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.
Following etiologies can affect any age group, but are more commonly observed in adult patients:[17][18][19][20][21][22]
Extrahepatic
Intrahepatic
Following unique etiologies of conjugated hyperbilirubinemia affecting infants:[1][23][24]
Following unique etiologies of conjugated hyperbilirubinemia affecting older children and adolescents:[1][25][25]
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.
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]
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 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]
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]
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:
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
Intrahepatic
Following unique etiologies of conjugated hyperbilirubinemia affecting infants:[1][23][24]
Following unique etiologies of conjugated hyperbilirubinemia affecting older children and adolescents:[1][25]
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.
[1] | Harb R,Thomas DW, Conjugated hyperbilirubinemia: screening and treatment in older infants and children. Pediatrics in review. 2007 Mar; [PubMed PMID: 17332167] |
[2] | Berk PD,Howe RB,Bloomer JR,Berlin NI, Studies of bilirubin kinetics in normal adults. The Journal of clinical investigation. 1969 Nov; [PubMed PMID: 5824077] |
[3] | van Dijk R,Aronson SJ,de Waart DR,van de Graaf SF,Duijst S,Seppen J,Elferink RO,Beuers U,Bosma PJ, Biliverdin Reductase inhibitors did not improve severe unconjugated hyperbilirubinemia in vivo. Scientific reports. 2017 May 10; [PubMed PMID: 28490767] |
[4] | Zhou J,Tracy TS,Remmel RP, Bilirubin glucuronidation revisited: proper assay conditions to estimate enzyme kinetics with recombinant UGT1A1. Drug metabolism and disposition: the biological fate of chemicals. 2010 Nov; [PubMed PMID: 20668247] |
[5] | Berk PD,Rodkey FL,Blaschke TF,Collison HA,Waggoner JG, Comparison of plasma bilirubin turnover and carbon monoxide production in man. The Journal of laboratory and clinical medicine. 1974 Jan; [PubMed PMID: 4808654] |
[6] | Bissell DM,Hammaker L,Schmid R, Liver sinusoidal cells. Identification of a subpopulation for erythrocyte catabolism. The Journal of cell biology. 1972 Jul; [PubMed PMID: 5038868] |
[7] | Sassa S,Kappas A,Bernstein SE,Alvares AP, Heme biosynthesis and drug metabolism in mice with hereditary hemolytic anemia. Heme oxygenase induction as an adaptive response for maintaining cytochrome P-450 in chronic hemolysis. The Journal of biological chemistry. 1979 Feb 10; [PubMed PMID: 762094] |
[8] | Drummond GS,Valaes T,Kappas A, Control of bilirubin production by synthetic heme analogs: pharmacologic and toxicologic considerations. Journal of perinatology : official journal of the California Perinatal Association. 1996 May-Jun; [PubMed PMID: 8817443] |
[9] | Kalakonda A,Jenkins BA,John S, Physiology, Bilirubin 2020 Jan; [PubMed PMID: 29261920] |
[10] | Vodret S,Bortolussi G,Schreuder AB,Jašprová J,Vitek L,Verkade HJ,Muro AF, Albumin administration prevents neurological damage and death in a mouse model of severe neonatal hyperbilirubinemia. Scientific reports. 2015 Nov 6; [PubMed PMID: 26541892] |
[11] | Čvorović J,Passamonti S, Membrane Transporters for Bilirubin and Its Conjugates: A Systematic Review. Frontiers in pharmacology. 2017; [PubMed PMID: 29259555] |
[12] | Singh A,Jialal I, Unconjugated Hyperbilirubinemia . 2020 Jan [PubMed PMID: 31747203] |
[13] | Kamisako T,Kobayashi Y,Takeuchi K,Ishihara T,Higuchi K,Tanaka Y,Gabazza EC,Adachi Y, Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance. Journal of gastroenterology. 2000; [PubMed PMID: 11023036] |
[14] | Sticova E,Jirsa M, New insights in bilirubin metabolism and their clinical implications. World journal of gastroenterology. 2013 Oct 14; [PubMed PMID: 24151358] |
[15] | Roberts WM, BLOOD PHOSPHATASE AND THE VAN DEN BERGH REACTION IN THE DIFFERENTIATION OF THE SEVERAL TYPES OF JAUNDICE. British medical journal. 1933 Apr 29; [PubMed PMID: 20777507] |
[16] | LATHE GH,RUTHVEN CR, Factors affecting the rate of coupling of bilirubin and conjugated bilirubin in the van de Bergh reaction. Journal of clinical pathology. 1958 Mar; [PubMed PMID: 13513791] |
[17] | Malchow-Møller A,Matzen P,Bjerregaard B,Hilden J,Holst-Christensen J,Staehr Johansen T,Altman L,Thomsen C,Juhl E, Causes and characteristics of 500 consecutive cases of jaundice. Scandinavian journal of gastroenterology. 1981; [PubMed PMID: 7233075] |
[18] | Malchow-Møller A, An algorithm for differential diagnosis in jaundice and its applications. Annales de medecine interne. 1986; [PubMed PMID: 3767199] |
[19] | Winger J,Michelfelder A, Diagnostic approach to the patient with jaundice. Primary care. 2011 Sep; [PubMed PMID: 21872092] |
[20] | Fletcher LL,Thomas DJ, The challenge of diagnosing the cause of jaundice. The Nurse practitioner. 1999 Oct; [PubMed PMID: 10546262] |
[21] | Roche SP,Kobos R, Jaundice in the adult patient. American family physician. 2004 Jan 15; [PubMed PMID: 14765767] |
[22] | Gordon SC, Jaundice and cholestasis. Some common and uncommon causes. Postgraduate medicine. 1991 Sep 15; [PubMed PMID: 1891435] |
[23] | Gottesman LE,Del Vecchio MT,Aronoff SC, Etiologies of conjugated hyperbilirubinemia in infancy: a systematic review of 1692 subjects. BMC pediatrics. 2015 Nov 20; [PubMed PMID: 26589959] |
[24] | Götze T,Blessing H,Grillhösl C,Gerner P,Hoerning A, Neonatal Cholestasis - Differential Diagnoses, Current Diagnostic Procedures, and Treatment. Frontiers in pediatrics. 2015; [PubMed PMID: 26137452] |
[25] | Pinto RB,Schneider AC,da Silveira TR, Cirrhosis in children and adolescents: An overview. World journal of hepatology. 2015 Mar 27; [PubMed PMID: 25848466] |
[26] | van der Woerd WL,Houwen RH,van de Graaf SF, Current and future therapies for inherited cholestatic liver diseases. World journal of gastroenterology. 2017 Feb 7; [PubMed PMID: 28223721] |
[27] | Chalya PL,Kanumba ES,McHembe M, Etiological spectrum and treatment outcome of Obstructive jaundice at a University teaching Hospital in northwestern Tanzania: A diagnostic and therapeutic challenges. BMC research notes. 2011 May 23; [PubMed PMID: 21605428] |
[28] | Weiss JS,Gautam A,Lauff JJ,Sundberg MW,Jatlow P,Boyer JL,Seligson D, The clinical importance of a protein-bound fraction of serum bilirubin in patients with hyperbilirubinemia. The New England journal of medicine. 1983 Jul 21; [PubMed PMID: 6866015] |
[29] | Woolbright BL,Jaeschke H, Inflammation and Cell Death During Cholestasis: The Evolving Role of Bile Acids. Gene expression. 2019 Nov 4; [PubMed PMID: 31253204] |
[30] | Tarmalinggam Y,Prakash ES, How does conjugated bilirubin appear in the bloodstream? Advances in physiology education. 2007 Dec; [PubMed PMID: 18057413] |
[31] | Belinsky MG,Dawson PA,Shchaveleva I,Bain LJ,Wang R,Ling V,Chen ZS,Grinberg A,Westphal H,Klein-Szanto A,Lerro A,Kruh GD, Analysis of the in vivo functions of Mrp3. Molecular pharmacology. 2005 Jul; [PubMed PMID: 15814571] |
[32] | Kumar A,Mehta D, Rotor Syndrome . 2020 Jan [PubMed PMID: 30335339] |
[33] | Rocchi E,Balli F,Gibertini P,Trenti T,Pietrangelo A,Cassanelli M,Frigieri G,Ventura E, Coproporphyrin excretion in healthy newborn babies. Journal of pediatric gastroenterology and nutrition. 1984 Jun [PubMed PMID: 6737185] |
[34] | [PubMed PMID: 30725679] |
[35] | [PubMed PMID: 15017648] |
[36] | Schuppan D,Afdhal NH, Liver cirrhosis. Lancet (London, England). 2008 Mar 8; [PubMed PMID: 18328931] |
[37] | Wu Z,Han M,Chen T,Yan W,Ning Q, Acute liver failure: mechanisms of immune-mediated liver injury. Liver international : official journal of the International Association for the Study of the Liver. 2010 Jul; [PubMed PMID: 20492514] |
[38] | McKnight JT,Jones JE, Jaundice. American family physician. 1992 Mar; [PubMed PMID: 1543099] |
[39] | Taylor T,Wheatley M, Jaundice in the emergency department: meeting the challenges of diagnosis and treatment. Emergency medicine practice. 2018 Apr; [PubMed PMID: 29565526] |
[40] | Belay ED,Bresee JS,Holman RC,Khan AS,Shahriari A,Schonberger LB, Reye's syndrome in the United States from 1981 through 1997. The New England journal of medicine. 1999 May 6; [PubMed PMID: 10228187] |
[41] | Chalasani N,Younossi Z,Lavine JE,Diehl AM,Brunt EM,Cusi K,Charlton M,Sanyal AJ, The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012 Jun; [PubMed PMID: 22656328] |
[42] | Chalasani N,Younossi Z,Lavine JE,Diehl AM,Brunt EM,Cusi K,Charlton M,Sanyal AJ, The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology (Baltimore, Md.). 2012 Jun; [PubMed PMID: 22488764] |
[43] | [PubMed PMID: 22213561] |
[44] | Lindor KD,Kowdley KV,Harrison ME, ACG Clinical Guideline: Primary Sclerosing Cholangitis. The American journal of gastroenterology. 2015 May [PubMed PMID: 25869391] |
[45] | Dobric S,Popovic D,Nikolic M,Andrejevic S,Spuran M,Bonaci-Nikolic B, Anti-neutrophil cytoplasmic antibodies (ANCA) specific for one or several antigens: useful markers for subtypes of ulcerative colitis and associated primary sclerosing cholangitis. Clinical chemistry and laboratory medicine. 2011 Nov 23 [PubMed PMID: 22107137] |
[46] | Crownover BK,Covey CJ, Hereditary hemochromatosis. American family physician. 2013 Feb 1 [PubMed PMID: 23418762] |
[47] | [PubMed PMID: 30190489] |
[48] | Moussavian SN,Becker RC,Piepmeyer JL,Mezey E,Bozian RC, Serum gamma-glutamyl transpeptidase and chronic alcoholism. Influence of alcohol ingestion and liver disease. Digestive diseases and sciences. 1985 Mar; [PubMed PMID: 2857631] |
[49] | Sugimoto M, Recent advances in visualization, imaging, and navigation in hepatobiliary and pancreatic sciences. Journal of hepato-biliary-pancreatic sciences. 2010 Sep; [PubMed PMID: 19806300] |
[50] | [PubMed PMID: 25781184] |
[51] | [PubMed PMID: 10751470] |
[52] | Nalankilli K,Kannuthurai S,Moss A, A modern approach to ERCP: maintaining efficacy while optimising safety. Digestive endoscopy : official journal of the Japan Gastroenterological Endoscopy Society. 2016 Apr; [PubMed PMID: 26684277] |
[53] | Cotton PB, Fifty years of ERCP: a personal review. Gastrointestinal endoscopy. 2018 Aug; [PubMed PMID: 29654739] |
[54] | Kavanagh PV,vanSonnenberg E,Wittich GR,Goodacre BW,Walser EM, Interventional radiology of the biliary tract. Endoscopy. 1997 Aug; [PubMed PMID: 9342573] |
[55] | Ozden I,Tekant Y,Bilge O,Acarli K,Alper A,Emre A,Rozanes I,Ozsut H,Ariogul O, Endoscopic and radiologic interventions as the leading causes of severe cholangitis in a tertiary referral center. American journal of surgery. 2005 Jun; [PubMed PMID: 15910723] |
[56] | Savader SJ,Trerotola SO,Merine DS,Venbrux AC,Osterman FA, Hemobilia after percutaneous transhepatic biliary drainage: treatment with transcatheter embolotherapy. Journal of vascular and interventional radiology : JVIR. 1992 May; [PubMed PMID: 1627884] |
[57] | Choi SH,Gwon DI,Ko GY,Sung KB,Yoon HK,Shin JH,Kim JH,Kim J,Oh JY,Song HY, Hepatic arterial injuries in 3110 patients following percutaneous transhepatic biliary drainage. Radiology. 2011 Dec; [PubMed PMID: 21875851] |
[58] | Shiau EL,Liang HL,Lin YH,Li MF,Chiang CL,Chen MC,Huang JS,Pan HB, The Complication of Hepatic Artery Injuries of 1,304 Percutaneous Transhepatic Biliary Drainage in a Single Institute. Journal of vascular and interventional radiology : JVIR. 2017 Jul; [PubMed PMID: 28461005] |
[59] | Chalasani NP,Hayashi PH,Bonkovsky HL,Navarro VJ,Lee WM,Fontana RJ, ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. The American journal of gastroenterology. 2014 Jul; [PubMed PMID: 24935270] |
[60] | Abraham S,Rivero HG,Erlikh IV,Griffith LF,Kondamudi VK, Surgical and nonsurgical management of gallstones. American family physician. 2014 May 15; [PubMed PMID: 24866215] |
[61] | Vincent A,Herman J,Schulick R,Hruban RH,Goggins M, Pancreatic cancer. Lancet (London, England). 2011 Aug 13; [PubMed PMID: 21620466] |
[62] | Riaz A,Pinkard JP,Salem R,Lewandowski RJ, Percutaneous management of malignant biliary disease. Journal of surgical oncology. 2019 Jul; [PubMed PMID: 30977913] |