Gus M. Garmel and Tobias D. Barker
JAUNDICE, APPROACH TO JAUNDICE, ICTERUS, BILIRUBIN METABOLISM, BILIRUBIN CONJUGATION
Jaundice may be defined as the yellowing of skin, sclera, and other tissues owing to deposition of excess circulating bilirubin. The clinical challenge is not the identification of jaundice but with the workup to delineate the responsible pathologic process, typically liver disease or a hemolytic condition. This chapter describes an approach to the jaundiced patient, with particular attention to understanding bilirubin metabolism. It includes historical, physical examination, laboratory, and imaging findings that should help clinicians establish an etiology. This chapter also discusses diagnostic and management strategies based on findings associated with the presentation of jaundice.
BILIRUBIN METABOLISM
Bilirubin is an end product of heme metabolism. Approximately 75% of bilirubin is derived from the hemoglobin of senescent red blood cells; the remainder comes from myoglobin, cytochromes, and respiratory enzymes with structures similar to that of heme (1,2). Initially, bilirubin produced in the body is unconjugated. Physiological jaundice in newborns is due to the relatively low activity of glucuronosyltransferase, an enzyme responsible for the conversion of unconjugated bilirubin to conjugated bilirubin. Unconjugated bilirubin is able to cross the placenta, which prevents fetal accumulation. Unconjugated bilirubin is actively transported from albumin into liver cells. Here, bilirubin is combined with glucuronic acid in the smooth endoplasmic reticulum, where it becomes conjugated. Conjugated bilirubin is then excreted from the hepatocyte to the biliary tract, where it eventually reaches the intestines and is excreted from the body (eFig. 102.1A).
eFIGURE 102.1 Mechanisms of hyperbilirubinemia. A: Normal bilirubin metabolism. B: Gilbert disease and certain drugs: defective bilirubin uptake from the blood, resulting in unconjugated hyperbilirubinemia. C: Physiologic jaundice of the newborn and Crigler–Najjar syndrome, inability to conjugate bilirubin. D: Hemolytic anemia, the capacity of the hepatocytes is overwhelmed, resulting in unconjugated hyperbilirubinemia. E: Dubin–Johnson syndrome: Hepatocytes are unable to secrete conjugated bilirubin into the biliary system. F: Obstruction in the biliary outflow tract (e.g., gallstones, tumor, mass) results in backup and reabsorption of conjugated bilirubin. (Baggott J, Dennis SE. Diseases associated with hyperbilirubinemia. Available at: http://library.med.utah.edu/NetBiochem/hi7d.htm. Accessed 9 June, 2014. Modified and used with permission.)
CLINICAL PRESENTATION
Sir William Osler stated, “Jaundice is the disease your friends diagnose” (3). Regardless of who identifies the color changes associated with jaundice (also known as icterus), patients are likely to be concerned about the underlying cause. Skin color changes may occur in isolation or with nausea, vomiting, abdominal pain, pruritus, and/or fever. Patients may notice darkening or discoloration of their urine (often described as “tea” or “cola” in color). Although rarely a true medical emergency in itself, physicians must quickly assess for and begin treating any concomitant life-threatening conditions, such as hypotension, sepsis, or alterations in mental status.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of jaundice is extensive. Jaundice has many possible etiologies, including biliary obstruction, hepatocellular dysfunction, hemolysis, and hereditary disorders of bilirubin metabolism. Certain epidemiologic factors may provide clues to the cause of a patient’s jaundice. In general, younger patients are more likely to have parenchymal liver disease, whereas older patients are more likely to have biliary stones or malignancy. Jaundice in the newborn (neonatal jaundice) is discussed in Chapter 221. Worldwide, the most common cause of hepatocellular disease-causing jaundice is viral hepatitis, whereas in the developed world, alcoholic hepatitis is increasingly prevalent. Liver injury may be the result of sepsis or ischemia (4), in addition to toxic effects of drugs, alcohol, or pathogens. Zoonotic infections have been reported as a rare cause of jaundice (5). Table 102.1 suggests common causes of jaundice grouped by age.
TABLE 102.1
Common Causes of Jaundice According to Age
Causes of yellow skin in the absence of hyperbilirubinemia include carotenemia (carotenoderma), quinacrine ingestion, and occupational exposure to phenols (6). One feature that differentiates jaundice from other causes of yellow skin is that bilirubin stains the sclera. Other areas where jaundice may be identified are those regions relatively free of melanin, such as the palms, soles, and the undersurface of the tongue.
ED EVALUATION
The underlying pathology behind a patient’s jaundice can often be discovered after a thorough history, physical examination, selected laboratory tests, and focused imaging studies. The cause of jaundice was successfully identified as either obstructive or nonobstructive in 75% of cases in one study (7). A diagnostic approach to the jaundiced patient is provided in Figure 102.1 (8).
FIGURE 102.1 Algorithm for patient with jaundice (8). (Modified from Pratt DS, Kaplan MM. Jaundice. In: Longo DL, Fauci AS, Kasper DL, et al., eds. Access Medicine, Harrison’s Principles of Internal Medicine, Harrison’s Online. 18th ed. McGraw Hill Professional; 2011). Accessed June 9, 2014 through www.AccessMed.com. Used with permission.)
History
As always, a good history can help delineate possible etiologies responsible for any patient’s presentation. Important historical points in a jaundiced patient include the following:
New-onset dark urine indicates conjugated hyperbilirubinemia, as unconjugated bilirubin is bound to albumin in the serum and is not filtered into the urine. Patients often notice dark urine before skin discoloration, which may be the first indication of hyperbilirubinemia.
Clay-colored stool indicates that bilirubin is not leaving the biliary ducts due to an obstruction, resulting in conjugated hyperbilirubinemia.
Medications, alcohol, and environmental hepatotoxins (such as phosphorus, petrochemicals, organic solvents, or toxic mushrooms) may result in jaundice. Medications such as acetaminophen, anabolic steroids, and sulfonamides can cause jaundice through direct cellular damage or by interfering with biliary secretion. Idiosyncratic drug-induced liver injury may result in jaundice (9).
Nausea and vomiting preceding jaundice most often indicate acute hepatitis or obstruction of the common biliary duct by a gallstone. Abdominal pain, fever, chills, or rigors favor the latter. Recent flu-like symptoms and aspirin use raise the possibility of Reye syndrome in younger patients. Anorexia and malaise, especially long-standing, suggest alcoholic liver disease, chronic hepatitis, or pancreatic cancer.
Infectious exposures, intravenous drug use, or blood transfusions increase the possibility of viral hepatitis.
Pregnancy suggests benign recurrent cholestasis or acute fatty liver of pregnancy.
Family history of jaundice or liver disease increases the likelihood of a hereditary cause of hyperbilirubinemia, such as Gilbert, Crigler–Najjar, Dubin–Johnson, or Rotor syndrome.
Physical Examination
Jaundice is best seen in natural light and is usually detectable when serum bilirubin exceeds 2.5 mg/dL (about twice the upper limit of normal) (10). The identification of jaundice may be more difficult in artificial light, especially in the fluorescent lights found in many emergency departments (EDs). Jaundice may also be more difficult to identify depending on the patient’s skin color, age, or hydration status. The greater the bilirubin level, the more easily jaundice is recognized. One study calculated the clinical sensitivity of diagnosing jaundice in patients with a bilirubin level >3.0 mg/dL at 78.4%, reaching a sensitivity of 100% with a bilirubin level >15 mg/dL (11).
Other useful physical examination findings include the following:
Signs of cirrhosis include ascites (serous fluid accumulation in the abdominal cavity resulting from salt and water retention in patients with cirrhosis); spider hemangiomas (red tufts of fine blood vessels which blanch with pressure, oriented in a spider-like pattern on the trunk, face, forearms and hands, thought to be a result of increased levels of circulating estrogens); or caput medusae (dilated veins in the abdominal wall, radiating from the umbilicus, which develop as portosystemic collateral vessels secondary to portal hypertension).
Right upper quadrant (RUQ) tenderness and inspiratory arrest on palpation of the gallbladder (Murphy sign) suggest cholecystitis. Charcot triad (RUQ pain, jaundice, and fever) and Reynold pentad (RUQ pain, jaundice, fever, hypotension, and mental status changes) are indicative of cholangitis.
Fetor hepaticus (a musty, sweetish breath odor) may develop in patients with advanced liver disease or hepatic encephalopathy.
Diffuse lymphadenopathy is suggestive of infectious mononucleosis in acute jaundice, and lymphoma or leukemia in chronic illness with jaundice. Specific lymph node enlargement, such as an enlarged left supraclavicular (Virchow) node or periumbilical (Sister Mary Joseph) node, increases the likelihood of abdominal malignancy.
Hepatosplenomegaly without other signs of chronic liver disease may be the result of an infiltrative disorder, such as lymphoma or amyloidosis. Nodularity or a small liver may suggest cirrhosis. A palpable mass suggests an abscess or malignancy.
Temporal and proximal muscle wasting suggest long-standing diseases, such as cirrhosis or malignancy.
Asterixis and altered mentation are ominous findings that indicate fulminant hepatic failure.
Kayser–Fleischer rings are seen in Wilson disease (a rare, progressive, autosomal recessive disease due to a defect in copper metabolism), which may result in cirrhosis.
Skin pigmentation (often bronze in nature) is seen in hemochromatosis, a condition resulting in liver dysfunction due to abnormal deposits of hemosiderin in the liver.
Laboratory Evaluation
Laboratory testing is important in the evaluation of a patient with jaundice, as the results may identify a specific etiology or assist in the next stage of the evaluation, such as imaging or consultation. The minimum laboratory tests needed in these patients include bilirubin level with fractionation, aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphatase, prothrombin time, and complete blood count. The first step in the decision analysis is to determine whether hyperbilirubinemia is isolated or associated with liver function abnormalities (see Fig. 102.1).
Hyperbilirubinemia Without Other Laboratory Abnormalities
In a patient with isolated hyperbilirubinemia, it is important to determine whether the bilirubin is unconjugated or conjugated. Isolated unconjugated (indirect) hyperbilirubinemia is due to either a hemolytic process or impaired hepatic function. Therefore, isolated unconjugated (indirect) hyperbilirubinemia is caused either by decreased uptake (see eFig. 102.1B), decreased conjugation (see eFig. 102.1C), or overproduction of bilirubin (see eFig. 102.1D). The drugs rifampin, probenecid, and ribavirin can decrease bilirubin uptake into the hepatocyte. Gilbert syndrome is a hereditary disorder resulting in abnormal bilirubin metabolism, in part through decreased bilirubin uptake (12,13). It is the most common hereditary cause of isolated unconjugated hyperbilirubinemia, occurring in approximately 9% of Caucasians (14). This benign condition is usually noted as an incidental laboratory finding and is not responsible for liver damage or hematologic abnormalities.
Decreased bilirubin conjugation may be the result of decreased levels or inactivity of UDP-glucuronosyltransferase (UGT), the enzyme necessary for the formation of conjugated bilirubin. Crigler–Najjar syndrome is a more serious condition than Gilbert syndrome and has varying degrees of jaundice directly related to the degree of UGT available. In type I Crigler–Najjar syndrome, UGT is absent; these patients often die in the neonatal period. In type II disease, there is reduced but variable UGT activity, so the diagnosis may not be established until later in childhood. These patients may have a normal life expectancy and usually take phenobarbital, which increases UGT activity. Physiologic jaundice of the newborn is thought to be secondary to decreased conjugation as a result of delayed expression of UGT during the newborn period (see Chapter 221).
Disorders resulting in overproduction of bilirubin cause jaundice by overwhelming the capacity of hepatocytes to conjugate bilirubin (eFig. 102.1D). One cause is hemolysis, which may occur from mechanical shearing (disseminated intravascular coagulation, artificial valves). Other causes include hereditary red cell fragility (G6PD deficiency, sickle cell anemia, paroxysmal nocturnal hemoglobinuria), environmental stressors (heat, envenomation), or reactions following blood transfusion. Hemolysis due to vitamin B12 deficiency from pernicious anemia has been reported as an underlying cause of jaundice (15). Increased bilirubin that occurs from the resorption of hematoma following trauma is a more benign cause. A complete blood count in these patients may reveal anemia or an abnormal red blood cell morphology implicating an underlying pathologic cause for the anemia.
Isolated conjugated (direct) hyperbilirubinemia is usually caused by one of two inherited disorders. Dubin–Johnson syndrome (rare except in Jews of Middle Eastern descent) and Rotor syndrome both have fairly benign clinical courses. These are the result of an inability to secrete conjugated bilirubin through the canalicular membrane into the biliary system (eFig. 102.1E).
ED imaging is not generally required in the primary diagnosis of isolated hyperbilirubinemia. However, one may find secondary signs of the underlying pathology responsible for the hyperbilirubinemia (paravertebral masses seen in extramedullary hematopoiesis, avascular necrosis of the femoral head seen in sickle cell disease). In such cases, focused imaging directed at a potential etiology is appropriate, although this may occur in the outpatient setting based on the patient’s medical condition and the availability of follow-up care.
Hyperbilirubinemia With Other Laboratory Abnormalities
In patients with jaundice due to hyperbilirubinemia and other laboratory abnormalities, it is important to determine whether a hepatocellular condition or cholestasis is responsible. This can be determined by identifying which laboratory abnormalities predominate—elevated transaminases or an elevated alkaline phosphatase.
If elevated transaminases predominate, direct hepatocellular damage in hepatitis is likely (16,17). There are two common transaminase enzymes: AST (found primarily in the liver, although it is also in several other tissues) and ALT (found predominantly in hepatocytes). AST activity is increased in alcoholics; therefore, an AST:ALT ratio >2:1 suggests alcohol toxicity (18,19). AST levels >400 IU/mL indicate hepatocellular injury, whereas higher levels may be associated with liver ischemia, viral infection, or toxins. Imaging for these intrahepatic causes of jaundice often reveal no specific findings. The liver parenchyma often has diffuse interstitial edema and infiltration of inflammatory cells that causes diffuse decreased parenchymal echogenicity on ultrasound. This gives rise to the “starry sky” appearance of the relatively bright portal triads against the background of dark parenchyma (20).
If elevated alkaline phosphatase predominates, clinicians must be concerned about biliary obstruction. Whether the cause of obstruction is intrahepatic or extrahepatic, the synthesis and release of alkaline phosphatase into the serum is increased (eFig. 102.1F). However, extrahepatic tissues also synthesize and release alkaline phosphatase. To confirm the hepatic origin for the elevated alkaline phosphatase, enzymes such as γ-glutamyl transferase may be tested. In a jaundiced patient, however, an increased alkaline phosphatase with normal transaminases strongly suggests biliary tract obstruction. Patients in this category should have their gallbladder and liver evaluated with abdominal ultrasound. This test is noninvasive and has a sensitivity of 77% and a specificity of 83% to 95% for bile duct obstruction (21).
The goal of imaging jaundiced patients is to identify which patients have an obstructive (and therefore perhaps correctable) cause of their jaundice. Ultrasound is particularly suited to this purpose because of its ability to visualize the intra- and extrahepatic biliary tree in detail. If dilated ducts are present, one must determine whether sonographic signs consistent with cholecystitis or cholangitis are present. Ultrasound findings consistent with cholecystitis include the sonographic Murphy sign, calculi in the gallbladder, gallbladder wall thickening of >3 mm, distention of the gallbladder, and pericholecystic fluid. Any of these findings warrant antibiotics and surgical consultation. A gastroenterology consultation to discuss whether a computed tomography (CT) scan or endoscopic retrograde cholangiopancreatography (ERCP) is prudent if these findings are absent should occur in a patient with dilated ducts, as extrinsic compression of the bile duct must be excluded. Magnetic resonance cholangiopancreatography (MRCP) is gaining favor among specialists as a diagnostic examination for a jaundiced patient without or with borderline common biliary duct dilatation if choledocholithiasis is a possible etiology. If available, MRCP has fewer risks than ERCP, although it does not provide the option for therapeutic maneuvers. Endoscopic ultrasound may serve as the standard for identifying gallbladder and bile duct stones in some institutions (22). If dilated ducts are not seen on ultrasound, further workup should focus on sources of intrahepatic cholestasis, such as viral infection (hepatitis, Epstein–Barr virus, cytomegalovirus), toxin damage (alcohol, steroids), or disorders such as primary biliary cirrhosis and primary sclerosing cholangitis. This workup can generally be performed on an outpatient basis if the patient does not appear ill, can tolerate oral intake, and has reliable follow-up.
KEY TESTING
• Bilirubin (fractionated), transaminases, alkaline phosphatase, CBC, PT
• Biliary ultrasound if laboratory tests suggest biliary obstruction
ED MANAGEMENT
When evaluating a patient with jaundice, emergency physicians must quickly determine whether a life-threatening condition is present. During assessment of the airway, breathing, and circulation (ABCs), history, and physical examination, patients should be given oxygen, placed on a cardiac monitor, and intravenous access should be obtained. Caution is advised during invasive procedures, as hepatitis transmission through occupational exposures is a concern. Patients may require aggressive intravenous fluid resuscitation, as they may be dehydrated, hypotensive, or in shock due to decreased oral intake, vomiting, infection, sepsis, or third-space losses (such as occurs with ascites). Antiemetics should be given as needed. Patients with ascending cholangitis are often critically ill and require aggressive resuscitation. Airway intervention, cardiovascular support (including pressors after aggressive fluid resuscitation), early antibiotics, and emergent surgical consultation are all important measures in reducing morbidity and mortality.
Depending on the cause of jaundice and the toxicity of the patient, surgical, gastroenterologic, or radiologic intervention may be necessary to relieve an obstruction or address the cause of underlying infection. A general surgeon may need to perform an open or laparoscopic cholecystectomy depending on the patient’s condition, the underlying pathology, and their skill set. A gastroenterologist (or a surgeon at some institutions) may do an ERCP to stent an obstruction, to remove an obstructing gallstone from the common bile duct, or to perform a sphincterotomy. An interventional radiologist may execute a percutaneous transhepatic cholangiogram (PTC), a diagnostic and therapeutic procedure that may allow drainage of an obstructed bile duct with or without cholangitis. Further information about the evaluation and management of ascending cholangitis may be found in Chapter 103.
Fortunately, most patients with jaundice are not acutely ill. Pruritus may be their most troublesome symptom. Drugs such as cholestyramine (4 g PO qd-tid) and rifampin (300 to 450 mg PO qd) improve pruritus in patients with cholestasis, although these do not act immediately. Of note, long-term administration of rifampin for refractory pruritus has been associated with occasional hepatotoxicity (23). Oral naltrexone (50 mg qd) has also been shown to significantly decrease symptoms in patients with pruritus (24). Antihistamines should be used with caution, as they may precipitate hepatic encephalopathy. Additional treatment options depend on the underlying pathology.
CRITICAL INTERVENTIONS
• When a serious infection is likely, aggressive fluid administration, broad-spectrum parenteral antibiotics, and emergent consultation are mandatory.
• Aggressive fluid resuscitation and blood transfusion may be necessary in patients presenting in acute hemolytic crisis. Administration of folic acid is useful because hemolysis depletes folate.
• Patients with jaundice presenting in fulminant liver failure and confusion may require emergent airway management. Fluids, broad-spectrum antibiotics, and lactulose and/or neomycin should be administered, and any critical electrolyte abnormalities should be aggressively corrected.
DISPOSITION
Acute hemolysis must be ruled out in patients with isolated unconjugated hyperbilirubinemia. If hemolysis is present, the patient should be admitted and a diligent search for the underlying cause (either inherited or acquired) must occur in consultation with hematology. If hemolysis or resorption of a hematoma do not appear to be the cause of the unconjugated hyperbilirubinemia, hereditary problems of bilirubin metabolism are likely. Affected patients may be candidates for outpatient follow-up with gastroenterology consultation.
In patients with isolated conjugated hyperbilirubinemia, hereditary metabolic problems are most likely. These patients may need gastroenterology consultation, although they can usually be followed on an outpatient basis as long as critical laboratory abnormalities do not exist, reliable follow-up arrangements can be made, and symptoms are controlled.
Patients with hyperbilirubinemia and elevated transaminases to a degree greater than the alkaline phosphatase require medical evaluation for causes of hepatocellular injury, often in the inpatient setting if these are not known to be chronic. Treatment may include cessation of offending toxins (e.g., alcohol, acetaminophen, isoniazid, other drugs), antiviral treatment for hepatitis, or treatment for autoimmune or metabolic causes (e.g., Wilson disease, hemochromatosis).
Patients with hyperbilirubinemia and an elevated alkaline phosphatase to an extent greater than the transaminases require urgent abdominal ultrasound to search for obstructive causes. Those patients with dilated ducts and fever, leukocytosis, bandemia, or toxic appearance should be aggressively hydrated, started on broad-spectrum antibiotics in the ED, and admitted to the hospital. It is prudent to keep these patients nil per os, provide analgesia and antiemetics as needed, as well as antipyretics if fever is present and no signs of acute hepatotoxicity exist. Prompt consultation with surgery (for possible laparotomy or laparoscopy, depending on the condition of the patient and the skills of the surgeon) or gastroenterology (for possible ERCP) is essential. Further workup of these patients is discussed in Chapter 103. Afebrile patients with dilated ducts who are less acutely ill may have extrinsic compression of the biliary tree from such sources as pancreatic cancer, nearby arterial aneurysms, or other abdominal masses. These patients may benefit from abdominal CT scan, MRCP, or PTC. Patients without dilated ducts require a medical workup for causes of intrahepatic jaundice, such as infiltrative disorders, drugs or toxins, primary biliary cirrhosis, primary sclerosing cholangitis, or complications of pregnancy. The disposition of these patients depends on their clinical status and degree of laboratory abnormalities. Patients with chronic alcoholism who present with jaundice, especially of new onset, should be carefully managed and observed prior to release from the ED. This is extremely important for those who are unreliable, have uncertain follow-up care, or live in suboptimal conditions.
Common Pitfalls
• Delayed fluid intervention, broad-spectrum antibiotic administration, and emergent consultation in an acutely ill patient with jaundice and signs of cholangitis, such as Charcot triad (RUQ pain, jaundice, fever) or Reynold pentad (RUQ pain, jaundice, fever, hypotension, mental status changes).
• Failure to recognize signs and symptoms of fulminant liver failure (e.g., confusion, asterixis, abnormal vital signs), as well as predict associated problems related to the airway, cardiovascular status, glucose, and electrolytes.
• Failure to order appropriate imaging studies for patients with hyperbilirubinemia and an elevated alkaline phosphatase, suggestive of biliary obstruction requiring intervention.
• Failure to arrange or ensure reliable follow-up care for patients with unclear etiologies of their jaundice, as these patients will likely require serial evaluations and repeat testing before a diagnosis is confirmed.
ACKNOWLEDGMENTS
Drs. Garmel and Barker would like to thank Elaine Barnes from the Kaiser Santa Clara Health Sciences Library for her research assistance and Dr. Timothy Steck from the Department of Gastroenterology at Kaiser Santa Clara Medical Center for his thoughtful review.
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