Pathologic elevation of conjugated or direct bilirubin (concentration higher than 2 mg/dL or more than 20% of total bilirubin) is termed conjugated hyperbilirubinemia. It is a biochemical marker of cholestasis and hepatocellular dysfunction. Approximately 80% of the bilirubin is derived from hemoglobin metabolism. The breakdown of heme molecules in hemoglobin, myoglobin, cytochromes, catalase, tryptophan pyrrolase, and peroxidase results in the production of the catabolic product, bilirubin. Heme is converted into biliverdin, which is further reduced to unconjugated bilirubin. Subsequently, unconjugated bilirubin is conjugated with glucuronate to create conjugated bilirubin in the liver.
Mononuclear heme oxygenase catalyzes the degradation of heme into biliverdin, which in turn is reduced into bilirubin by biliverdin reductase. 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. Notably, heme oxygenase is suggested to be the rate-limiting entity in the unconjugated bilirubin production process.
In plasma, unconjugated bilirubin mainly binds to albumin and a lesser extent to high-density lipoprotein. Albumin binding prevents bilirubin from exiting vascular space. Albumin may be responsible for bilirubin transport to hepatocytes from extrahepatic sites of unconjugated bilirubin production.
Bilirubin contains intramolecular hydrogen bonding that buffers its polar hydrophilic groups; the resulting hydrophobic molecule is essentially water-insoluble at physiologic pH. This lipophilic form of bilirubin, also known as unconjugated bilirubin, is responsible for associated toxicities such as Kernicterus. 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. This process, occurring in the hepatocytes, is mediated by uridine-diphosphoglucoronate glucuronosyltransferase (UGT) and is vital in bilirubin detoxification and clearance from the body. 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.
After the structure alteration following bilirubin conjugation, laboratory tests can distinguish between the unconjugated or indirect bilirubin and conjugated or direct bilirubin. 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. Total bilirubin tallies direct and indirect bilirubin levels. Indirect bilirubin comprises over 90% of the total circulating bilirubin.
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.
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.
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.
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; a majority of these disease states can be categorized into hepatocellular injury, intrahepatic cholestasis, or extrahepatic cholestasis. 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.
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. 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.
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. 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. 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). A defect in OATP1B1 and OATP1B3, proteins involved in the uptake of conjugated bilirubin in normal hepatocytes, leads to conjugated hyperbilirubinemia. 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. 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.
Intrahepatic cholestasis is also observed in certain malignancies like prostate cancer and renal cell carcinoma; however, exact etiology is not clear.
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. In acute liver disease, bilirubin elevation correlates with the severity of the illness, e.g., viral and toxic hepatitis.
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.
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.
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. 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 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:
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.
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.
Following are some management pearls for a few of the common potential etiologies:
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.
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.
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.
Management of hyperbilirubinemia requires a multidisciplinary approach. Following specialties are needed for a better outcome:
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.
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.
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.
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