK is secreted by the duodenal mucosa when fat- or protein-rich chyme leaves the stomach and enters the duodenum. The hormone acts on the pancreas to stimulate the secretion of a juice rich in digestive enzymes, including trypsinogen, chymotrypsinogen (which are converted to trypsin and chymotrypsin in the duodenum), amylase and lipase. Together these pancreatic digestive enzymes catalyze the digestion of fat, protein, and carbohydrate.
CCK also causes the increased production of hepatic bile, and stimulates the contraction of the gallbladder and the relaxation of the Sphincter of Oddi (Glisson's sphincter), resulting in the delivery of bile into the duodenal part of the small intestine. Bile salts form amphipathic micelles that emulsify fats, aiding in their digestion and absorption.
[edit] Neurobiology
As a neuropeptide, CCK mediates satiety by acting on the CCK receptors distributed widely throughout the central nervous system. In humans, CCK administration causes nausea and anxiety, and weakly decreases the desire to eat [1].
The effects of CCK vary between individuals. For example, in rats, CCK administration significantly reduces hunger in young males, but is less effective in older subjects, and even less effective in females. The hunger-suppressive effects of CCK also diminish in obese rats [2]
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