A Systematic Approach to Patients with Jaundice

Abstract

Jaundice is a clinical manifestation of disorders of underlying bilirubin metabolism, hepatocellular dysfunction, or biliary obstruction. As clinical presentations of yellowing of eyes or skin can be somewhat nonspecific for the underlying etiology of disease, a stepwise approach to evaluation is necessary for accurate diagnosis and effective treatment plan. In this review, we discuss underlying mechanisms of cholestasis and jaundice as well as laboratory and imaging modalities needed to evaluate a patient presenting with hyperbilirubinemia. Jaundice occurs in settings of cholestasis or inability to effectively secrete bile as well as disorders of bilirubin metabolism and hepatocellular dysfunction. Clinical signs of jaundice occur when the serum bilirubin level exceeds 2.5 to 3 mg/dL. In all cases, evaluation begins with liver chemistry tests which include bilirubin (conjugated and unconjugated), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total protein. In patients with hepatobiliary causes of jaundice, the alkaline phosphatase is usually elevated. In these cases, evaluation of hepatic synthetic function is crucial to the formulation of a treatment plant. When serologic evaluation is combined with hepatobiliary imaging, underlying mechanism of disease can often be elucidated. A stepwise approach to evaluation can be cost and time saving as well as a framework to improve patient outcomes. In this review, we will outline a diagnostic approach to jaundice, beginning with pathophysiology of cholestasis followed by hyperbilirubinemia and markers of synthetic dysfunction.

Objectives: Upon completion of this article, the reader will be able to identify the pathophysiology of hyperbilirubinemia, its etiology, clinical presentation, and diagnostic approach to assess and manage a patient with jaundice.

Accreditation: This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Tufts University School of Medicine (TUSM) and Thieme Medical Publishers, New York. TUSM is accredited by the ACCME to provide continuing medical education for physicians.

Credit: Tufts University School of Medicine designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Cholestasis

Cholestasis occurs as a result of any condition which impairs the liver's ability to secrete bile. This may be due to decreased bile synthesis, defective bile secretion, or bile flow obstruction.¹ The hallmark laboratory abnormality of cholestasis is elevation of the alkaline phosphatase. Concomitant elevation of the alkaline phosphatase and bilirubin is a hallmark of hepatobiliary dysfunction.

Alkaline Phosphatase

Alkaline phosphatase represents a group of zinc metalloenzymes that catalyze hydrolysis of esters.² In the liver, alkaline phosphatase is predominantly found in the canalicular membrane of the hepatocytes³; however, it can also be found in osteoblasts of the bone, small intestinal brush border, the placenta, proximal tubules of the kidney, and white blood cells.⁴ The majority of serum alkaline phosphatase originates from the liver, bone, and intestine. Within the liver, bile acids induce translation of alkaline phosphatase mRNA. In a clinical setting of biliary obstruction, increased concentrations of bile acids promote expression of alkaline phosphatase, which results in translocation of the enzyme from the canalicular membrane to the basolateral or sinusoidal surface. High concentrations of alkaline phosphatase within the hepatic sinusoids can be measured as elevated levels in the serum.⁵ In healthy patients, alkaline phosphatase levels have been shown to have variability as a function of age, gender, race, and blood type.⁶ For example, mild elevations of alkaline phosphatase are commonly seen at times of bone growth such as in an adolescent during puberty and during pregnancy due to placental production of the enzyme.^{1 7} Decreased levels of alkaline phosphatase can also be seen in Wilson disease, zinc deficiency, malnutrition, hypothyroidism, vitamin C deficiency, pernicious anemia, and phosphorus deficiency.¹ In most cases of pure cholestasis, alkaline phosphatase levels are proportionally higher than serum aminotransferases. Unlike hepatocellular injury, where the degree of aminotransferase elevation is indicative of certain mechanisms of injury, the magnitude of elevation is usually less helpful in distinguishing specific etiology of cholestasis.

5′-Nucleotidase

The function of 5′-nucleotidase (5′NT) is to convert extracellular nucleotides to nucleosides via catalyzing hydrolysis at the 5′ position on the pentose moiety. 5′NT is found in many tissues, including liver, brain, intestine, heart, blood vessels, and endocrine pancreas; however, for unclear reasons, serum levels become elevated only when originating from a hepatobiliary source.^{3 8} There can be discordance between serum alkaline phosphatase and serum 5′NT. In a study that used liver-specific alkaline phosphatase as the gold standard, 5′NT had a sensitivity of 47% and a specificity of 86% in detecting hepatobiliary disease.⁹ Given the relatively high specificity, 5′NT has the greatest clinical utility as a confirmatory test of hepatobiliary origin in patients with elevated alkaline phosphatase.

Gamma-Glutamyl Transpeptidase

Gamma-glutamyl transpeptidase (GGT) is a sialoglycoprotein that plays an important role in glutathione metabolism.¹⁰ Similar to alkaline phosphatase and 5′NT, GGT has a wide distribution throughout the body and can be found in the liver, kidney, spleen, brain, lungs, intestine, and prostate.¹¹ Elevations of serum GGT are sensitive to reflect hepatobiliary disease; however, they are not specific and can be seen in diabetes, renal disease, myocardial infarction, rheumatic disease, neurologic disease, and pancreatitis.¹² Many drugs, notably anticonvulsants, and alcohol use have been shown to cause increased GGT enzyme activity.¹³ Importantly, GGT levels are not elevated in musculoskeletal disease; therefore, this test is useful in ruling out a bone disease in a patient with an elevated alkaline phosphatase.

Evaluation of a Patient with Abnormal Alkaline Phosphatase Levels

Determining the source of alkaline phosphatase is the initial step in the evaluation of a patient with cholestasis (Fig. 1). In these patients, bilirubin may be normal or elevated. In a jaundiced patient, elevated alkaline phosphatase may represent diffuse hepatocellular dysfunction or significant bile duct obstruction which impedes adequate bile flow. A hepatobiliary source of alkaline phosphatase can be verified by an elevated 5′NT or GGT levels. Alternatively, fractionating alkaline phosphatase isoenzyme via electrophoresis will identify the origin of each component.^{1 14} However, in settings where alkaline phosphatase is elevated along with other liver chemistry abnormalities such as hyperbilirubinemia or elevated aminotransferases, confirmation of hepatobiliary source of alkaline phosphatase is usually not necessary. Once a hepatobiliary source of cholestasis is confirmed, the next step in evaluation is to determine whether the abnormality is intrahepatic or extrahepatic.

Fig. 1.

Evaluation of a patient with cholestasis.

Extrahepatic Source of Cholestasis

Patients with an extrahepatic source of cholestasis may present with fevers, right upper quadrant abdominal pain, or jaundice; however, they may also be asymptomatic. Initial evaluation of extrahepatic sources of cholestasis should begin with a right upper quadrant ultrasound to evaluate for the presence of biliary dilatation. Ultrasound is a safe and relatively inexpensive imaging modality and has a high specificity (95–100%) in the identification of common bile duct stones.¹⁵ Limitations of ultrasound include decreased sensitivity for obstruction, especially in obese patients, extensive overlying bowel gas, or in those with smaller culprit lesions.¹⁶ Computed tomography (CT) has been shown to be more accurate than ultrasound in the identification of both the level and the cause of biliary obstruction; however, this test is less sensitive in detecting choledocholithiasis and exposes patients to radiation.^{16 17} Finally, endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP) are highly effective in diagnosing sources of extrahepatic cholestasis. Although ERCP has long been the gold standard, MRCP has been shown to be a safe noninvasive method with comparable sensitivity and specificity in diagnosing biliary obstruction.¹⁸

Choledocholithiasis is the most common cause of extrahepatic biliary obstruction; however, in patients with cholestasis, other sources of obstruction should also be considered (Table 1). In settings of predominant cholestasis, we recommend evaluation for extrahepatic causes of obstruction early in the evaluation, as many causes may be reversible and without intervention, it may pose a risk of infection or progressive hepatic fibrosis.

Table 1. Extrahepatic causes of cholestasis.

Gallstones

Biliary cysts

Biliary stricture

Parasitic infection

Pancreatitis

Pancreatic pseudocyst

AIDS cholangiopathy

Immunoglobulin G4–related disease

Malignancy

Cholangiocarcinoma

Lymphoma

Pancreatic cancer

Ampullary cancer

Metastatic disease

Gallbladder cancer

Intrahepatic Source of Cholestasis

Once extrahepatic causes of elevated alkaline phosphatase have been ruled out, intrahepatic causes should be considered. Jaundice is a common clinical finding in patients with intrahepatic sources of cholestasis, especially at late stages of disease. Patients with intrahepatic cholestasis may present with pruritus and fatigue.¹ Laboratory evaluation may reveal hyperlipidemia¹⁹ and deficiencies of fat-soluble vitamins A, D, E, and K.²⁰ A thorough history should be obtained which includes medication and supplement use to identify possible drug-induced cholestasis. Table 2 describes potential causes of intrahepatic cholestasis, which include viral, genetic, immune-mediated, and infiltrative etiologies. Table 3 describes the nonhepatic causes of elevated alkaline phosphatase. Serologic evaluation is often helpful to identify the specific etiology; however, at times, liver biopsy or imaging of the biliary system with MRCP is needed.

Table 2. Intrahepatic causes of cholestasis.

Primary biliary cirrhosis

Primary sclerosing cholangitis

Viral causes

• Hepatitis B

• Hepatitis C

Infiltrative causes

• Amyloidosis

• Lymphoma

• Tuberculosis

• Sarcoidosis

• Other granulomatous diseases

Genetic causes

• Dubin-Johnson

• Rotor syndrome

• Benign recurrent intrahepatic cholestasis

• Progressive familial intrahepatic cholestasis

• Gilbert syndrome

• Alagille syndrome

Pregnancy

• Intrahepatic cholestasis of pregnancy

TPN

Sepsis

Vanishing bile duct syndrome

Cystic fibrosis

Medications

Abbreviation: TPN, total parenteral nutrition.

Table 3. Nonhepatic causes of elevated alkaline phosphatase.

Pregnancy

Bone disease

Chronic renal failure

Congestive heart failure

Lymphoma

Normal childhood growth

Infection

Inflammation

Source: Adapted from Green and Flamm.³

Bilirubin

Bilirubin is derived from the catabolism of heme-containing proteins, the majority of which originates from senescent red blood cells.²¹ Initially, heme is oxidized within reticuloendothelial cells to form biliverdin, which is then reduced by biliverdin reductase to form water-insoluble unconjugated bilirubin. Within the liver, unconjugated bilirubin is taken up by the hepatocytes and conjugated by a group of enzymes called “uridine diphospho-glucuronosyltransferase” (UDP-glucuronosyltransferase). Once conjugated, bilirubin is water soluble and may be excreted by the kidneys. In addition, it is actively transported against concentration in an ATP-mediated step across the hepatocyte canalicular membrane into the bile. The half-life of bilirubin is approximately 4 hours; however, in settings of impairment of hepatic excretion of conjugated bilirubin, the conjugated bilirubin may become covalently bound to albumin and exhibit a half-life similar to that of albumin—approximately 21 days.²²

Evaluation of a Patient with Hyperbilirubinemia

Liver disease that results in impairment of hepatic metabolism, transport of bilirubin, or injury to any portion of the hepatobiliary system may result in hyperbilirubinemia.^{4 23} Bilirubin is often elevated along with liver test abnormalities, in which case investigation of etiology of liver disease should be directed toward the predominant pattern: either a hepatocellular or cholestatic. When jaundice occurs with predominant hepatocellular pattern of injury diseases such as viral hepatitis, alcohol-related liver disease (including alcoholic hepatitis) and autoimmune diseases should be considered. When jaundice occurs with a predominantly cholestatic pattern of injury, biliary disorders are more likely the cause (Fig. 2). In cases of an isolated hyperbilirubinemia, determining whether this is predominantly due to unconjugated or conjugated hyperbilirubinemia is a key step in evaluation.

Fig. 2.

Overview of approach to hyperbilirubinemia.

Isolated Unconjugated Hyperbilirubinemia

Isolated unconjugated hyperbilirubinemia may be due to bilirubin overproduction, impaired hepatic uptake, or ineffective conjugation.⁴ Bilirubin overproduction is commonly seen in settings without any true hepatic injury such as hemolysis, hematoma resorption, or other diseases of red blood cells.²⁴ In these cases, serum bilirubin is frequently less than 3 to 4 mg/dL. The most common nonhemolytic cause of isolated hyperbilirubinemia is Gilbert syndrome, which occurs in up to 8% of the population.^{25 26} In Gilbert syndrome, a genetic mutation leading to decrease expression of UDP-glucuronosyltransferase causes impaired glucuronidation of bilirubin, which causes a mildly increased unconjugated hyperbilirubinemia. Patients remain asymptomatic with the absence of clinical liver disease except for a mild jaundice which may be more apparent during fasting states or stress. Even in these states, serum bilirubin levels rarely exceed 3 mg/dL (Table 4). Although genetic testing is available in an asymptomatic patient without hemolysis and otherwise normal liver chemistry tests, a presumptive diagnosis of Gilbert syndrome can be made without genetic testing.

Table 4. Isolated unconjugated hyperbilirubinemia.

Hematologic disorders

Sickle cell disease

Hereditary spherocytosis

Glucose-6-phosphate deficiency

Medication effects (i.e., ribavirin)

Microangiopathic hemolytic anemia

Immune-mediated hemolysis

Blood transfusion

Hematoma resorption

Ineffective erythropoiesis

Impaired uptake or conjugation

Gilbert syndrome

Crigler-Najjar syndrome

Isolated Conjugated Hyperbilirubinemia

Elevation in serum-conjugated bilirubin levels is always indicative of some hepatic disorder. In the vast majority of cases, this elevation coincides with other perturbations of liver tests and usually supports a diagnosis of either hepatocellular or cholestatic disease. Isolated conjugated hyperbilirubinemia is far less common and is seen in Dubin-Johnson syndrome and Rotor syndrome. In both cases, there is impairment if bilirubin excretes into the bile,²⁵ which may result in clinical jaundice. Treatment is usually not necessary because the clinical course is otherwise benign.

Tests of Hepatic Synthetic Function

Commonly measured laboratory tests such as albumin and prothrombin time can be a useful reflection of hepatic synthetic function. These tests are most helpful when prognosticating patients with cholestasis and jaundice.

Albumin

The adult liver synthesizes approximately 15 g of albumin per day. Hypoalbuminemia can be seen in conditions of poor hepatic function; however, there can be decreased production of albumin during environmental, toxic, or traumatic stress.²⁷ Conditions such as nephrotic syndrome, malabsorption, and poor nutrition may also decrease serum albumin levels. In clinical settings of hypoalbuminemia especially with otherwise normal liver functions tests, nonhepatic etiologies should always be considered. The half-life of albumin is approximately 19 to 21 days; therefore, hypoalbuminemia is a more reliable marker for synthetic dysfunction seen in chronic liver diseases including cirrhosis, rather than acute hepatic injury.²⁸

Prothrombin Time

As a part of the coagulation cascade, prothrombin is converted to thrombin utilizing the liver synthesized coagulation factors II, V, VII, and X. The prothrombin time measures this rate of conversion and becomes elongated in states of hepatic dysfunction when production of these coagulation factors is reduced. Since the half-life of these coagulation factors is relatively short, the prothrombin time can be a useful tool in measuring more acute changes in hepatic synthetic dysfunction and has been shown to have predictive capacity in determining the prognosis in fulminant hepatic failure.²⁹ Caution is advised in interpreting prothrombin time results as a marker of hepatic dysfunction because elongation may also be seen in disseminated intravascular coagulation and vitamin K deficiency. In these cases, supplementation of vitamin K and measurement of individual coagulation factors can help differentiate these conditions from liver disease. The international normalized ratio (INR) is a standardized measurement of the prothrombin time that is often used as a marker of liver dysfunction. The INR is a key component of the Model of End-Stage Liver Disease (MELD) score which stratifies 3-month mortality risk in patients with cirrhosis and is currently used to prioritize patients on the liver transplant list.³⁰

When to Refer to a Specialist

There are no evidence-based guidelines that specify criteria for referral to a gastroenterologist or a hepatologist. It is generally accepted that a referral should be considered when liver test abnormalities are unexplained and are persistently more than 1.5 to 2 times the upper limit of normal in more than one occasion. In addition, otherwise unexplained abnormalities in markers of synthetic function (such as albumin and prothrombin time) should also lead to consideration of referral. Finally, many practitioners choose to refer to a specialist when a liver biopsy may be needed. Liver biopsy can be helpful to obtain a diagnosis when serologic and radiographic evaluation is unrevealing as well as staging and prognosis when a diagnosis has already been made (Table 5).³¹

Table 5. Conditions that may require liver biopsy for diagnosis, staging, or prognosis³¹ .

Abnormal liver tests of unknown etiology

Hepatitis B

Hepatitis C

Hemochromatosis

Wilson disease

Alpha-1-antitrypsin

Autoimmune hepatitis

Alcoholic liver disease

NAFLD/NASH

Infiltrative liver disease

Drug-induced liver disease

Acute liver failure

Post–liver transplantation

Primary biliary cirrhosis

Abbreviations: NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

Conclusion

Clinical signs of jaundice occur when serum bilirubin levels exceed 2.5 to 3.0 mg/dL. This finding itself is nonspecific and can represent disorders of bilirubin metabolisms, biliary obstruction, or hepatocellular dysfunction. Evaluation for cholestasis, characterized by an elevated alkaline phosphatase, is a key step in the differentiation of these disorders. Utilization of a standardized approach to patients with hyperbilirubinemia will minimize unnecessary testing and improve patient outcomes.