| Definition of jaundice |
Jaundice describes the yellow discoloration of the skin, mucous membranes, and sclera. Normal serum bilirubin levels are <0.99 mg/dl; jaundice manifests clinically when bilirubin is >1.99 mg/dl. It may mean hepatobiliary or pancreatic disease that requires investigation.
| Pathology and pathogenesis |
An understanding of the metabolism and elimination of bilirubin can help in the effective management of jaundice. Most bilirubin (80%) is formed after the breakdown of red blood cells. The typical lifespan of a red blood cell is 120 days. After that period, the destroyed in the reticuloendothelial system. Heme from hemoglobin is converted to biliverdin and then (unconjugated) to bilirubin.
Bilirubin circulates in the blood bound to albumin until it is absorbed by hepatocytes. Within the hepatocyte, bilirubin is conjugated with glucuronic acid by diphosphate-uridine glucuronosyltransferase, a water-soluble product.
Conjugated bilirubin can be excreted in the bile and when it passes to the intestine, in which only 2% of the bilirubin is absorbed, the rest is degraded by colonic bacterial enzymes to form urobilinogen. Some urobilinogen re-enters the liver, but about 90% is converted to stercobilinogen, which is excreted in the feces.
Establishing whether hyperbilirubinemia is due to conjugated or unconjugated bilirubin may reveal where bilirubin metabolism or clearance is defective and thus may provide clues to the underlying etiology.
Unconjugated hyperbilirubinemia may result from excess bilirubin production, impaired hepatic uptake, or abnormalities of bilirubin conjugation. Conjugated hyperbilirubinemia may be caused by hepatocellular injury, intrahepatic cholestasis, or obstruction.
| Studies for the diagnosis of jaundice |
The initial diagnosis of patients with jaundice includes a careful history and examination.
> History
Ask about:
- Onset and duration of jaundice:
- Associated symptoms (pruritus, anorexia, pale stools, steatorrhea, dark urine, fever, abdominal pain).
- History of obesity, metabolic syndrome and other systemic disorders, conditions such as cystic fibrosis and inflammatory bowel disease.
- Drug history (prescription medications; illicit drugs).
- Family history (jaundice, liver disease, cancer, hemolytic anemia).
- Social background (alcohol consumption, occupation).
- Risk factors for viral hepatitis and HIV (sexual contacts, blood transfusions, intravenous drugs, tattoos, country of birth, travel abroad).
The physical examination may reveal signs of chronic liver disease, such as:
- clubbing, leukonychia,
- palmar erythema,
- Dupuytren’s contracture.
- bruises.
- scratch marks,
- spider nevus,
- gynecomastia
- jellyfish head
- hepatomegaly
- splenomegaly
- hepatic encephalopathy
- ascites
There may also be signs suggesting specific diseases , such as:
- hyperpigmentation (hemochromatosis)
- Kayser-Fleischer rings (Wilson disease)
- tendon xanthomas primary biliary cholangitis
- Courvoisier sign, which is more suggestive of malignancy of the pancreas or gallbladder (jaundice associated with a painless, enlarged gallbladder is unlikely to be caused by gallstones).
| Research |
> Urinalysis : can help determine whether hyperbilirubinemia is conjugated or unconjugated since unconjugated bilirubin is insoluble in water and is not detectable in urine. However, if excess conjugated bilirubin cannot enter the intestine (e.g. obstructive jaundice; 50-90% is excreted in the urine (turns a dark color) and is detectable in urinalysis, while stools are pale (since there is no stercobilinogen in them.
> Blood tests: includes a complete blood count, quantification of conjugated (direct) and unconjugated (indirect) bilirubins in the blood, and liver function tests. The basic liver panel includes measurement of total bilirubin, alkaline phosphatase, aminotransferases, gamma-glutamyltransferase, and serum albumin, as well as prothrombin time. Serum albumin and prothrombin time are used to indicate liver synthetic function. A low concentration of prothrombin with a prolonged prothrombin time (due to reduction in vitamin K) suggests liver failure.
In general, patients with jaundice resulting from hepatocellular injury have a disproportionate increase in serum aminotransferases, compared to cholestatic processes , in which the opposite occurs, that is, increased alkaline phosphatase and gamma-glutamyltransferase.
The aminotransferase pattern may also be important; Alcoholic steatohepatitis is generally associated with higher values of aspartate aminotransferase (AST) than alanine aminotransferase (ALT), while in viral hepatitis, ALT is usually higher than AST. However, there is often a mixed picture and this distinction is not always clear.
Sometimes the only abnormality in blood tests of liver function is an elevated concentration of unconjugated bilirubin , suggesting normal liver and biliary tree. The cause of this hyperbilirubinemia may be increased hemolysis or inherited disorders of bilirubin metabolism, as in Gilbert’s syndrome.
In the presence of hemolysis , the degree of hyperbilirubinemia is relatively mild (typically 3.98 mg/dl-5.96 mg/dl).
Isolated conjugated hyperbilirubinemia can be caused by Rotor and Define Johnson syndromes. In patients with abnormal liver function tests, alternative causes of skin pigmentation should be considered, such as Addison’s disease, anorexia nervosa, ingestion of foods rich in ß-carotenemia, or use of spray tanning products.
A synthesis of information from the history, examination, and basic urine and blood tests usually determines the next step:
- If cholestatic jaundice is suspected , the next step is to do an abdominal ultrasound to determine if there is biliary dilation, which suggests an obstruction.
- If hepatocellular injury is suspected, the next step is to perform studies to detect liver causes. This includes serological tests for viral hepatitis (A, B, C and, in certain patients, also E), other viruses ( Cytomegalovirus , HIV, Epstein-Barr), antimitochondrial antibodies (for primary biliary cholangitis), serum immunoglobulins, antinuclear antibodies, antismooth muscle and antimicrosomal, hepatic and renal (for autoimmune hepatitis), ferritin and transferrin saturation (for hemochromatosis), serum ceruloplasmin (for Wilson’s disease), serum α1-antitrypsin (for α1-antitrypsin deficiency) and α -fetoprotein (for liver malignancy).
- If isolated hyperbilirubinemia is present , α testing is required, including serum lactate dehydrogenase, haptoglobin, Combo test, and blood smear. These tests help diagnose hemolytic anemia.
- Imaging of the liver and biliary tree : Ultrasound is generally the initial imaging modality of choice for suspected cholestatic jaundice. It is a non-invasive, economical and widely available method. It has a sensitivity of 55-91% to detect dilated bile ducts and biliary obstruction. It can also detect gallstones and periampullary masses and provide information on the echostructure and characteristics of portal hypertension.
- If the cause of biliary dilation remains unclear , detailed imaging is needed, so magnetic resonance cholangiopancreatography (MRCP) may be used. This non-invasive technique provides high-resolution images without contrast. MRCP is commonly used to confirm choledocholithiasis, prior to embarking on more invasive procedures such as endoscopic retrograde cholangiopancreatography (ERCP). Magnetic resonance images, with different contrast and weighted in diffusion, can allow evaluation of the liver parenchyma and characterize liver lesions.
Computed tomography ( CT) can reliably detect ductal dilation and is superior to ultrasound in determining the underlying cause of jaundice, in particular, in visualizing the pancreas. However, CT involves exposure to radiation and nephrotoxic contrast agents while only 10% of gallstones are detected.
Endoscopic ultrasonography is an invasive technique since, during gastroscopy, an ultrasound probe is introduced into the duodenum, which provides detailed information about the biliary tree and pancreas. It allows for biopsies and fine needle aspiration, and is particularly useful for staging periampullary malignant tumors.
Intraductal ultrasound ( IDUS) is a newer imaging modality that involves cannulation of the common bile duct or main pancreatic duct, using a miniprobe, to visualize the bile duct and pancreatic ducts.
Passage of the tube may be difficult if the ducts are tortuous, but EID is more accurate than ERCP in detecting small stones in dilated ducts, and in determining the nature of bile duct stricture. Typically, more invasive procedures, such as ERCP, are reserved for therapeutic interventions, such as stone removal or stricture dilation.
ERCP can also be used to obtain tissue from the biliary stricture to identify malignancy. It has an associated morbidity of 3% and mortality of 0.2%. The most common complications are bleeding, cholangitis and pancreatitis. Particularly in cases with difficulty distinguishing between benign and malignant biliary stricture, ERCP can be combined with cholangioscopy, which allows direct visualization of the biliary tree, through the use of fiber optic or video endoscope.
Percutaneous transhepatic cholangiography involves percutaneous access to a peripheral hepatic bile duct, with contrast injection. Similar to ERCP, biliary brushings can be done and stents inserted. This modality is very valuable when the ampulla is not easily accessible, and in patients with hilar/biliary stenosis after hepatectomy.
In general, the choice of imaging technique is governed by availability, patient-related factors, and clinical suspicion.
> Liver biopsy : it is indicated if the patient presents jaundice with normal liver function tests and images, and no hepatic etiology was found. This decision depends on the likelihood of clinically significant liver disease and potential therapeutic benefit. Liver biopsy is particularly useful for the diagnosis of autoimmune liver disease and certain disorders of the biliary tract (eg, primary sclerosing cholangitis of the small duct).
However, adverse effects include pain (20%) and serious complications (hemoperitoneum, puncture of other organs, pneumothorax, and biliary peritonitis) that occur in 0.57% of patients. Furthermore, sampling errors can occur while research has shown discordance rates of up to 30% when comparing biopsies done on the right and left eggs, even in homogeneously distributed diseases.
