Table 1 A modified failure mode and effects analysis of the human biliary system
Anatomy and physiology | Potential failure/pathophysiological process | Effects of the failure | Main clinical features (symptoms and signs) | Investigationa | Note |
|---|---|---|---|---|---|
Gallbladder | Cholecystolithiasis (stones in the gallbladder) [6] | Non-obstructive [6] | Asymptomatic [6] | Abdominal X-ray and CT [6] | |
Cholecystitis –usually associated with obstruction of the outlet of the gallbladder by a gallstone [6] | The obstruction results in inflammation of the gallbladder, and may be complicated by secondary bacterial infection [6] | Murphy’s sign [6] | Abdominal ultrasound [6] | ||
Cholecystitis associated with gallbladder torsion (unusual but critical) [7] | Torsion of the gallbladder around the cystic duct caused necrotic gallbladder [7] | Acute onset abdominal pain in the RUQ, with nausea and malaise [7] | Abdominal ultrasound and CT [7] | ||
Malignancy – e.g. adenocarcinoma [8] | The gallbladder tumor invaded adjacent structures, caused acute and chronic cholecystitis with cholelithiasis and choledochoduodenal fistula [8] | 1-month history of episodic nausea and vomiting, and epigastric pain on admission [8] | Abdominal ultrasound, CT, barium study [8] | ||
Perforation – acute on chronic gallbladder inflammation possibly due to ischemia and bile stasis secondary to preoperative fasting [9]. Perforation – other causes can be Epstein–Barr virus [10], liver abscess [11], blunt abdominal trauma [12], and spontaneous [13] | Bile leaked into the peritoneum [9] | Umbilical pain and a bluish discoloration of the skin around a known umbilical hernia presumably due to tracking of bile within the abdomen [9] | Liver function test, laparotomy [9] | The patient had spontaneous acalculous gallbladder perforation [9]. This condition is rare but critical | |
Gallbladder herniation: parastomal [14–18], incisional [19–21], spontaneous ventral [22, 23], epigastric [24], transdiaphragmatic herniation [25] | A midline abdominal hernia with small bowel loops, and a parastomal hernia containing the gallbladder [14] | Abdominal pain [14] | CT scan with oral Gastrograffin (sodium diatrizoate and meglumine diatrizoate) contrast [14] | ||
Gallbladder torsion [17] | Torsion of the neck of the gallbladder with secondary suppuration leading to gangrenous changes in the gallbladder [17] | Abdominal pain [17] | Abdominal CT [17] | Other case of gallbladder torsion [26], a new case of gallbladder torsion within an incisional hernia [27], complete gallbladder torsion [28], gallbladder torsion caused acute cholecystitis [7] | |
A gallstone enters via the Vater papilla and later increases in size [29] | Transition of a gallstone in the gastrointestinal tract leading to mechanical bowel obstruction (gallstone ileus) [29] | Nausea, vomiting and abdominal pain [29] | Abdominal CT, MRCP [29] | Other case: gallbladder-colon fistula [30] and cholecystogastric fistula [31] | |
Biliary-enteric fistula e.g. gallbladder-duodenal fistula [8] | “Spontaneous biliary fistulas have been associated with gallbladder cancer; if they are the cause of cancer, or acomplication of it, this has not yet been defined.” [8] | 1-month history of episodic nausea and vomiting, and epigastric pain on admission [8] | Abdominal ultrasound, CT, barium study [8] | ||
Failure of the cystic bud to develop in utero [32] | Gallbladder agenesis [32] | Reduced appetite, unintentional weight loss, and a history of fatty food intolerance [32] | Abdominal ultrasound, CT, ERCP; preoperative MRCP should be considered in cases in which ultrasound suggests non-visualization of the gallbladder [32] | Agenesis of the gallbladder could be made only at laparotomy after having searched for, and excluded, an ectopic gallbladder [32] | |
Cystic duct | Obstruction such as due to gallstone; chronic obstruction due to other causes [33] | Hydropic gallbladder – accumulation of mucus in the distended gallbladder [33] | Abdominal pain in the RUQ [33] | Abdominal ultrasound and MRI [33] | |
Cystic duct obstruction (+/– cystic artery strangulation) due to torsion of the neck of the gallbladder [34] | Leading to mural ischemia/gallbladder becomes gangrenous, and may perforate [34] | Epigastric pain with involuntary guarding and rebound tenderness in the epigastrium and RUQ [34] | Abdominal ultrasound and CT [34] | Another case [35] | |
Cystic duct infection e.g. streptococcal infection [36] | Streptococcal toxic shock syndrome; local necrosis in the cystic duct due to microcirculatory failure as a result of hypoperfusion and microthrombosis leading to perforation of the cystic duct [36] | Abdominal tenderness, rash and fever after an episode of pharyngitis* [36] | Liver function test, abdominal ultrasound and CT | * Refer to the case report for the time-course of the clinical features [36] Another case of cystic duct perforation with acalculous cholecystitis [37] | |
Common bile duct | Choledocholithiasis (stones in the common bile duct) [6] | Non-obstructive [6] | Asymptomatic [6] | ERCP [6] | |
Infection: bacterial [38] | Cholangitis [38] | Charcot’s triad (abdominal pain, fever and jaundice), nausea, and dark urine [38] | Ultrasound biliary tree, ERCP [38] | ||
Infection: liver flukes from consumption of undercooked contaminated seafood [5] | The metacercariae then excyst and migrate to the bile duct where they mature; prolonged infection may result in cholangiocarcinoma [5] | Abdominal pain, watery stools. The patients in this case also had malaria; they also had malaria-like symptoms (fever, headache) [5] | Microscopy examination after staining the stools with Giemsa or Ziehl–Neelsen stains [5] | The authors encourage clinicians to consider clonorchiasis/opisthorchiasis infection a possible diagnosis for all undiagnosed abdominal pain since the infection has propensity to cause hepatic fibrosis, liver cancer and cholangiocarcinoma [5] | |
Bleeding from the biliary tree is usually associated with trauma (can be iatrogenic), cholelithiasis, vascular disorders, tumors [39] | Hemobilia; tumor invasion into the intrahepatic bile duct, the tumor may rupture into the biliary system [39, 40] | Hematemesis and epigastric pain [39] | Abdominal CT [39] Multislice CT angiography is increasingly being used in the investigation [41] | Hemobilia may present as upper abdominal pain, gastrointestinal bleeding, and jaundice in some patients (22–38 %) [42] | |
Hepatic bile duct | Gallstones [6] | Biliary obstruction [6] | Pain in the RUQ +/– jaundice [6] | Abdominal ultrasound, ERCP [6] | |
Pigmented-stone formation and bacterial superinfection; Ascaris lumbricoides and Gram-negative bacteria consistent with Klebsiella species [43] "Through the portal circulation, larvae of Ascaris lumbricoides migrate from the stomach or small intestine to the liver and then to the lungs, where they break out into the airspaces, migrate up the trachea, and are swallowed. The larvae develop into sexually mature adults in the small intestine where they live and lay eggs that pass in the feces." [44] | Hepatolithiasis; inflammation in portal tracts, often with portal pylethrombophlebitis; patients with advanced disease have chronic lesions characterized by periductal fibrosis [43] | Recurrent pain in the RUQ of the abdomen [43] | Liver function test, abdominal ultrasound, CT, ERCP, MRI, MRCP, blood cultures, microscopy examination on stool specimen [43] | The 35-year-old patient was born in Vietnam and she immigrated to USA in her early 20s. Multiple large stones in the common bile duct, the left hepatic duct, and the left intrahepatic duct. A wide range of differential diagnoses were discussed in this article [43]. “Obstruction along the pancreatobiliary tree may occur if aberrant migration of larvae or adult worms through the ampulla of Vater occurs.” [45] | |
Malignancy e.g. hepatocellular carcinoma [46] | Intrahepatic and extrahepatic bile duct obstruction [46] | Upper abdominal pain, jaundice and weight loss; icterus, and hepatomegaly [46] | Ultrasound and CT abdomen [46] | ||
Malignancy in the intrahepatic biliary duct [47] | Intrahepatic cholangiocarcinoma [47] | Episodic epigastric pain and iron-deficiency anemia, jaundice [47] | Liver function test, full blood examination, iron studies, abdominal ultrasound, CT, and ERCP [47] | ||
Intrahepatic perforated cholecystitis [11] | Intrahepatic abscess [11] | Intermittent fever, anorexia, and weight loss [11] | Ultrasound of the liver, and CT angiogram [11] | Other case [48] | |
Cholesterol hepatolithiasis [49] | Heterotopic pancreatic tissues were distributed along the wall of the biliary tract and were composed of acinar cells and duct elements without islets of Langerhans [49] | Abdominal pain (45.5 %), epigastric discomfort (12.0 %), nausea and vomiting (9.6 %), bleeding (8.0 %) [49] | Ultrasound, CT scan, and definitive diagnosis by histopathological examination on the excised mass, ERCP [49] | The patient in the case was asymptomatic [49] | |
Multifocal congenital dilatations of the intrahepatic bile ducts [50] | Caroli’s disease (the dilated intrahepatic ducts, which may be diffuse or limited, presenting in a sack form that produces cystic structures, which communicate with the biliary tree) [50] | Asymptomatic in this case [50]. Others have reported RUQ abdominal pain, jaundice, and recurrent cholangitis [51] | Abdominal CT, MRI, MRCP, histopathologic findings on resected liver specimen [50] | ||
Obliterative cholangiopathy – biliary atresia [52] | Neonatal biliary obstruction and cholestasis [52] | Jaundice [52] | Urinary urobilinogen combined with GGT; liver biopsy; diagnosis of biliary atresia was confirmed by operative cholangiography and/or laparotomy findings [52] | ||
Immune-mediated destruction of the intrahepatic bile ducts [53] | Primary biliary cirrhosis leads to decreased bile secretion and the retention of toxic substances within the liver, resulting in further hepatic damage, fibrosis, cirrhosis, and eventually, liver failure [53] | Fatigue and pruritus; unexplained discomfort in the RUQ of the abdomen; hepatomegaly; jaundice, portal hypertension and steatorrhea may occur in advanced disease; splenomegaly (uncommon); rarely ascites, hepatic encephalopathy, or hemorrhage from esophageal varices [53] | Antimitochondrial antibodies, which are present in 90–95 % of patients and are often detectable years before clinical signs appear; liver enzymes; liver biopsy [53] | ||
Intense inflammatory fibrosis of the intrahepatic and extrahepatic biliary ducts [54] | Primary sclerosing cholangitis (PSC): fibrosis involving the common bile duct, hepatic ducts, and sometimes the gallbladder; may progress to secondary biliary cirrhosis [54] | Progressive obstructive jaundice, pruritus, weight loss, pain (RUQ or epigastric pain) [54] | Elevation of total and direct (conjugated) serum bilirubin, serum alkaline phosphatase were 3 to 5 times normal; operative cholangiograms [54] | PSC can be associated with inflammatory bowel disease. Primary biliary cirrhosis and sclerosing cholangiocarcinoma should be ruled out prior to diagnosing PSC [54] | |
Extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs including bile duct and gallbladder [55] | Systemic fibroinflammatory causing sclerosing cholangitis [55] | Painless jaundice and weight loss [55] | CT abdomen, liver function test, serum IgG4; “ERCP with intraductal ultrasonography (IDUS), brush cytology and endobiliary biopsy would be helpful” [55] | Another recent case reported that IgG4-related cholangitis is a rather uncommon cause of biliary obstruction, which can be easily mistaken for a cholangiocarcinoma [56] | |
Abnormality in the genes encoding for canalicular bile formation [57] | Defective bile canaliculi leading to intrahepatic cholestasis which may progress to fibrosis and endstage liver disease (progressive familial intrahepatic cholestasis) [57] | Progressive jaundice [57] | Radiological, laboratory, and liver biopsy findings [57] | ||
Cystic dilatation of extrahepatic bile ducts, with or without the dilatation of the intrahepatic duct [58] | Choledochal cyst [58] | In this case, an antenatal diagnosis of an abdominal cyst [58]. Patient can be asymptomatic [6] | Abdominal ultrasound and operative cholangiogram [58]. Liver function test, ERCP, CT or MRI [6] | Choledochal cyst may be associated with biliary atresia [59] | |
Malignancy e.g. SCC at the bifurcation of the common hepatic duct, and adenocarcinoma in the common bile duct [60] | Biliary obstruction leading to hyperbilirubinemia [60] | Jaundice, dark urine, itch, and weight loss [60] | Abdominal ultrasound, CT, positron emission tomography-CT [60] | ||
Bile synthesis, conjugation, transport | Hepatic glucuronidating activity is reduced [63] | Mild, chronic unconjugated hyperbilirubinemia in the absence of hepatocellular disease or hemolysis (Gilbert syndrome) [63] | Intermittent mild jaundice [64] | Genetic testing [64] | Reduced expression of bilirubin UDP-glucuronosyltransferase 1 gene; an autosomal recessive mode of inheritance was suggested [63] |
Deficiency of hepatic glucuronyl transferase [65] | Hyperbilirubinemia of the unconjugated type; complication includes kernicterus (Crigler–Najjar syndrome) [65] | Jaundice since birth; hepatomegaly; frequent generalized, tonic and clonic convulsions due to kernicterus [65] | Serum bilirubin (direct/conjugated and indirect/unconjugated) test, genetic testing [65] | This disease is inherited as an autosomal recessive trait [65] | |
A defect in the canalicular multispecific organic anion transporter (cMOAT) gene (ABCC2/MRP2 superfamily) located at 10q24 [66] | Impaired hepatobiliary transport of non-bile salt organic anions leading to chronic conjugated hyperbilirubinemia (Dubin–Johnson syndrome) [66] | This patient presented with repeated episodes of jaundice during illness; other patients may present with abdominal pain, fatigue, liver enlargement, or dark urine [67] [68] | Liver function test, abdominal ultrasound, liver biopsy showed presence of parenchymal pigmentation, urinary coproporphyrin level, genetic testing [67] | This is an autosomal recessive disorder [67] | |
Homozygous inactivation of two adjacent genes SLCO1B1 and SLCO1B3 encoding organic anion transporting polypeptides OATP1B1 and OATP1B3 [69] | Chronic conjugated hyperbilirubinemia without abnormal hepatic pigmentation (Rotor syndrome) [69, 70]. Abnormal transfer of sulfobromophthalein from plasma into the liver [70] | Nonhemolytic jaundice [71] | Urinary coproporphyrin and plasma sulfobromophthalein, genetic testing [70] | This is an autosomal recessive disorder [70] | |
Portal vein | Iatrogenic injury from surgical procedure [72] | Portal vein thrombosis [72] | Pain in the RUQ of the abdomen [72] | Abdominal CT and angiography [72] | Another case of portal vein thrombosis secondary to hyperhomocysteinemia with pernicious anemia was reported [73] |
Hepatic artery | Iatrogenic injury from surgical procedure [72] | Hepatic ischemia [72], unrecognized vasculobiliary injury (VBI) can lead to biliary strictures, cholangitis and liver atrophy [74] | Pain in the RUQ of the abdomen [72] | Abdominal CT and angiography [72] | |
Hepatic vein | Blood clots completely or partially block the hepatic veins that carry blood from the liver into the inferior vena cava [75] | Fatigue, abdominal pain, nausea, jaundice, hepatosplenomegaly, edema in the legs, ascites, and sometimes esophageal varices [75] | Doppler ultrasound examination of suprahepatic and cava veins [76] | Budd–Chiari syndrome is a vascular complication that can be associated with Behçet’s disease [76] | |
Sphincter of Oddi | Spasm or stenosis of the sphincter of Oddi (see note in the last column) [77] | Sphincter of Oddi dysfunction; idiopathic recurrent acute pancreatitis (can be controversial) [78] | Persistent or unexplained episodic abdominal pain in patients following cholecystectomy [77, 78]. The symptoms may precede cholecystectomy [77] | Sphincter of Oddi manometry [78] | Yaghoobi and Romagnuolo reviewed recent literature on sphincter of Oddi dysfunction; little is known about the etiology of the disease [78] |
Ampulla of Vater | Adenoma at the ampulla [79] | Lithiasis of the bile duct and chronic pancreatitis [79] | Icterus/jaundice, and painless swelling of the gallbladder (Courvoisier sign) [79] | Abdominal ultrasound, CT, ERCP with biopsy of the lesion [79] | Adenoma has potential for malignancy [80] |
Pancreas | Malignancy (e.g. tumor in the head of pancreas) [6] | The tumor compresses the common bile duct and pancreatic duct leading to hyperbilirubinemia [6] | Anorexia, weight loss, upper abdominal pain, and jaundice [6] | Abdominal CT and ERCP [6] | A recent case of a tumor in the head of pancreas [81] |
Hematological process | Red blood cell enzyme (G6PD) deficiency [82] | The enzyme-deficient red blood cells are susceptible to hemolysis induced by certain drugs, bacterial and viral infections. Excessive hemolysis leads to increase in unconjugated bilirubin | Jaundice; generalized tonic–clonic seizure when kernicterus occurs [82] | Liver function test, serum G6PD level, G6PD deficiency phenotyping [82] | G6PD deficiency is an X-linked recessive disease |
Paroxysmal nocturnal hemoglobinuria | Prolonged and recurrent red blood cell breakdown results in increased bilirubin in the gallbladder. The excess bilirubin can precipitate bilirubin stones. Gallstones in the common bile duct [83] | Jaundice and abdominal pain [83] | CT, ERCP, MRCP [83] | ||
Red blood cell membrane defect resulting in spherical, osmotically fragile erythrocytes (hereditary spherocytosis) [84] | Premature red blood cell destruction leading to hyperbilirubinemia [84] | Anemia, jaundice, and splenomegaly [84] | Peripheral blood smear showed small and dense spherocytes; osmotic fragility test [84] | The patient in the case has coexistence of hereditary spherocytosis and Gilbert syndrome [84] | |
Endocrinological process | Poorly controlled diabetes mellitus [85] | The excess glucose increases glycogen storage in the liver and blocks glycogenolysis resulting in glycogenic hepatopathy [85] | Hepatomegaly and pain in the RUQ [85] | Ultrasound abdomen, liver function test, and liver biopsy [85] |