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Soonchunhyang Med Sci > Volume 28(2); 2022 > Article
Kim: Obstructive Jaundice

ABSTRACT

Jaundice is a medical condition in which the skin or sclera of the eyes becomes yellow, and elevation of bilirubin production or obstruction of bile excretion can cause jaundice while disrupting the balance between bilirubin production and bile excretion. Jaundice is a very visual clinical sign that both patients and physicians can easily recognize. It warrants further investigation regarding the cause of jaundice because jaundice is always a pathological sign regardless of its seriousness. Clinical manifestations of obstructive jaundice can be understood in terms of bile formation and secretion, and the anatomy of the biliary tree. Obstruction of a critical part of the biliary tree such as the common bile duct can cause jaundice, and investigating the etiology of jaundice is the first step of managing this condition. Choledocholithiasis, pancreatic ductal adenocarcinoma, cholangiocarcinoma, and biliary atresia are some of the common medical conditions that cause obstructive jaundice. Whenever jaundice is observed by a physician, early diagnosis and prompt treatment should be performed as early as possible for better outcomes.

INTRODUCTION

Jaundice is a medical condition in which the skin or sclera of the eyes become yellow, and it is a very distinct sign of the hepatobiliary diseases. Elevation of bilirubin production or obstruction of bile excretion can cause jaundice while disrupting the balance between bilirubin production and bile excretion [1]. Jaundice is always a pathological sign so that it should never be ignored. Although it can be a sign of relatively nonlethal conditions such as Dubin Johnson syndrome, choledocholithiasis, red blood cell disorders, and drug-induced liver injury [24], it can also be a sign of more grievous diseases such as advanced pancreatic cancer, cholangiocarcinoma, biliary atresia, hepatocellular carcinoma, and liver metastases [58]. Jaundice can even be a sign of diseases such as tuberculosis lymphadenitis, autoimmune pancreatitis, cholangiohydatidosis, duodenal diverticulum (i.e., Lemmel’s syndrome), duodenal ulcer, fascioliasis (i.e., parasitic disease caused by Fasciola hepatica), and coronavirus disease 2019 [915]. Moreover, obstructive jaundice can even cause endotoxemia because of intestinal barrier failure [16]. Fortunately, jaundice is a very visual sign so that physicians as well as patients can recognize it easily as long as enough attention is paid. In this article, special attention is paid to obstructive jaundice in which jaundice occurs due to obstruction of bile flow after bile is produced in the liver. By recognizing this simple yet important clinical sign, physicians can greatly benefit their patients in terms of early diagnosis and treatment as well as prevention of more grievous stages of the hepatobiliary and pancreatic diseases.
This review aims to discuss the bile formation and secretion, anatomy and pathophysiology of obstructive jaundice, and clinical significance of obstructive jaundice.

BILE FORMATION AND SECRETION

Bilirubin is the final degradation product of heme, which is derived from breakdown of red blood cells in the spleen, liver, and bone marrow. An enzyme called heme oxygenase oxidizes heme to biliverdin, which is again converted into bilirubin by another enzyme called biliverdin reductase. In the liver, bilirubin is conjugated with glucuronic acid by an enzyme called bilirubin uridine diphosphate glucuronyltransferase, and conjugated bilirubin is water-soluble while unconjugated bilirubin is not water-soluble and tightly bound to albumin in blood stream [1].
Bile consists of bile acids (primarily, chenodeoxycholic acid and cholic acid), cholesterol, conjugated bilirubin, biliverdin, amino acids, steroids, enzymes, porphyrins, vitamins, heavy metals, exogenous drugs, xenobiotics, and environmental toxins [1720]. Bile acids are synthesized by hepatocytes from cholesterol in the liver [21,22]. Furthermore, conjugation of bile acids occurs in the liver, and the conjugation increases their solubility [23]. Bile has some important functions as follows: the major excretory route for potentially harmful exogenous lipophilic substances, emulsification of fats and facilitation of their absorption in the intestines, secretion of polymeric immunoglobulin A to help protect the biliary and upper intestinal tracts from infection, and the major route of cholesterol elimination [17,24]. Brownish bilirubin and greenish biliverdin are responsible for the color of bile. Bile is stored in the gallbladder. Once the bile is released into the small intestines, it mixes with food and travels through the small intestines and large intestines. In the distal ileum and colon, bilirubin is converted into colorless urobilinogen by gut bacteria [23,25]. Of note, bile acids are biotransformed by gut bacteria as well during their intestinal transit, and the majority of bile acids is reabsorbed in the intestines, thereby going back to the liver via the portal vein [18,21,26].
The majority of urobilinogen is excreted in the feces, and the remaining portion undergoes enterohepatic cycling, and only a small fraction of it is excreted in urine [27]. In the kidney, urobilinogen is also excreted in urine as urobilin, which is responsible for urine color. Some urobilinogen in the intestines is converted into stercobilinogen, which is again converted into brownish stercobilin. Stercobilin is responsible for stool color and excreted in feces. Of note, the enterohepatic circulation of bile acids is affected by clinical conditions such as metabolic disorders, hepatic impairment, diarrhea, and gallstone disease [28].

ANATOMY AND PATHOPHYSIOLOGY OF OBSTRUCTIVE JAUNDICE

After liver cells produce bile, it travels via bile canaliculi, bile ductules, right and left hepatic ducts, and finally common bile duct to meet with the pancreatic duct of Wirsung and arrive at the major duodenal papilla of Vater where the bile is released into the small intestine [17,29,30]. As long as the sphincter of Oddi, which surrounds the major duodenal papilla of Vater and pancreatic duct of Wirsung, contracts, the bile flows upward due to pressure and goes into the gallbladder via the cystic duct; hence, the gallbladder becomes a storage of bile. Upon digestion of food, cholecystokinin is released from the small intestines, and it contracts the gallbladder, relaxes the sphincter of Oddi, and induces the release of digestive enzymes from the pancreas. After the bile is released into the second part of the duodenum via the major duodenal papilla of Vater, the bile mixes with food and travels through the intestines.
Both unconjugated and conjugated bilirubin can accumulate in the body, and normal serum bilirubin levels are about between 0.3 and 1.2 mg/dL. Jaundice becomes noticeable when the serum bilirubin level reaches about 2. Causes of jaundice are different depending on a type of hyperbilirubinemia so that measurement of both unconjugated and conjugated bilirubin helps to assess jaundice more accurately [1].
If jaundice occurs because of obstruction of bile flow after bile is produced, it is essentially obstructive jaundice. Although this is not a general rule, it commonly occurs at the level of the common bile duct because the common bile duct is the last conduit that bile travels through before being released into the intestines. In other words, obstruction at the level of the common bile duct causes backflow of bile into the liver, as well as into the blood stream, thereby causing jaundice.

CLINICAL SIGNIFICANCE OF OBSTRUCTIVE JAUNDICE

Once jaundice occurs, it makes sclerae yellow first. After that, yellowish skin becomes noticeable. Also, pruritus is a very prominent feature of cholestasis so that patients often feel itchiness and scratches their skin although the mechanism of pruritus is still not understood well [19,31,32]. Since jaundice is a very visual sign, patients as well as their physicians are likely to recognize it with their naked eyes. Jaundice itself warrants further investigation as it is always a pathological sign. Taking a good history and performing a complete physical exam is an essential first step, and doing the comprehensive blood work including complete blood count, basic metabolic panel, liver function test, gamma-glutamyl transferase, and prothrombin time/international normalized ratio/partial thromboplastin time should follow. Also, ultrasound of liver and gallbladder and/or computed tomography (CT) as well as magnetic resonance imaging or endoscopic retrograde cholangiopancreatography (ERCP) should be seriously considered if appropriate. Moreover, based on the physicians’ discretion, additional tests including hepatitis panel and so forth can be performed. Based on these basic tests and appropriate consultations, correct diagnosis and treatment plan should be made promptly.
Some of the most common diseases that cause obstructive jaundice are discussed here. Pancreatic ductal adenocarcinoma is notorious for its low 5-year survival rate, and it is known to be difficult to detect early because it usually does not produce any specific sign until its late stage; thus, it is usually detected at an advanced stage, and early diagnosis of pancreatic cancer prolongs the survival time [33,34]. One of the common signs that the pancreatic ductal adenocarcinoma manifests at a late stage is that it causes obstructive jaundice. The growing tumor of the pancreas head pushes into the common bile duct where the pancreatic head gently surrounds in a non-pathologic condition. Since the bile cannot be released into the intestines, it flows back into the liver and blood stream. At this point, depending on the stage of the cancer, treatment plan including surgery should be made with the patient. Also, for malignant obstructive jaundice caused by pancreatic cancer, percutaneous transhepatic biliary drainage or endoscopic biliary drainage as well as biliary stent placement can be performed [3538]. Alternatively, endoscopic ultrasound (EUS)-guided biliary drainage can be performed in addition to obtaining cytological and histological diagnosis (EUS-guided fine needle aspiration) [38,39]. Resectable pancreatic cancer can be treated with surgery and adjuvant chemotherapy, but metastatic and unresectable pancreatic cancer is managed with chemotherapy or supportive care [40]. As the first-line chemotherapy for both resectable and metastatic pancreatic cancer is to use FOLFIRINOX or gemcitabine with nab-paclitaxel, and radiotherapy helps to control the cancer growth or even convert the unresectable cancer to the resectable one [41]. Also, although there is no clear definition of “resectability,” 4–6 months of neoadjuvant therapy, no disease progression, stable value of cancer antigen (CA) 19-9, and good Eastern Cooperative Oncology Group (ECOG) performance status score (ECOG ≤1) should be supported for a decision of surgical resection [41].
Cholangiocarcinoma can cause obstructive jaundice as well. Cholangiocarcinoma originates from cholangiocytes and occurs at any level of the biliary tree [42]. Cholangiocarcinoma is the second most common primary liver cancer [42]. Measurement of levels of alkaline phosphatase and bilirubin as well as carcinoembryonic antigen and CA 19-9 can be helpful for diagnosis [42]. Ultrasonography is the initial choice of imaging studies, and CT and magnetic resonance cholangiopancreatography (MRCP) can be taken for further assessment [42]. Especially, MRCP is the preferred imaging study for evaluation of biliary tree anatomy including variations [43]. In addition, positron emission tomography can be useful to rule out metastasis [42]. For biliary drainage to relieve obstructive jaundice, percutaneous transhepatic biliary drainage or endoscopic biliary drainage as well as biliary stent placement can be performed [35,44,45]. Surgical resection is currently the mainstay of treatment for cure of cholangiocarcinoma, but palliative therapy should be considered if appropriate [42]. Diagnosing cholangiocarcinoma at an early stage is difficult because of its location and silent clinical features, so a lot of patients with cholangiocarcinoma are found to have advantaged-stage cancer, which is not resectable anymore [46]. Currently, the gemcitabine and cisplatin combination therapy is the current first-line chemotherapy for such patients who have unresectable advanced-stage cholangiocarcinoma, and in the near future, molecularly targeted therapies and immunotherapy might be used for cholangiocarcinoma as these therapies are actively investigated in multiple ongoing clinical trials [46].
Choledocholithiasis is another common cause of obstructive jaundice. Depending on the location of gallstones, it can cause colicky pain as well. Ultrasound of liver and gallbladder would be a very helpful test for diagnosis, and if the common bile duct is dilated, ERCP can be performed to extract the stones from the common bile duct [47]. If needed, a biliary stent can be placed as well [48,49]. However, as most gallstones accumulate in the gallbladder initially, cholecystectomy is a reasonable treatment for patients with recurrent symptomatic gallstones [18]. In addition, endoscopic lithotripsy can be performed for failed endoscopic sphincterotomy or difficult cases of choledocholithiasis [50].
As a pediatric condition, biliary atresia is a condition in which a progressive fibrosing and inflammatory cholangiopathy occurs to obstruct the extrahepatic bile ducts [6]. Affected patients develop jaundice rapidly, and a surgical procedure called Kasai portoenterostomy is the primary treatment while liver transplantation is the salvage treatment when Kasai portoenterostomy fails biliary drainage restoration [18,51]. However, more than 40% of patients who have received Kasai portoenterostomy eventually require liver transplantation, so the necessity of novel treatments has emerged, and pharmacological treatments such as using B-cell modifying therapy with rituximab are currently being studied [52].

CONCLUSION

Jaundice is one of the most visual clinical signs that both patients and physicians can easily recognize. It warrants further investigation regarding the cause of jaundice. Especially for obstructive jaundice, there are common medical conditions that are responsible for it. It would be crucial for physicians to diagnose and treat them as early as possible. By being aware of this simple yet important clinical sign, a numerous hepatobiliary and pancreatic diseases can be diagnosed early for benefiting patients through appropriate and prompt treatment.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

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