Continuing Education Activity

Conjugated hyperbilirubinemia is usually secondary to hepatocellular disease or cholestasis (intrahepatic and extra-hepatic ). Early workup and diagnosis is necessary for the appropriate management and to prevent future complications. This activity outlines the evaluation and management of conjugated hyperbilirubinemia and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of conjugated hyperbilirubinemia.
• Outline the pathophysiology of conjugated hyperbilirubinemia.
• Summarize the treatment considerations for patients with conjugated hyperbilirubinemia.
• Describe the reasons for a delayed diagnosis of conjugated hyperbilirubinemia.

Introduction

Pathologic elevation of conjugated or direct bilirubin (concentration higher than 2 mg/dL or more than 20% of total bilirubin) is termed conjugated hyperbilirubinemia.[1] It is a biochemical marker of cholestasis and hepatocellular dysfunction.[1] Approximately 80% of the bilirubin is derived from hemoglobin metabolism.[2] The breakdown of heme molecules in hemoglobin, myoglobin, cytochromes, catalase, tryptophan pyrrolase, and peroxidase results in the production of the catabolic product, bilirubin.[2] Heme is converted into biliverdin, which is further reduced to unconjugated bilirubin.[3] Subsequently, unconjugated bilirubin is conjugated with glucuronate to create conjugated bilirubin in the liver.[4]

 Mononuclear heme oxygenase catalyzes the degradation of heme into biliverdin, which in turn is reduced into bilirubin by biliverdin reductase.[5] The primary site of this sequential degradation, reticuloendothelial cells, as well as phagocytic cells such as the Kupffer cells in the liver, contain high concentrations of heme oxygenase.[6] Notably, heme oxygenase is suggested to be the rate-limiting entity in the unconjugated bilirubin production process.[7][8]

In plasma, unconjugated bilirubin mainly binds to albumin and a lesser extent to high-density lipoprotein.[9] Albumin binding prevents bilirubin from exiting vascular space. Albumin may be responsible for bilirubin transport to hepatocytes from extrahepatic sites of unconjugated bilirubin production.[10]

Bilirubin contains intramolecular hydrogen bonding that buffers its polar hydrophilic groups; the resulting hydrophobic molecule is essentially water-insoluble at physiologic pH.[11] This lipophilic form of bilirubin, also known as unconjugated bilirubin, is responsible for associated toxicities such as Kernicterus.[12] Hepatic and renal elimination of bilirubin, at the physiologic level, requires its conversion into the hydrophilic form through the breakdown of hydrogen bonds via glucuronic acid conjugation of the propionic acid side chains of bilirubin.[11] This process, occurring in the hepatocytes, is mediated by uridine-diphosphoglucoronate glucuronosyltransferase (UGT) and is vital in bilirubin detoxification and clearance from the body.[13] With this conversion, the hydrophilic bilirubin glucuronide, or conjugated bilirubin, travels into the bile canaliculus via ATP  binding cassette transporter, the multi-drug resistance protein 2 (MRP2), and subsequently, enters the intestine. Intestinal bacteria degrade bilirubin to urobilinogen; while half of these entities are reabsorbed into the circulation via the portal system for renal excretion, the remaining are converted to stercobilinogen for fecal excretion.[14]

After the structure alteration following bilirubin conjugation, laboratory tests can distinguish between the unconjugated or indirect bilirubin and conjugated or direct bilirubin.[15] Hydrophilic direct bilirubin reacts readily when reagents are added to the blood specimen; likewise, lipophilic indirect bilirubin reacts to the reagents solely following the addition of accelerants like caffeine or methanol.[16] Total bilirubin tallies direct and indirect bilirubin levels. Indirect bilirubin comprises over 90% of the total circulating bilirubin.

Etiology

Following etiologies can affect any age group, but are more commonly observed in adult patients:[17][18][19][20][21][22]

Extrahepatic 

• Cholelithiasis 

• Pancreatitis (chronic and acute) 
• Pancreatic or biliary malignancies 
• Portal adenopathy 
• Biliary strictures following an invasive procedure 
• Primary sclerosing cholangitis 

• AIDS cholangiopathy 
• Choledochal cyst 
• Sphincter of Oddi dysfunction 
• Parasites 
• Eosinophilic granuloma 

• Periampullary diverticulum 
• Mirizzi’s syndrome 

Intrahepatic  

• Viral hepatitis: Hepatitis A-E, Cytomegalovirus, Epstein-Barr virus 
• Alcoholic hepatitis and nonalcoholic steatohepatitis 

• Cirrhosis 
• Ischemic hepatopathy (shock liver) 
• Drugs and toxins 
• Primary sclerosing and biliary cholangitis 
• Autoimmune hepatitis 

• Systemic infection 
• Total parenteral nutrition 
• Postoperative jaundice 
• Sickle cell disease 
• Budd-Chiari syndrome 

• Parasites 
• Liver infiltration 
• Intrahepatic cholestasis of pregnancy 
• Organ transplantation (e.g., bone marrow and liver) 
• Sarcoidosis and amyloidosis 

• Inherited disorders of bilirubin metabolisms (e.g., Dubin-Johnson syndrome, Rotor syndrome, benign recurrent cholestasis, progressive familial intrahepatic cholestasis, Caroli disease) 
• Paraneoplastic syndromes, e.g., Hodgkin disease, Stauffer syndrome, prostate, etc 

Following unique etiologies of conjugated hyperbilirubinemia affecting infants:[1][23][24]

• Extrahepatic biliary atresia 
• Choledochal cyst 
• Idiopathic neonatal hepatitis  
• Caroli disease  
• Metabolic diseases (tyrosinemia, Gaucher disease, Niemann-Pick disease, galactosemia)  
• Alpha-1-antitrypsin deficiency  
• Sepsis  
• TORCH infections (toxoplasmosis, rubella, cytomegalovirus, herpesvirus, syphilis)  
• Budd-Chiari syndrome 

Following unique etiologies of conjugated hyperbilirubinemia affecting older children and adolescents:[1][25][25]

• Choledochal cyst 
• Autoimmune hepatitis 
• Primary biliary cirrhosis 
• Primary sclerosing cholangitis 
• Wilson disease  
• Sepsis 

Epidemiology

United States

Conjugated hyperbilirubinemia is a common abnormality, usually due to hepatocellular or cholestatic diseases; moreover, it may be observed in systemic illnesses with hepatic involvement. As conjugated hyperbilirubinemia may result from secondary causes, the epidemiology will correlate with the specific disease state.

International

In certain countries, parasitic infections like clonorchiasis and ascariasis can cause biliary obstruction. Certain infections like malaria can also lead to hemolytic anemia with increased indirect bilirubin and causing pigment gallstones resulting in cholestasis.

Demographics

Demographic distribution varies by disease state, causing conjugated hyperbilirubinemia; age, sex, and racial differences are unique for each underlying disease process. Nonetheless, children may experience distinct causes of conjugated hyperbilirubinemia, including but not limited to, biliary atresia and neonatal hepatitis. The diagnosis of Wilson disease needs to be considered when there is a liver disease associated with neurological signs in a young adult.

Pathophysiology

Various congenital and acquired etiologies of conjugated hyperbilirubinemia have been listed above. Vastly distinct physiological and histological pathologies, precipitating impaired biliary flow into the intestine or reduced conjugated bilirubin secretion into the bile, can result in conjugated hyperbilirubinemia;[26] a majority of these disease states can be categorized into hepatocellular injury, intrahepatic cholestasis, or extrahepatic cholestasis.[27] Bilirubin binding to albumin is usually reversible; however, in cases of prolonged conjugated bilirubinemia such as biliary obstruction, albumin-conjugated bilirubin binding results in the formation of delta-bilirubin. Delta-bilirubin persists in blood for a prolonged period due to the long half-life of albumin of around 21 days.[28]

Extrahepatic Cholestasis: Extrahepatic cholestasis occurs due to biliary duct obstruction; obstruction of biliary flow into the intestine induces accumulation of conjugated bilirubin within the hepatocytes.[29] For instance, primary sclerosing cholangitis, AIDS cholangiopathy, and cholangiocarcinoma may obstruct bile ducts. Likewise, distended gallbladder due to impacted cystic duct stone, in Mirizzi syndrome, may compress extrahepatic ducts. Furthermore, various intestinal parasites may travel to bile ducts leading to extrahepatic obstructions. The resulting pressure may allow conjugated bilirubin to overcome the resistance of tight junctions in hepatocytes and reflux into the plasma.[30]

Intrahepatic Cholestasis:

Intrahepatic cholestasis is a hepatocellular condition associated with aberrations in bilirubin transport, bile canalicular membrane fluidity, as well as hepatocyte cytoskeletal function; these deviations caused by a myriad of disease processes with or without bile duct alterations, render the hepatocyte inept in metabolizing and releasing bile.[29] Dubin-Johnson syndrome, one of the inherited causes of intrahepatic cholestasis, results from a defect in multidrug-resistant protein 2 (MRP2) that mediates the transport of conjugated bilirubin into bile resulting in elevated conjugated bilirubin. Its inheritance is autosomal recessive and results in a pigmented (black) liver.[31] Dubin-Johnson syndrome is benign and needs no treatment but is exacerbated by pregnancy and oral contraceptive use. Similarly, Rotor syndrome is an autosomal recessive disorder, characterized by homozygous mutation in SLCO1B1 and SLCO1B3 genes on chromosome 12, resulting in abnormally short organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3).[32] A defect in OATP1B1 and OATP1B3, proteins involved in the uptake of conjugated bilirubin in normal hepatocytes, leads to conjugated hyperbilirubinemia.[32] Dubin-Johnson syndrome and Rotor syndrome have many features in common; however, there is an absence of pigmented liver in Rotor syndrome. Dubin-Johnson syndrome is also characterized by the unusual ratio of byproducts of heme biosynthesis. In a healthy subject, the ratio of coproporphyrin 3 to coproporphyrin 1 is around 3-4:1; however, in patients with Dubin-Johnson syndrome, the ratio is reversed.[33] Urinalysis for porphyrins reveals the normal level of coproporphyrin; however, the I isomer is about 80% of the total. Similarly, the gall bladder is visible with oral cholecystogram in Rotor syndrome, and not visible in Dubin-Johnson syndrome.[34]

Intrahepatic cholestasis is also observed in certain malignancies like prostate cancer and renal cell carcinoma; however, exact etiology is not clear.[35]

Hepatocellular Injury: Hepatocellular injury usually entails the release of intracellular proteins into the plasma. Over time, such liver injury advances to cirrhosis and liver failure impairing protein synthesis and excretion. In chronic liver diseases, serum bilirubin concentration remains within the normal range until a significant degree of hepatic damage has occurred with the presence of cirrhosis.[36] In acute liver disease, bilirubin elevation correlates with the severity of the illness, e.g., viral and toxic hepatitis.[37]

History and Physical

The initial workup must be aimed towards identifying the underlying etiology, manifestations of hyperbilirubinemia, and complications of hyperbilirubinemia. The presenting symptoms and signs are likely to be vague and vary according to the primary condition. They may include but not be limited to yellow skin discoloration, pruritus, altered mental status, fatigue, malaise, anorexia, nausea, vomiting, unintentional weight loss, weight gain due to edema, dyspnea, diarrhea, abdominal distention, abdominal pain, lower extremity swelling, bruising, subjective fever, myalgia, chills, hematemesis, dark urine, altered stool appearance, and menstrual disturbances.[38][39]

History of Present Illness: Onset, duration, progression, severity, other associated symptoms, and exacerbating and alleviating factors of the above-mentioned presenting symptoms must be explored. Typically, the presence of fever with or without colicky abdominal pain suggests gallstone disease. Constitutional symptoms with recent weight loss may point to underlying malignancy or chronic infections. The presence of pruritus can indicate cholestatic disease secondary to biliary obstruction or intrahepatic cholestasis. If a patient has a concurrent illness, sepsis, hepatic ischemia, and opportunistic infections should be considered as well. Moreover, pregnancy can predispose patients to benign recurrent cholestasis or acute fatty liver of pregnancy.

Past Medical and Surgical History: Uncovering the history of underlying conditions that lead to hepatobiliary diseases is the mainstay of conjugated hyperbilirubinemia etiology identification. Accurately identifying associated findings is essential. Severe right-sided heart failure or tricuspid insufficiency with hepatomegaly may indicate hepatic congestion; AIDS cholangiopathy may be a sequela of AIDS. Infection, ischemia, or drugs may serve as secondary causes of bilirubin elevation in patients with chronic liver disease. The presence of diabetes mellitus, skin pigmentation, hypogonadism, arthritis, and dilated cardiomyopathy may suggest the presence of hemochromatosis. Obesity is often associated with nonalcoholic fatty liver disease. Inflammatory bowel diseases elevate the risk of primary sclerosing cholangitis and gallstones. Alpha-1 antitrypsin deficiency may lead to early-onset emphysema and liver cirrhosis. Celiac disease and thyroid disease are known to cause liver disease. Likewise, a history of blood transfusion can be a risk factor for viral hepatitis; transient elevation of bilirubin post blood transfusion may occur due to the rapid turnover of infused cells in chronic hepatic disease.

Home Medications Including Illicit Drug Usage: Detailed history of utilization of all medications including prescription, over the counter, herbal and illicit drugs, as well as dietary supplements, should be obtained to assess their potential hepatobiliary effects. The amount and duration of use must be noted. Many commonly accessed and utilized medications may induce liver injury. Numerous classes of drugs such as analgesics (acetaminophen), antibiotics, antiretrovirals, anti-tuberculosis, non-steroidal anti-inflammatory, anabolic steroids, anticonvulsants, oncologic, anti-TNF, halothanes, among others, carry a significant risk of such injury. Occupational or recreational hepatotoxin exposures, such as vinyl chloride from factories and amatoxin during mushroom picking from Amanita phalloides and Amanita verna, may also lead to liver injuries. Furthermore, the use of salicylates in children and adolescents (<18 years) with viral illnesses has the potential to cause Reye syndrome.[40]

Family History: Family history may be valuable while identifying any hepatobiliary diseases or associated genetic diseases leading to conjugated hyperbilirubinemia. For instance, a family history of jaundice may suggest inborn errors of bilirubin metabolism; a family history of early pancreatic cancers may increase its risk.

Social History: Intravenous drug use, unsafe sexual practices, and exposure to infected individuals are risk factors for viral hepatitis. Alcohol use is a pertinent finding; consumption of >210 grams of alcohol per week in men and >140 grams of alcohol per week in women for over two year period is considered significant alcohol consumption based on the American College of Gastroenterology, the American Association for the Study of Liver Diseases and the American Gastroenterological Associations’ joint guideline on 2012.[41][42] The amount of alcohol in a standard drink (12 oz/360 mL of beer, five oz/150 ml of wine, 1.5 oz/45 mL of 80-proof spirits) is approximately 14 grams. 

 Physical Exam: A brownish discoloration of urine may be evident in conjugated hyperbilirubinemia as hydrophilic conjugated bilirubin can be filtered through glomerulus. Yellowish to greenish pigmentation of skin, sclera, and mucus membranes may occur in the presence of an adequate increase in bilirubin. Thus, the physical exam must focus primarily on identifying these discolorations and determining their underlying etiology. Cholecystic, hepatic, pancreatic, or other abdominal tumors may be located through an abdominal exam. Hepatic tenderness may represent hepatitis or other liver-related disorders. Murphy sign may indicate acute cholecystitis; whereas, in cholangitis, non-specific pain may be present. Ascites often represent decompensated liver cirrhosis or malignancy with peritoneal spread. Inexplicable darkening of skin, diabetes, or heart failure may be present in hemochromatosis. Stigmata of chronic liver disease include palmar erythema, spider nevi, gynecomastia, and caput medusae. Additionally, the longstanding liver disease leads to temporal and proximal muscle wasting. Acholic or light gray stool may indicate biliary stasis or obstruction.

Evaluation

Evaluation is usually directed to the underlying etiology of the conjugated hyperbilirubinemia based on history and physical findings, which includes biliary obstruction, intrahepatic cholestasis, hepatocellular injury, or an inherited condition. Following studies are performed as a part of a workup for conjugated hyperbilirubinemia:[21]

• Serum Bilirubin, Total and Direct: Jaundice, discoloration of body tissues, usually results from bilirubin levels greater than 3 mg/dl. Following identification of jaundice, unconjugated and conjugated fractions of bilirubin need to be obtained to distinguish between prehepatic and posthepatic jaundice. Elevation in unconjugated bilirubin indicates prehepatic or hepatic jaundice and may be managed medically;[12] whereas an increase in conjugated bilirubin suggests hepatocellular injury or cholestasis, which may necessitate bile duct surgery or therapeutic endoscopy. No consensus of direct bilirubin levels defining conjugated hyperbilirubinemia was encountered. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition deem direct bilirubin level above 1.0 mg/dL as anomalous when total bilirubin is elevated. In newborns, conjugated bilirubin of >= 0.5 mg/dL warrants infection workup; levels >=2 mg/dL requires more exhaustive hepatobiliary assessment. Total and direct bilirubin levels must be obtained in infants who are icteric after ages two weeks and three weeks in formula-fed and breast-fed infants, respectively.  
• Urine Bilirubin: The presence of bilirubin in urine suggests conjugated hyperbilirubinemia.
• Complete Blood Count (CBC): CBC will facilitate evaluation for anemia and the presence of hemolysis or hypersplenism with thrombocytopenia. 
• Serum Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT): AST and ALT serve as markers of hepatocellular injury. ALT increases are more specific to liver injury. Nonetheless, in chronic liver disease, these markers may be less significant as they may be normal or slightly elevated due to minimally remaining undamaged hepatic parenchymal cells. AST and ALT levels in 1000s are typically secondary to ischemia or liver toxins. Viral hepatitis may also yield ALTs in 1000s. AST to ALT ratio greater than or equal to 2:1 may suggest alcohol-induced liver damage.  
• Prothrombin Time/INR and Albumin: These values evaluate the synthetic function of the liver. INR more than or equal to 1.5 with hepatic encephalopathy in a patient without underlying liver cirrhosis or chronic liver disease represents acute liver failure and needs transplant referral.[43]
• Viral Hepatitis, Serologic Studies: Serologic studies for viral hepatitis must be conducted to identify potential etiologies. 
• Alkaline Phosphatase (ALP) With or Without Gamma-Glutamyl Transpeptidase (GGTP): If elevated, these values may indicate obstruction; furthermore, GGTP may distinguish the hepatic source of increased ALP from alternate sources such as bone. A rise in these enzymes suggests the presence of cholestasis and may necessitate bile duct imaging. An increase in ALP over greater than fivefold usually supports extra-hepatic cholestasis. 
• Blood Alcohol: Obtaining blood alcohol level is useful in confirming etiology in cases of suspected alcohol-induced liver damage. 
• Serum Acetaminophen: Serum acetaminophen level will allow confirmation of acetaminophen toxicity as an underlying cause.  
• Serum or Urine Drug Screen: Drug screen confirms suspected drugs as the potential cause.  
• Serum Lipase: Elevated serum lipase, in an appropriate clinical setting, suggests acute pancreatitis.  
• Antimitochondrial Antibody: Elevated antimitochondrial antibody may indicate primary biliary cholangitis. 
• Autoimmune Hepatitis Screening: Serologic tests, including antinuclear antibodies and anti-smooth muscle antibodies, may reveal autoimmune etiology. Primary sclerosing cholangitis (PSC), thought to be secondary to autoimmune etiology, is often associated with inflammatory bowel disease and is complicated by cholangiocarcinoma.[44] 84% of PSC patients have perinuclear antineutrophil cytoplasmic antibodies (p-ANCA), whereas 66% of patients have anticardiolipin antibodies, and 53% of patients have antinuclear antibodies.[45]
• Genetic and Iron Studies: Genetic and iron studies must be conducted if differential includes hemochromatosis. Hemochromatosis involves iron overload and can cause damage to vital organs like the liver, heart, and pancreas. Transferrin saturation greater than or equal to 60%, serum ferritin greater than 300 nanograms/ milliliter in male and greater than 200 nanograms/ milliliter in females suggests the presence of hemochromatosis. Hemochromatosis is an autosomal recessive disease mostly affecting Whites, with the most common mutation being HFE C282Y mutation.[46]
• Copper Studies: Copper studies must be performed when differential includes Wilson disease. Wilson disease is characterized by abnormal copper accumulation, the mutation in the ATP7B gene,  reduced serum ceruloplasmin levels, and increased urinary copper excretion.[47]
• Alpha-1 Antitrypsin (AAT) Phenotyping: Alpha-1 antitrypsin phenotyping is performed when hereditary AAT deficiency is suspected.  

To summarize, elevation in AST and ALT suggests hepatocellular injury; whereas, elevation in alkaline phosphatase indicates biliary obstruction. ALT is more specific than AST for liver disease. Elevated bilirubin and low albumin may result due to both hepatocellular injury and biliary obstruction. Alcoholic liver disease may have an AST to ALT ratio 2:1 or greater, especially in the presence of gamma-glutamyl transpeptidase.[48]

• Right Upper Quadrant Ultrasonography (USG): Right upper quadrant ultrasound allows the exclusion of biliary obstruction; it also enables the assessment of parenchymal liver diseases, including cirrhosis, steatosis, congestion, and tumor. It is often the initial imaging performed as it is widely accessible, less expensive, and devoid of radiation exposure.[21] Ultrasound can also be safely performed in pregnancy. While the USG provides an adequate view of gall bladder along with cystic ducts and lesions, allowing detection of parenchymal disorders, its insufficient resolution prevents the detection of choledocholithiasis. Dilated bile ducts suggest extra-hepatic cholestasis.
• Computed Tomography (CT) Abdomen: CT scans are utilized to assess hepatobiliary anatomy and may serve as the initial or preferred imaging if suspicion for biliary obstruction is low. CT offers improved resolution compared to the USG and allows guided needle biopsies. Nonetheless, some limitations of CT include increased expense, radiation exposure, potential contrast exposure, and limited sensitivity to choledocholithiasis.
• Magnetic Resonance Cholangiopancreatography (MRCP): MRCP may be conducted when suspected biliary obstruction is not appreciated on the right upper quadrant ultrasound or CT abdomen. A thorough assessment of the biliary tract is feasible with contrast agents due to the availability of various available contrasts and scanning modalities. Cystic and pancreatic ducts may be visible with appropriate contrast. Without radiation exposure, MRCP visualization is comparable to that of the USG.  Thus, it may be utilized for assessment of cholestasis of pregnancy or in patients unable to tolerate traditional cholangiography. Guided needle biopsies may be possible, but MRCP can't provide therapeutic intervention. Moreover, MRCP may have limited accessibility and clinical experience; it is also inappropriate with metallic implants.[49] The presence of lace-like fibrosis and periportal halo sign together have about 70% sensitivity in the diagnosis of primary biliary cholangitis (PBC).[50] Similarly, PSC is characterized by the presence of multiple segmental strictures and biliary dilatation on MRCP and ERCP.[51]

• Endoscopic Retrograde Cholangiopancreatography (ERCP): Endoscopic ultrasound (EUS) or ERCP may be the initial screening procedure if suspicion for extra-hepatic obstruction is high. ERCP is primarily advantageous in the evaluation and diagnosis of biliary obstruction, pancreatic cancer, primary sclerosing cholangitis, and choledochal cysts. This modality is preferred for the identification and treatment of bile duct stones. With the possibility of stone extraction, sphincterotomy, balloon-dilation, and stent placement, ERCP offers treatment for extra-hepatic obstructions. Direct visualization allows reliable biopsies and clear assessment of bile ducts. Despite these opportunities, the patient is exposed to radiation, sedation, and potential for pancreatitis, among other complications.[52][53]
• Percutaneous Transhepatic Cholangiography (PTC or PTHC): PTC or PTHC is both diagnostic and therapeutic via interventions including extraction of biliary calculi, drainage of infected bile, dilation of strictures, and placement of stents.[54] PTC is performed if biliary dilatation is visible on imaging, and ERCP is unavailable or inappropriate, for instance, due to altered biliary anatomy.  Additionally, this modality may be efficacious following failed ERCP attempts and in cases of biliary obstruction. It allows clear bile duct visibility and facilitates biopsies; nonetheless, PTC is invasive and causes contrast and radiation exposure. Additional complications of PTC include bacteremia[55], and severe hemobilia.[56][57][58]
• Biopsy: Liver biopsy may be performed if the diagnosis remains uncertain following extensive workup. With insight into liver architecture, it may also aid in establishing prognosis.[21] Moreover, a biopsy may also be indicated in etiologies causing irreversible liver damage, such as biliary atresia.

Treatment / Management

As conjugated hyperbilirubinemia is a manifestation of a broad spectrum of diseases, rather than a disease itself, the overall management strategy must vary accordingly. Management may be curative or palliative. Nonetheless, few common strategies are likely to alleviate the finding. All hepatotoxic medications must be held while determining the potential etiology of the conjugated bilirubinemia as an ongoing toxin or drug exposure can lead to progressive liver damage and death.[59]

Following are some management pearls for a few of the common potential etiologies: 

• Cholelithiasis: For patients who are not a surgical candidate or refuse surgery, oral bile salts (e.g., ursodeoxycholic acid 10 mg/kg/day) or extracorporeal shock wave lithotripsy (ESWL) may be considered. Ursodeoxycholic acid reduces the biliary secretion of cholesterol, leading to the dissolution of cholesterol stones; however, once the medication is discontinued, 50% of patients experience gallstone recurrence within five years. ESWL is contraindicated in cholecystitis, biliary pancreatitis, choledocholithiasis, pregnancy, coagulopathy, and concurrent anticoagulants. The recurrence rate for gallstones after lithotripsy is 70%.[60]
• Pancreatic Cancer: Chemoradiation and surgery, including the Whipple procedure, are the preferred treatment options.[61]
• Malignant Obstruction of the Biliary Tract: Endoscopic stenting or endoscopic biliary drainage may relieve symptoms of hyperbilirubinemia.[62]

Differential Diagnosis

As conjugated hyperbilirubinemia is a manifestation of the disease, rather than a disease itself, the potential etiologies listed below serve as possible differential diagnoses as well. 

Following etiologies can affect any age group, but are more commonly observed in adult patients:[17][18][19][20][21][22]

Extrahepatic 

• Cholelithiasis

• Pancreatitis (chronic and acute)
• Pancreatic or biliary malignancies
• Portal adenopathy
• Biliary strictures following an invasive procedure
• Primary sclerosing cholangitis

• AIDS cholangiopathy
• Choledochal cyst
• Sphincter of Oddi dysfunction
• Parasites
• Eosinophilic granuloma

• Periampullary diverticulum
• Mirizzi syndrome

Intrahepatic

• Viral Hepatitis: Hepatitis A-E, cytomegalovirus, Epstein-Barr virus
• Alcoholic hepatitis and nonalcoholic steatohepatitis

• Cirrhosis
• Ischemic hepatopathy (shock liver)
• Drugs and toxins
• Primary sclerosing and biliary cholangitis
• Autoimmune hepatitis

• Systemic infection
• Total parenteral nutrition
• Postoperative jaundice
• Sickle cell disease
• Budd-Chiari syndrome

• Parasites
• Liver infiltration
• Intrahepatic cholestasis of pregnancy
• Organ transplantation (e.g., bone marrow and liver)
• Sarcoidosis and amyloidosis

• Inherited disorders of bilirubin metabolisms (e.g., Dubin-Johnson syndrome, Rotor syndrome, benign recurrent cholestasis, progressive familial intrahepatic cholestasis, Caroli disease)
• Paraneoplastic syndromes, e.g., Hodkin, Stauffer syndrome, prostate, etc

Following unique etiologies of conjugated hyperbilirubinemia affecting infants:[1][23][24]

• Extrahepatic biliary atresia
• Choledochal cyst
• Idiopathic neonatal hepatitis
• Caroli disease
• Metabolic diseases (tyrosinemia, Gaucher disease, Niemann-Pick disease, galactosemia)
• Alpha-1-antitrypsin deficiency
• Sepsis
• TORCH infections (toxoplasmosis, rubella, cytomegalovirus, herpesvirus, syphilis)
• Budd-Chiari syndrome

Following unique etiologies of conjugated hyperbilirubinemia affecting older children and adolescents:[1][25]

• Choledochal cyst
• Autoimmune hepatitis
• Primary biliary cirrhosis
• Primary sclerosing cholangitis
• Wilson disease
• Sepsis

Prognosis

As conjugated hyperbilirubinemia is a manifestation of a disease, rather than a disease itself, the prognosis varies depending on underlying disease conditions leading to conjugated hyperbilirubinemia. Malignancy related to hepatobiliary system carries a poor prognosis; however, non-malignant causes like infections, toxins, non-malignant strictures tend to have a better outcome if treated promptly. Bilirubin levels correlate pointedly with short term mortality in some conditions, including primary biliary cholangitis and alcoholic hepatitis; nonetheless, the elevated bilirubin level does not contribute to the early mortality.

Complications

As conjugated hyperbilirubinemia is a manifestation of a disease, rather than a disease itself, complications of conjugated hyperbilirubinemia vary based on underlying etiology. Nonetheless, complications arising solely from the elevated bilirubin level also exist. As conjugated bilirubin does not significantly bind to nervous tissues, it never causes kernicterus or other associated toxicities. On the other hand, cholestasis can lead to fat malabsorption; thus, levels of fat-soluble vitamins should be monitored and corrected. Greenish pigmentation of teeth due to prolonged conjugated hyperbilirubinemia may occur in low birth weight infants as a delayed complication.

Infections in hepatobiliary systems can lead to sepsis or septic shock, peritonitis, and gall bladder perforation, among other complications. Infections, pain, cachexia, thrombosis, intractable vomiting, and death may occur secondary to malignancy.

Consultations

Management of hyperbilirubinemia requires a multidisciplinary approach. Following specialties are needed for a better outcome:

• Gastroenterology 
• Hepatology 
• Hepatobiliary surgery 
• Liver transplant 
• Nutrition specialists 
• Social services 

Referrals are indicated in cases of unexplained and persistent elevation of bilirubin alone or combination with AST, ALT, and alkaline phosphatase; typically, total bilirubin greater than 3 mg/dL, aminotransferases two times and alkaline phosphatase 1.5 times the upper limit of normal are considered significant. Additionally, if multiple etiologies are suspected, specialist referral is advantageous.

Deterrence and Patient Education

Difficulty with the accurate diagnosis can lead to patient and provider frustration. As initial symptoms are often vague and mild, diagnosis is often delayed with loss of opportunity for early interventions. Patients, especially with a family history of hepatobiliary cancers, should be educated regarding recognizing early signs and symptoms of jaundice. As most of the etiologies of conjugated hyperbilirubinemia represent chronic medical problems, reliable social support is imperative for improved outcomes.

Enhancing Healthcare Team Outcomes

As conjugated hyperbilirubinemia comprises multiple underlying diseases, early diagnosis and management require excellent communication between patients and various providers taking care of the patient. Improving public awareness about preventable diseases such as viral hepatitis and alcoholism is of paramount importance.