Jaundice and pruritus

23 Jaundice and pruritus




Introduction


Jaundice is yellow pigmentation of the sclera, skin, and mucous membranes caused by deposition of bilirubin in tissue. Jaundice becomes apparent when the serum bilirubin level rises above 50–75 μmol/L (normal: 3–15 μmol/L). It is most often associated with hepatocellular dysfunction or cholestatic syndromes including biliary obstruction, and is often associated with pruritus. The history and physical examination of the patient with suspected liver disease and an approach to abnormal liver function tests are discussed in Chapter 24. Here, bilirubin physiology and diagnostic methods are outlined, focusing on the clinical approach to patients with obstructive jaundice.



Physiology


Jaundice results from either increased production and/or decreased excretion of bilirubin. The metabolism of bilirubin is summarised in Figure 23.1. Under normal conditions, 80% of serum bilirubin is generated by senescent red blood cells, which are broken down by the reticuloendothelial system in the spleen, liver and bone marrow. The released haeme (ferroprotoporphyrin IX) is oxidatively cleaved to biliverdin and then bilirubin, which is tightly bound to albumin and transported in the serum. The other 20% of serum bilirubin arises from the breakdown of other haeme-containing proteins (e.g. cytochrome, myoglobin and haeme-containing enzymes) and ineffective erythropoiesis (the premature breakdown of red cells in the bone marrow before release). Bilirubin, which is lipid soluble, is made water soluble by conjugation in the liver.



Unconjugated bilirubin is delivered to the liver via the portal vein and hepatic artery. Bilirubin is conjugated in the liver by UDP-glucuronyl-transferase (in the endoplasmic reticulum); glucuronic acid is joined to propionic acid groups on bilirubin. Hepatocytes take up and conjugate 30% of available bilirubin on each pass. Conjugated bilirubin is then secreted into bile canaliculi by an active transport mechanism. It flows through the intrahepatic biliary system to the common bile duct and then into the small intestine where it is either deconjugated or metabolised to urobilinogen by gut bacteria. Conjugated bilirubin is not absorbed by the bowel but some urobilinogen is resorbed. Faecal urobilinogen gives stools their colour. Following absorption in the terminal ileum or colon, urobilinogen undergoes enterohepatic circulation.


Jaundice may be caused by obstruction or overloading at various points in the bilirubin metabolism pathway (Fig 23.1). The proportions of conjugated and unconjugated bilirubin detected in the serum depend on the site of the obstruction or overloading. Haemolysis or reabsorption of a haematoma leads to an unconjugated hyperbilirubinaemia because the hepatocytes become overloaded. Reduced uptake and rates of conjugation will likewise lead to increases in serum unconjugated bilirubin.


Hepatic diseases lead to increases in both serum conjugated and unconjugated bilirubin. Uptake, conjugation and excretion will all be affected. However, transport across the canalicular membrane into the bile ductules is reduced more than uptake and conjugation—this is the rate-limiting step for excretion of bilirubin.


Therefore, conjugated bilirubin is produced but is not excreted into the biliary system. It accumulates and diffuses back into the serum with consequent increase in conjugated serum bilirubin. There may be parallel increases in the levels of unconjugated bilirubin due to decreased rates of conjugation, portal systemic shunting of blood around the liver, and low-grade haemolysis associated with hepatocellular diseases.


Bile duct obstruction results in elevations of conjugated bilirubin in the serum because uptake and conjugation are unaffected, whereas secretion into the biliary system is compromised. Unconjugated bilirubin is tightly bound to albumin and cannot be filtered by the kidneys, but conjugated bilirubin is only 60% bound and some is filtered. The urine then becomes dark. Finding bilirubin in the urine by dipstick indicates the presence of conjugated bilirubin.



Measurement of serum bilirubin


The normal range for serum bilirubin is 3–15 μmol/L in adults. Bilirubin is classified as direct (conjugated) and indirect (unconjugated). This terminology is derived from the commonly used assay that makes use of a diazo reaction. Diazotised aromatic amines cleave the bilirubin molecule into two identical molecules, which are bound to the azo compound. These are measured spectrophotometrically. In an acidic aqueous media, conjugated bilirubin reacts ‘directly’ with the azo compound; whereas unconjugated bilirubin requires the addition of an accelerator molecule such as alcohol, thus reacting ‘indirectly’.


In adults, the measurement of direct and indirect fractions of bilirubin is not routine but may sometimes be clinically useful when the total serum bilirubin concentration is less than 70–90 μmol/L. Levels greater than this will most often be due to conjugated hyperbilirubinaemia. Chronic overproduction from haemolysis and ineffective erythropoiesis can increase bilirubin loads by up to eight times the normal level, but the hepatocytes are easily capable of increased conjugation rates to meet the demand. However, if there is acute, severe haemolysis, as in sickle cell crisis or paroxysmal nocturnal hemoglobinuria, short-term production can overwhelm hepatocytes and lead to temporary levels of unconjugated serum bilirubin greater than 90 μmol/L. Impaired hepatocellular function in the setting of chronic overproduction can also cause indirect serum bilirubin levels greater than 90 μmol/L due to impaired rates of conjugation and transport.


The causes of jaundice are typically classified into three groups corresponding to the site of impaired bilirubin metabolism: prehepatic, hepatic and posthepatic (cholestasis, obstruction). This classification is clinically useful when evaluating patients with jaundice or hyperbilirubinaemia. There are distinctive clinical features and liver function test profiles and clinical presentations for each group (Table 23.1). These help the physician to identify the likely site of impaired bilirubin metabolism, narrow the differential diagnosis, and then order the most appropriate investigations.


Table 23.1 Clinical features and liver function test profiles in hepatic (hepatocellular) and cholestatic (or obstructive) jaundice























  Suggests hepatocellular jaundice Suggests obstructive jaundice
Clinical features Nausea, anorexia, fatigue, myalgia, known infectious exposure, IV drug use, blood transfusions, alcohol, medication abuse, positive family history of liver disease or jaundice Pain, pruritus, dark urine, pale stools, fever, past biliary surgery, weight loss, older age
Transaminases (AST, ALT) ++ (> 3 × normal) + (< 3 × normal)
Alkaline phosphatase Normal to increased (< 3 × normal) ++ (> 3 × normal)
INR or prothrombin time after vitamin K Does not correct Corrects if extrahepatic obstruction

ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalised ratio.





Obstruction or cholestasis


Obstructive jaundice occurs when bile flow through the extrahepatic biliary tree is impaired, usually by a stone or tumour. Intrahepatic cholestasis occurs when excretion of conjugated bilirubin from the liver cell into the bile canaliculus is disrupted. The most common cause is a drug reaction, but some cases of viral hepatitis and some chronic liver diseases (e.g. primary biliary cirrhosis) can also cause cholestasis.


The clinical features and liver function test abnormalities produced by cholestasis and obstruction are similar. Both present with prominent jaundice, dark urine and pale stools. Pruritus may be present if the cholestasis or obstruction is longstanding. The serum alkaline phosphatase level is usually greater than three times the normal level, transaminases are usually less than three times normal, and serum bilirubin concentration is elevated. It should be noted that in acute biliary obstruction, as may occur in choledocholithiasis, serum transaminase levels rise earlier than the alkaline phosphatase. The prothrombin time may be prolonged due to poor absorption of vitamin K but is rapidly corrected by administering parenteral vitamin K in obstruction. Constant pain in the right upper quadrant may be present. Severe episodic pain lasting a few hours suggests stones in the bile duct. Painless jaundice is the hallmark of malignant biliary obstruction commonly seen in patients with pancreatic cancer (Ch 17) (Fig 23.2).



Abdominal ultrasound scans showing dilated extrahepatic and/or intrahepatic ducts indicate the presence of obstruction, while normal duct calibre suggests intrahepatic cholestasis. The process of duct dilatation usually appears 3–5 days after the onset of extrahepatic obstruction.



Clinical Syndromes



Prehepatic jaundice








Cholestatic and obstructive jaundice



May 30, 2016 | Posted by in GASTROENTEROLOGY | Comments Off on Jaundice and pruritus

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