Jaundice

Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and whites of the eyes due to high bilirubin levels.[3][6] Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme metabolism, liver dysfunction, or biliary tract obstruction.[7] The prevalence of jaundice in adults is rare, while jaundice in babies is common with an estimated 80% affected during their first week of life.[8] The most commonly associated symptoms of jaundice are itchiness,[2] pale feces, and dark urine.[4]

"Icteric" redirects here. For the physiological event, see Ictal. For the songbird Icteria, see Yellow-breasted chat. For Jaundice in babies, see Neonatal jaundice.
Jaundice
Other namesIcterus[1]
Jaundice of the skin caused by pancreatic cancer
Pronunciation
  • /ˈdʒɔːndɪs/
SpecialtyGastroenterology, hepatology, general surgery
SymptomsYellowish coloration of skin and whites of the eyes, itchiness[2][3]
CausesHigh bilirubin levels[3]
Risk factorsPancreatic cancer, Pancreatitis, Liver disease, Certain infections
Diagnostic methodBlood bilirubin, liver panel[3]
Differential diagnosisCarotenemia, taking rifampin[4]
TreatmentBased on the underlying cause[5]

Normal levels of bilirubin in blood are below 1.0 mg/dl (17 μmol/l), while levels over 2–3 mg/dl (34-51 μmol/L) typically result in jaundice.[4][9] High blood bilirubin is divided into two types - unconjugated bilirubin and conjugated bilirubin.[10]

Causes of jaundice vary from nonserious to potentially fatal.[10] High unconjugated bilirubin may be due to excess red blood cell breakdown, large bruises, genetic conditions such as Gilbert's syndrome, not eating for a prolonged period of time, newborn jaundice, or thyroid problems.[4][10] High conjugated bilirubin may be due to liver diseases such as cirrhosis or hepatitis, infections, medications, or blockage of the bile duct.[4] Blockage of the bile duct may occur due to gallstones, cancer, or pancreatitis.[4] Other conditions can also cause yellowish skin, but are not jaundice, including carotenemia — which can develop from eating large amounts of foods containing carotene — or medications such as rifampin.[4]

Treatment of jaundice is typically determined by the underlying cause.[5] If a bile duct blockage is present, surgery is typically required; otherwise, management is medical.[5] Medical management may involve treating infectious causes and stopping medication that could be contributing to the jaundice.[5] Jaundice in newborns may be treated with phototherapy or exchanged transfusion depending on age and prematurity when the bilirubin is greater than 4–21 mg/dl (68-360 μmol/L).[9] The itchiness may be helped by draining the gallbladder or ursodeoxycholic acid.[2] The word "jaundice" is from the French jaunisse, meaning "yellow disease".[11][12]

Signs and symptoms
A 4-year-old boy with icteral sclerae due to G6PD deficiency

The most common signs of jaundice in adults are a yellowish discoloration of the white area of the eye (sclera) and skin[13] with scleral icterus presence indicating a serum bilirubin of at least 3 mg/dl.[14] Other common signs include dark urine (bilirubinuria) and pale,(acholia) fatty stool (steatorrhea).[15] Because bilirubin is a skin irritant, jaundice is commonly associated with severe itchiness.[16][17]

Eye conjunctiva have a particularly high affinity for bilirubin deposition due to high elastin content. Slight increases in serum bilirubin can therefore be detected early on by observing yellowing of sclerae. Traditionally referred to as scleral icterus, this term is actually a misnomer because bilirubin deposition technically occurs in the conjunctival membranes overlying the avascular sclera. Thus, the proper term for the yellowing of "white of the eyes" is conjunctival icterus.[18]

A much less common sign of jaundice specifically during childhood is yellowish or greenish teeth. In developing children, hyperbilirubinemia may cause a yellow or green discoloration of teeth due to bilirubin deposition during the process of tooth calcification.[19] While this may occur in children with hyperbilirubinemia, tooth discoloration due to hyperbilirubinemia is not observed in individuals with adult-onset liver disease. Disorders associated with a rise in serum levels of conjugated bilirubin during early development can also cause dental hypoplasia.[20]

Causes
Types of jaundice

Jaundice is a sign indicating the presence of an underlying diseases involving abnormal bilirubin metabolism, liver dysfunction, or biliary-tract obstruction. In general, jaundice is present when blood levels of bilirubin exceed 3 mg/dl.[14] Jaundice is classified into three categories, depending on which part of the physiological mechanism the pathology affects. The three categories are:

Category Definition
Pre-hepatic/hemolytic The pathology occurs prior to the liver metabolism, due to either intrinsic causes to red blood cell rupture or extrinsic causes to red blood cell rupture.
Hepatic/hepatocellular The pathology is due to damage of parenchymal liver cells.
Post-hepatic/cholestatic The pathology occurs after bilirubin conjugation in the liver, due to obstruction of the biliary tract and/or decreased bilirubin excretion.[21]

Pre-hepatic causes

Pre-hepatic jaundice is most commonly caused by a pathological increased rate of red blood cell (erythrocyte) hemolysis. The increased breakdown of erythrocytes → increased unconjugated serum bilirubin → increased deposition of unconjugated bilirubin into mucosal tissue. These diseases may cause jaundice due to increased erythrocyte hemolysis:

Hepatic causes
Microscopy of a biopsy of a cholestatic liver showing bilirubin pigment (brown pigment), H&E stain

Hepatic jaundice is caused by abnormal liver metabolism of bilirubin. The major causes of hepatic jaundice are significant damage to hepatocytes — due to infectious, drug/medication-induced, auto-immune etiology — or, less commonly, due to inheritable genetic diseases. The following is a non-exhaustive list of hepatic causes to jaundice:

Post-hepatic causes

Post-hepatic jaundice (obstructive jaundice), is caused by a blockage of bile ducts which transport bile containing conjugated bilirubin out of the liver for excretion. The following is a list of conditions that can cause post-hepatic jaundice:

Pathophysiology

Jaundice is typically caused by an underlying pathological process that occurs at some point along the normal physiological pathway of heme metabolism. A deeper understanding of the anatomical flow of normal heme metabolism is essential to appreciate the importance of pre-hepatic, hepatic, and post-hepatic categories. Thus, an anatomical approach to heme metabolism precedes a discussion of the pathophysiology of jaundice.

Pre-hepatic metabolism

When red blood cells complete their lifespan of about 120 days, or if they are damaged, they rupture as they pass through the reticuloendothelial system, and cell contents including hemoglobin are released into circulation. Macrophages phagocytose free hemoglobin and split it into heme and globin. Two reactions then take place with the heme molecule. The first oxidation reaction is catalyzed by the microsomal enzyme heme oxygenase and results in biliverdin (green color pigment), iron, and carbon monoxide. The next step is the reduction of biliverdin to a yellow color tetrapyrrole pigment called bilirubin by cytosolic enzyme biliverdin reductase. This bilirubin is "unconjugated", "free", or "indirect" bilirubin. Around 4 mg of bilirubin per kg of blood are produced each day.[23] The majority of this bilirubin comes from the breakdown of heme from expired red blood cells in the process just described. Roughly 20% comes from other heme sources, however, including ineffective erythropoiesis, and the breakdown of other heme-containing proteins, such as muscle myoglobin and cytochromes.[23] The unconjugated bilirubin then travels to the liver through the bloodstream. Because this bilirubin is not soluble, it is transported through the blood bound to serum albumin.

Hepatic Metabolism

Once unconjugated bilirubin arrives in the liver, a liver enzyme UDP-glucuronyl transferase conjugates bilirubin + glucuronic acid → bilirubin diglucuronide (conjugated bilirubin). Bilirubin that has been conjugated by the liver is water-soluble and excreted into the gallbladder.

Post-hepatic metabolism

Bilirubin enters the intestinal tract via bile. In the intestinal tract, bilirubin is converted into urobilinogen by symbiotic intestinal bacteria. Most urobilinogen is converted into stercobilinogen and further oxidized into stercobilin. Stercobilin is excreted via feces, giving stool its characteristic brown coloration.[24] A small portion of urobilinogen is reabsorbed back into the gastrointestinal cells. Most reabsorbed urobilinogen undergoes hepatobiliary recirculation. A smaller portion of reabsorbed urobilinogen is filtrated into the kidneys. In the urine, urobilinogen is converted to urobilin, which gives urine its characteristic yellow color.[24]

Abnormalities in Heme Metabolism and Excretion

One way to understand jaundice pathophysiology is to organize it into disorders that cause increased bilirubin production (abnormal heme metabolism) or decreased bilirubin excretion (abnormal heme excretion).

Pre-hepatic pathophysiology

Pre-hepatic jaundice is attributed to a pathologic increase in bilirubin production. The pathophysiology is quite simple: an increased rate of erythrocyte hemolysis → increased bilirubin production → increased deposition of bilirubin in mucosal tissue → appearance of yellow hue.

Hepatic Pathophysiology

Hepatic jaundice (hepatocellular jaundice) is due to significant damage to liver function → hepatic cell death and necrosis occur → impaired bilirubin transport across hepatocytes. Bilirubin transport across hepatocytes may be impaired at any point between hepatocellular uptake of unconjugated bilirubin and hepatocellular transport of conjugated bilirubin into the gallbladder. In addition, subsequent cellular edema due to inflammation causes mechanical obstruction of intrahepatic biliary tract. Most commonly, interferences in all three major steps of bilirubin metabolism — uptake, conjugation, and excretion — usually occur in hepatocellular jaundice. Thus, an abnormal rise in both unconjugated and conjugated bilirubin will be present. Because excretion (the rate-limiting step) is usually impaired to the greatest extent, conjugated hyperbilirubinemia predominates.[25]

The unconjugated bilirubin still enters the liver cells and becomes conjugated in the usual way. This conjugated bilirubin is then returned to the blood, probably by rupture of the congested bile canaliculi and direct emptying of the bile into the lymph leaving the liver. Thus, most of the bilirubin in the plasma becomes the conjugated type rather than the unconjugated type, and this conjugated bilirubin, which did not go to intestine to become urobilinogen, gives the urine the dark color.[26]

Post-hepatic pathophysiology

Post-hepatic jaundice (obstructive jaundice) is due to a blockage of bile excretion from the biliary tract → increased conjugated bilirubin and bile salts. In complete obstruction of the bile duct, conjugated bilirubin cannot access the intestinal tract → no further bilirubin conversion to urobilinogen → no stercobilin or urobilin. Instead, excess conjugated bilirubin is filtered into the urine without urobilinogen in obstructive jaundice. Conjugated bilirubin in urine (bilirubinuria) gives urine an abnormally dark brown color. Thus, the presence of pale stool (stercobilin absent from feces) and dark urine (conjugated bilirubin present in urine) suggest an obstructive cause of jaundice. Because these associated signs are also positive in many hepatic jaundice conditions, they cannot be a reliable clinical feature to distinguish obstruction versus hepatocellular jaundice causes.[27]

Diagnosis
Biliary tract dilation due to obstruction as seen on CT scan (sagittal plane)
Biliary tract dilation due to obstruction as seen on CT scan (axial plane)

Most people presenting with jaundice will have various predictable patterns of liver panel abnormalities, though significant variation does exist. The typical liver panel will include blood levels of enzymes found primarily from the liver, such as the aminotransferases (ALT, AST), and alkaline phosphatase (ALP); bilirubin (which causes the jaundice); and protein levels, specifically, total protein and albumin. Other primary lab tests for liver function include gamma glutamyl transpeptidase (GGT) and prothrombin time (PT).[28] No single test can differentiate between various classifications of jaundice. A combination of liver function tests as well as other physical examination findings is essential to arrive at a diagnosis.[29]

Laboratory tests
Pre-hepatic jaundice Hepatic jaundice Post-hepatic jaundice
Total serum bilirubin Normal / increased Increased Increased
Conjugated bilirubin Normal Increased Increased
Unconjugated bilirubin Normal / increased Increased Normal
Urobilinogen Normal / increased Decreased Decreased / negative
Urine color Normal[30] Dark (urobilinogen, conjugated bilirubin) Dark (conjugated bilirubin)
Stool color Brown Slightly pale Pale, white
Alkaline phosphatase levels Normal Increased Highly increased
Alanine transferase and aspartate transferase levels Highly increased Increased
Conjugated bilirubin in urine Not present Present Present

Some bone and heart disorders can lead to an increase in ALP and the aminotransferases, so the first step in differentiating these from liver problems is to compare the levels of GGT, which will only be elevated in liver-specific conditions. The second step is distinguishing from biliary (cholestatic) or liver causes of jaundice and altered laboratory results. ALP and GGT levels will typically rise with one pattern while aspartate aminotransferase (AST) and alanine aminotransferase (ALT) rise in a separate pattern. If the ALP (10–45 IU/L) and GGT (18–85 IU/L) levels rise proportionately as high as the AST (12–38 IU/L) and ALT (10–45 IU/L) levels, this indicates a cholestatic problem. On the other hand, if the AST and ALT rise is significantly higher than the ALP and GGT rise, this indicates a liver problem. Finally, distinguishing between liver causes of jaundice, comparing levels of AST and ALT can prove useful. AST levels will typically be higher than ALT. This remains the case in most liver disorders except for hepatitis (viral or hepatotoxic). Alcoholic liver damage may see fairly normal ALT levels, with AST 10 times higher than ALT. On the other hand, if ALT is higher than AST, this is indicative of hepatitis. Levels of ALT and AST are not well correlated to the extent of liver damage, although rapid drops in these levels from very high levels can indicate severe necrosis. Low levels of albumin tend to indicate a chronic condition, while it is normal in hepatitis and cholestasis.

Lab results for liver panels are frequently compared by the magnitude of their differences, not the pure number, as well as by their ratios. The AST:ALT ratio can be a good indicator of whether the disorder is alcoholic liver damage (above 10), some other form of liver damage (above 1), or hepatitis (less than 1). Bilirubin levels greater than 10 times normal could indicate neoplastic or intrahepatic cholestasis. Levels lower than this tend to indicate hepatocellular causes. AST levels greater than 15 times normal tend to indicate acute hepatocellular damage. Less than this tend to indicate obstructive causes. ALP levels greater than 5 times normal tend to indicate obstruction, while levels greater than 10 times normal can indicate drug (toxin) induced cholestatic hepatitis or cytomegalovirus infection. Both of these conditions can also have ALT and AST greater than 20 times normal. GGT levels greater than 10 times normal typically indicate cholestasis. Levels 5–10 times tend to indicate viral hepatitis. Levels less than 5 times normal tend to indicate drug toxicity. Acute hepatitis will typically have ALT and AST levels rising 20–30 times normal (above 1000), and may remain significantly elevated for several weeks. Acetaminophen toxicity can result in ALT and AST levels greater than 50 times normal.

Laboratory findings depend on the cause of jaundice.

  • Urine: conjugated bilirubin present, urobilinogen > 2 units but variable (except in children).
  • Plasma proteins show characteristic changes.
  • Plasma albumin level is low but plasma globulins are raised due to an increased formation of antibodies.

Unconjugated bilirubin is hydrophobic and therefore cannot be excreted in urine. Thus, the finding of increased urobilinogen in the urine without the presence of bilirubin in the urine (due to its unconjugated state) suggests hemolytic jaundice as the underlying disease process.[31] Urobilinogen will be greater than 2 units (i.e., hemolytic anemia causes increased heme metabolism; exception: infants where gut flora has not developed). Conversely, conjugated bilirubin is hydrophilic and thus can be detected as present in the urine — bilirubinuria — in contrast to unconjugated bilirubin which is absent in the urine.[32]

Imaging

Medical imaging such as ultrasound, CT scan, and HIDA scans are useful for detecting bile duct blockage.[32]

Differential diagnosis

Yellow discoloration of the skin, especially on the palms and the soles, but not of the sclera or inside the mouth is due to carotenemia—a harmless condition.[33]

Treatment

Treatment of jaundice will vary depending on the underlying cause.[5] If a bile duct blockage is present, surgery is typically required; otherwise, management will be medical.[5][34][35][36][37] Surgery in patients with obstructive jaundice are associated with significantly higher rates of complications (69% vs 38%, P=0.002) and mortality.[38] Medical management may involve treating infectious causes and stopping medication that could be contributing to the jaundice.[5] The itchiness may be helped by draining the gallbladder or ursodeoxycholic acid.[2]

Complications

Hyperbilirubinemia, more precisely hyperbilirubinemia due to the unconjugated fraction, may cause bilirubin to accumulate in the gray matter of the central nervous system, potentially causing irreversible neurological damage leading to a condition known as kernicterus. Depending on the level of exposure, the effects range from unnoticeable to severe brain damage and even death. Newborns are especially vulnerable to hyperbilirubinemia-induced neurological damage and therefore must be carefully monitored for alterations in their serum bilirubin levels.

Individuals with parenchymal liver disease who have impaired hemostasis may develop bleeding problems.[39]

Epidemiology

Jaundice in adults is rare.[40][38][41] Under the five year DISCOVERY programme in the UK, annual incidence of jaundice was 0.74 per 1000 individuals over age 45, although this rate may be slightly inflated due to the main goal of the programme collecting and analyzing cancer data in the population.[42] Jaundice is commonly associated with severity of disease with an incidence of up to 40% of patients requiring intensive care in ICU experiencing jaundice.[41] The causes of jaundice in the intensive care setting is both due to jaundice as the primary reason for ICU stay or as a morbidity to an underlying disease (i.e. sepsis).[41]

In the developed world, the most common causes of jaundice are blockage of the bile duct or medication-induced. In the developing world, the most common cause of jaundice is infectious such as viral hepatitis, leptospirosis, schistosomiasis, or malaria.[4]

Risk factors

Risk factors associated with high serum bilirubin levels include male gender, white ethnicities, and active smoking.[43] Mean serum total bilirubin levels in adults were found to be higher in men (0.72 ± 0.004 mg/dL) than women (0.52 ± 0.003 mg/dL).[43] Higher bilirubin levels in adults are found also in non-Hispanic white population (0.63 ± 0.004 mg/dL) and Mexican American population (0.61 ± 0.005 mg/dL) while lower in non-Hispanic black population (0.55 ± 0.005 mg/dL).[43] Bilirubin levels are higher in active smokers.[43]

Special Populations

Neonatal Jaundice
Main article: Neonatal jaundice

Symptoms

Jaundice in infants presents with yellowed skin and icteral sclerae. Neonatal jaundice spreads in a cephalo-caudal pattern, affecting the face and neck before spreading down to the trunk and lower extremities in more severe cases.[44] Other symptoms may include drowsiness, poor feeding, and in severe cases, unconjugated bilirubin can cross the blood-brain barrier and cause permanent neurological damage (kernicterus).

Causes

The most common cause of jaundice in infants is normal physiologic jaundice. Pathologic causes of neonatal jaundice include the following:

Pathophysiology

Transient neonatal jaundice is one of the most common conditions occurring in newborns (children under 28 days of age) with more than eighty percent affected during their first week of life.[46] Jaundice in infants, like adults, is characterized by increased bilirubin levels (total serum bilirubin greater than 5 mg/dL).

Normal physiological neonatal jaundice is due to immaturity of liver enzymes involved in bilirubin metabolism, immature gut microbiota, and increased breakdown of fetal hemoglobin (HbF).[47] Breastmilk jaundice is caused by an increased concentration of β-glucuronidase in breast milk → ↑ deconjugation and reabsorption of bilirubin → persistence of physiologic jaundice with unconjugated hyperbilirubinemia. Onset of breastmilk jaundice is within 2 weeks after birth and lasts for 4–13 weeks.

While most cases of newborn jaundice are not harmful, if bilirubin levels are very high, brain damage — kernicterus — may occur[48][8] leading to significant disability.[49] Kernicterus is associated with increased unconjugated bilirubin (which is not carried by albumin). Newborns are especially vulnerable to this due to increased permeability of the blood–brain barrier and increased unconjugated bilirubin given fetal hemoglobin breakdown and immature gut flora. This condition has been rising in recent years due to less time spent outdoors.

Treatment

Jaundice in newborns is usually transient and dissipates without medical intervention. In cases when serum bilirubin levels are greater than 4–21 mg/dL (68-360 μmol/L), infant may be treated with phototherapy or exchanged transfusion depending on the infant's age and prematurity status.[9] A Bili light is often the tool used for early treatment, which often consists of exposing the baby to intensive phototherapy. Sunbathing is effective treatment,[50][51] and has the advantage of ultra-violet-B, which promotes vitamin D production.[52] Bilirubin count is also lowered through excretion — bowel movements and urination —so frequent and effective feedings are vital measures to decrease jaundice in infants.[53]

Etymology

Jaundice comes from the French jaune, meaning yellow, jaunisse meaning "yellow disease". The medical term for it is icterus from the Greek word ikteros.[54] The origin of the word icterus is quite bizarre, coming from an ancient belief that jaundice could be cured from looking at the yellow bird icteria.[55] The term icterus is sometimes incorrectly used to refer to jaundice specifically of sclera.[54][56]


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