Chapter 159 – DISEASES OF THE GALLBLADDER AND BILE DUCTS

The biliary tract consists of the intrahepatic biliary canaliculus; the small, medium, and large intrahepatic bile ducts; the common bile duct; the gallbladder; the cystic duct; and the ampulla of Vater. The primary functions of the biliary system are secretion and storage of bile salts that solubilize intestinal lipids, excretion of cholesterol to maintain cholesterol homeostasis, excretion of excess bilirubin, and excretion of organic ions, including drug metabolites.

  CHOLESTASIS

Pathobiology

Cholestasis is the systemic retention of biliary constituents as a result of failure of formation and flow of bile ( Table 159-1 ). In the liver, hepatocytes are organized into cribriform, anastomosing plates along the sinusoids. At the apical pole, between adjacent hepatocytes, is the 1- to 2-μM biliary canaliculus or space. Each hepatocyte can have multiple canaliculi (up to three), which are characterized by microvilli that protrude into the canalicular lumen.

TABLE 159-1   -- CAUSES OF CHOLESTASIS

Extrahepatic Intrahepatic
Choledocholithiasis Viral hepatitis
Bile duct stricture Alcoholic hepatitis
Cholangiocarcinoma Drug induced
Pancreatic carcinoma Ductopenia syndromes
Chronic pancreatitis Primary biliary cirrhosis
Papillary stenosis Benign recurrent intrahepatic cholestasis
Ampullary cancer Byler's disease
Primary sclerosing cholangitis Primary sclerosing cholangitis
Choledochal cysts Alagille's syndrome
Parasites (e.g., Ascaris, Clonorchis) Sarcoid
Acquired immunodeficiency syndrome cholangiography Lymphoma
Biliary atresia Postoperative
Portal lymphadenopathy Total parenteral nutrition
Mirrizzi's syndrome α1-Antitrypsin deficiency

Bile consists of water, electrolytes, and organic solutes ( Table 159-2 ). It is continuously modified both by the cholangiocytes that line the bile ducts and by the gallbladder mucosa, and therefore gallbladder bile is markedly different from hepatic bile. The gallbladder mucosa absorbs water and concentrates bile, so the total lipid content of gallbladder bile is much higher than that of hepatic bile (10 vs. 3 g/dL, respectively).

TABLE 159-2   -- CONSTITUENTS OF HUMAN CANALICULAR BILE

Bile salts, 12 g/L Cholates, 35%
  Glycine conjugates, 75% Chenodeoxycholates, 35%
  Taurine conjugates, 24.8% Deoxycholates, 25%
  Free bile acids, 0.2% Lithocholates, 1%
    Miscellaneous, 40%
Phospholipids, 5 g/L Phosphatidylcholine, 96%
    Phosphatidylethanolamine, 3%
Cholesterol, 1 g/L Free, unesterified, 99%
Bilirubin, 0.2 g/L Diglucuronide, 80%
    Monoglucuronide, 18%
    Unconjugated, 2%
Proteins, 2 g/L Albumin, 50%
    Immunoglobulins, 23%
    Calcium binding protein/anionic
    peptide fraction, 17%
    Serum proteins, 9%
    Canalicular proteins, 1%
Electrolytes Sodium, 150 mEq/L
    Magnesium, 2 mEq/L
    Calcium, 3 mEq/L
    Potassium, 5 mEq/L
    Chloride, 110 mEq/L
    Bicarbonate, 30 mEq/L

The major primary bile acids are cholic and chenodeoxycholic acid. The secondary bile acids, lithocholic and deoxycholic acids, which are derived from the intestinal breakdown of primary bile acids, are more hydrophobic, increase in cholestasis, and can be toxic to hepatocytes. Amidation with glycine or taurine results in the formation of bile salts that are preferentially secreted into bile. Bile salts are amphophilic detergent-like molecules synthesized from cholesterol via a pathway dependent on either 7α-hydroxylase or sterol 27-hydroxylase. Bile salt synthesis accounts for approximately 50% of the liver metabolism of cholesterol. Bile salts are secreted into the canalicular space by an energy-dependent bile salt export pump ( Fig. 159-1 ). In the canalicular membrane, bile salts exist as simple (bile salt only) or mixed (with phosphatidylcholine and cholesterol) micelles and are transported into the gallbladder. A fatty meal results in contraction of the gallbladder with expulsion of bile salts into the duodenum, where they form micelles with intraluminal fat. About 95% of bile acids are absorbed by a sodium-dependent bile acid transporter in the terminal ileum. The total bile acid pool is circulated four to six times per day, and the volume of biliary secretion is approximately 1 L/day. The major phospholipid in bile is phosphatidylcholine, also called lecithin. Phosphatidylcholine in bile is derived from newly synthesized hepatic phosphatidylcholine, which is then transported through the hepatocyte by a phosphatidylcholine transfer protein and delivered to the multidrug resistance receptor 3 (MDR3), a phosphatidylcholine-specific transporter for final secretion into bile (see Fig. 159-1 ). All biliary lipids, including cholesterol, are secreted in a controlled manner by adenosine triphosphate (ATP) binding cassette transporters ( Table 159-3 ).

Schematic diagram of the metabolism of phospholipid and cholesterol by the hepatocyte

FIGURE 159-1  Schematic diagram of the metabolism of phospholipid and cholesterol by the hepatocyte. BSEP = bile salt export pump; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MDR2 = multidrug resistant receptor 2, a phospholipid lipase highly selective for phosphatidylcholine or lecithin; VLDL = very low density lipoprotein.

TABLE 159-3   -- CANALICULAR ATP-BINDING CASSETTE TRANSPORTERS FOR PRIMARY BILIARY CONSTITUENTS

Transporter Name Gene Code Substrate Associated Hereditary Disease
FIC1 ATP8B1 ? Byler's disease,
      PFIC type 1
BSEP ABCB11 Bile salts PFIC type 2
MDR3 ABCB4 Phosphatidylcholine PFIC type 3
MDR1 ABCB1 Amphipathic drugs  
MRP2 (cMOAT) ABCC2 Anionic neutral drugs Dubin-Johnson syndrome
ABCG5/ABCG8 ABCG5/8 Cholesterol Sitosterolemia

ATP = adenosine triphosphate; BSEP = bile salt export pump; cMOAT = canalicular multispecific organic anion transporter; MDR = multidrug-resistant receptor; MRP2 = multidrug resistance–associated protein 2; PFIC = progressive familial intrahepatic cholestasis.

Clinical Manifestations

The clinical manifestations depend on the location and cause of the obstructive process and the degree to which an associated increase in pro-inflammatory cytokines decreases bile salt synthesis and secretion. Intrahepatic cholestasis is usually the result of either hepatocellular dysfunction ( Chapter 149 ) or injury to the small and medium bile ducts secondary to viruses ( Chapters 151 and 152 ), alcohol ( Chapters 156 and 157 ), or drugs ( Chapter 153 ).

Bile salt retention can lead to an excess of hydrophobic bile salts, such as deoxycholate, which are hepatotoxic. These retained bile salts can overflow out of the liver and lead to increased levels of bile salts in serum and the skin; the result is pruritus. Excess cholesterol is deposited in all tissues, particularly as tendinous xanthomas and periorbital xanthelasmas, but clinically significant atherosclerosis is uncommon.

In cholestasis, concentrations of intestinal bile salts are inadequate to solubilize dietary lipids; the result is the excretion of excess nonabsorbed fat. Long-chain dietary fats also irritate the colonic mucosa. Steatorrhea, which is characterized by greasy, foul-smelling diarrhea, develops ( Chapter 143 ). Steatorrhea is suggested by the presence of stainable fat in stool (see Fig. 143-11 ) and confirmed by quantitative analysis of a 32-hour stool collection (see Table 143-6 ).

Because malabsorption of the fat-soluble vitamins A, D, E, and K can result in deficiency syndromes, fat-soluble vitamins and essential fatty acids should be given as dietary supplements. The combination of osteomalacia and osteoporosis is a serious consequence of cholestasis and chronic liver disease.

Diagnosis

In pure cholestasis, alkaline phosphatase and γ-glutamyltransferase levels are elevated significantly, whereas aminotransferase levels are normal or only mildly increased ( Chapter 150 ). Bilirubin may be elevated but can be normal even in severe intrahepatic cholestasis until the very late stages of disease. Dilation of the intrahepatic ducts on ultrasonography (US) suggests extrahepatic obstructive cholestasis.

Treatment

Therapy should attempt to remove the cause of cholestasis, such as bypassing an obstructing pancreatic cancer ( Chapter 204 ) with surgery or a stent. In the progressive cholestasis of intrahepatic biliary disease (e.g., primary biliary cirrhosis [PBC]), liver transplantation ( Chapter 158 ) may be the only recourse.

Bile acid binders or sequestrants, such as cholestyramine, can lower the bile acid concentration but are associated with bloating and constipation ( Table 159-4 ). Replacement of hydrophobic bile salts with hydrophilic bile salts, such as ursodeoxycholic acid (UDCA), treats all forms of intrahepatic cholestasis and the associated pruritus. The sensorineural pathway can also be blocked by using opioid antagonists such as naloxone and naltrexone, but care must be taken to avoid the risk for opioid withdrawal syndrome. Hepatic enzyme inducers such as phenobarbital and rifampicin have also been successfully used for pruritus. Rifampicin may induce drug-metabolizing transporters, thereby resulting in increased excretion of pruritogens but with a risk of hepatotoxicity. In some cases of intractable pruritus, marijuana or its synthetic form Marinol has been useful in controlling symptoms. Finally, for situations such as the intractable pruritus of biliary cirrhosis, liver transplantation is the only option.

Supplementation with calcium, 1500 mg daily, plus vitamin D is essential. If bone density scans show osteopenia, therapy with bisphosphonates should be instituted ( Chapter 264 ).

TABLE 159-4   -- CLINICAL FEATURES OF AND THERAPY FOR CHOLESTASIS

Clinical Syndrome Treatment
Pruritus Bile salt binders (e.g., cholestyramine), ursodeoxycholic acid, rifampicin, naltrexone, carbinoids, phenobarbital
Hypercholesterolemia Bile salt binders (e.g., cholestyramine) Statins—poor effect
Malabsorption Medium-chain triglycerides, fat-soluble vitamins (A, D, E, K), essential fatty acids
Osteopenia Calcium, vitamin D, bisphosphonates

   BILIARY TRACT DISEASES

Lesions of the intrahepatic and extrahepatic biliary tree, including the ampulla of Vater, are rare.

   Biliary Atresia

Biliary atresia is a fibro-obliterative process that affects the perinatal bile ducts from the hilar bifurcation to the duodenum in 1 in every 13,000 live births in the United States. Associated genetic abnormalities in 25% of cases include polysplenia, anomalies of the portal vein and hepatic artery, abdominal situs inversus, intestinal malrotation, and cardiovascular and urinary tract anomalies. The clinical findings consist of jaundice with acholic stools persisting for 2 weeks after birth. The diagnosis can be suspected by endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) but is usually confirmed by laparotomy. Surgical correction by portoenterostomy should be performed within the first 60 days of life. About 80% of children grow normally through the first years of life, but subsequent stenosis of the anastomosis with progressive biliary cirrhosis and liver failure is common and an indication for liver transplantation.

   Choledochal Cysts

Choledochal cysts are congenital ductal ectasias involving either a segment or the entirety of the biliary tree. The incidence is 1 per 13,000 live births in the United States but is 13 times higher in Japan and Asia. Female gender carries a four-fold greater prevalence, and there is an association of cysts with an abnormal pancreatic ductal junction and congenital hepatic fibrosis. The usual clinical manifestation is a right upper quadrant mass, jaundice, and pain. Acute pancreatitis, cholangitis, variceal hemorrhage, and cyst rupture are alternative findings. The diagnosis is usually made by imaging studies, including US, computed tomography (CT), MRCP, and ERCP. Therapy is generally surgical excision of the cyst with a Roux-en-Y hepaticojejunostomy because of the high (3 to 26%) incidence of malignant transformation of the cysts into cholangiocarcinoma. When there is extensive intrahepatic ductal dilation (Caroli's disease), recurrent cholangitis and intrahepatic stones are common, and liver transplantation is the optimal therapy.

   Oriental Cholangiohepatitis

Recurrent cholangitis with hepatolithiasis is endemic in East Asia, especially in Taiwan where the incidence is as high as 13% in areas where infection with Ascaris lumbricoides ( Chapter 378 ) and Clonorchis sinensis ( Chapter 377 ) are common. These worms cause local strictures and dilation of the intrahepatic biliary tree. Biliary stasis ensues, and the bile becomes infected with bacteria that are able to deconjugate bilirubin and cause brown stones to be formed. Recurrent cholangitis is the usual finding, but malignant transformation to cholangiocarcinoma can also occur. The diagnosis is made by US or CT. Treatment includes intravenous fluids and antibiotics. Endoscopic stone removal plus clearance of infected biliary segments is a primary option, but surgical resection of localized segments of the liver may be necessary.

   Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is a chronic cholestatic condition characterized by segmental fibrosing inflammation of the intrahepatic and extrahepatic bile ducts.

Epidemiology

The prevalence of primary sclerosing cholangitis is 1 to 6 cases per 100,000 in the U.S. population, with a male-to-female ratio of 2.3:1. The mean age at diagnosis is 32 to 40 years of age, but children can be affected.

Pathobiology

The etiology remains unknown, but primary sclerosing cholangitis is thought to be a primary autoimmune disease. The disease is progressive, with obliteration of small, medium, and large bile ducts leading to three distinct clinical syndromes: (1) cholestasis with eventual biliary cirrhosis, (2) recurrent cholangitis and large duct strictures, and (3) cholangiocarcinoma. The multiple causes of secondary sclerosing cholangitis can be accompanied by symptoms and signs that are indistinguishable from the primary form ( Table 159-5 ).

TABLE 159-5   -- DISEASES ASSOCIATED WITH SCLEROSING CHOLANGITIS

Primary Sclerosing Cholangitis Secondary Sclerosing Cholangitis
Ulcerative colitis Choledocholithiasis
Crohn's colitis or ileocolitis Infections in immunocompromised patients (Cryptosporidium, Trichosporon, cytomegalovirus, Cryptococcus, visceral protothecosis)
Type 1 autoimmune hepatitis HTLV-1–associated myelopathy
  Ischemic injury to the hepatic artery or arterioles
  Trauma
  Neoplasia
  Toxic injury
    Floxuridine (hepatic artery injection)
    Formalin injection of echinococcal cysts
  Congenital abnormalities
  Celiac sprue

HTLV = human T-cell lymphotropic virus.

Primary sclerosing cholangitis is associated with both ulcerative colitis and Crohn's disease of the colon ( Chapter 144 ). Between 70 and 90% of patients with primary sclerosing cholangitis have clinical or microscopic colitis, and between 1.3 and 13% of patients with colitis have primary sclerosing cholangitis. Inflammatory bowel disease usually precedes primary sclerosing cholangitis, but in some cases the colitis is asymptomatic and discovered only by subsequent colonoscopy and biopsy. There is also a crossover syndrome between primary sclerosing cholangitis and primary autoimmune hepatitis ( Chapter 152 ).

Clinical Manifestations

The most common laboratory finding is an elevated alkaline phosphatase level, which is present in 90% of patients, and mildly elevated aminotransferase levels. The bilirubin level is initially normal in 60% of patients but increases over time and is an important prognostic factor. Autoantibodies, including antinuclear antibodies and anti–smooth muscle antibodies, are seen in 22% of patients, but a positive antimitochondrial antibody (AMA) is rare and suggests PBC. Perinuclear antineutrophilic cytoplasmic antibody (pANCA) is positive in 90% of patients with primary sclerosing cholangitis and colitis, but pANCA is nonspecific and is also found in ulcerative colitis and in autoimmune hepatitis without primary sclerosing cholangitis.

Diagnosis

The diagnosis is based on pathologic and radiologic findings, and all patients should undergo both liver biopsy and cholangiography. Large duct disease, which is diagnosed most frequently by ERCP or MRCP, includes strictures, beading, and dilation ( Fig. 159-2 ). Liver biopsy shows an obliterative cholangitis with inflammation and characteristic periductular onion ring fibrosis ( Fig. 159-3 ). As the disease progresses, ductopenia and secondary biliary cirrhosis predominate. In stage I, inflammation is confined to the portal tracts; in stage II, there is hepatitis and portal fibrosis; in stage III, bridging fibrosis appears; and stage IV is characterized by biliary cirrhosis and regenerative nodules. Associated conditions include pancreatitis (15% of patients), perihepatic lymphadenopathy, and cholangiocarcinoma (27 to 41% of patients at autopsy or transplantation).

Endoscopic retrograde cholangiopancreatography for primary sclerosing cholangitis with contrast injected through a balloon catheter

FIGURE 159-2  Endoscopic retrograde cholangiopancreatography for primary sclerosing cholangitis with contrast injected through a balloon catheter (seen in the lower common duct). The intrahepatic ducts are mainly affected and show diminished arborization (pruning); diffuse segmental strictures alternating with normal-caliber or mildly dilated duct segments (cholangiectases) have resulted in a beaded appearance.  (From Mahadevan U, Bass NM: Sclerosing cholangitis and recurrent pyogenic cholangitis. In Feldman M, Friedman LS, Sleisenger MH [eds]: Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management, 7th ed. Philadelphia, Saunders, 2002, p 1137.)

 Microscopically, this bile duct in a case of sclerosing cholangitis is surrounded by marked collagenous connective tissue deposition

FIGURE 159-3  Microscopically, this bile duct in a case of sclerosing cholangitis is surrounded by marked collagenous connective tissue deposition.  (Reproduced from http://library.med.utah.edu/WebPath/GUIDE/INTRO.html with permission.)

Treatment

No treatment slows disease progression. Medical therapy includes treatment of cholangitis and endoscopic therapy for large strictures via balloon dilation and stent insertion. Surgery is avoided, if possible, because it increases the risk for recurrent cholangitis. Immunosuppressive therapy is not effective. In randomized trials, UDCA (15 mg/kg/day) has improved bilirubin, alkaline phosphatase, and albumin levels but has not provided any definite benefit on survival or time to liver decompensation. Higher doses (20 mg/kg) are often used because some preliminary reports have suggested a better biochemical response to these doses.[1]

Liver transplantation ( Chapter 158 ), which is the only potentially curative therapy, provides an actuarial survival rate of 83% at 1 year and 73% at 5 years. All patients with primary sclerosing cholangitis who undergo transplantation should be screened periodically for colon carcinoma because they have chronic colitis ( Chapter 144 ). Recurrent primary sclerosing cholangitis after transplantation is rare and difficult to distinguish from other causes of bile duct injury. If small (<1 cm), incidental cholangiocarcinomas are found at transplantation, survival is not affected, but larger cholangiocarcinomas (>2 cm) detected in the pretransplant evaluation by CT or magnetic resonance imaging are a contraindication to liver transplantation.

Patients with primary sclerosing cholangitis should be screened for possible cholangiocarcinoma by cholangiography of strictures every 6 to 12 months with brushings and biopsies. If cholangiocarcinoma is detected, patients should be offered surgical resection or radiotherapy ( Chapter 206 ).

Prognosis

The natural history is variable. Some patients have severe recurrent cholangitis, whereas others progress to biliary cirrhosis. The median survival to death or transplantation is approximately 12 years, with a range of up to 21 years. Actuarial survival is greater for asymptomatic patients (10-year survival rate of 80%) than for symptomatic patients (10-year survival rate of 50%).

   Primary Biliary Cirrhosis

Definition

PBC is a slowly progressive obliterative autoimmune cholangiopathy involving the small and medium-sized bile ducts. It leads to ductopenia, progressive fibrosis, cholestasis, and liver failure.

Epidemiology

PBC is predominantly a disease of women (95% of cases) between the ages of 20 and 60. The age- and gender-adjusted prevalence has been estimated at 65 and 12 per 100,000 persons, respectively, for women and men. The incidence of the disease may be increasing, and a U.S. study estimated it at 2.7 per 100,00 person years or 4.5 and 0.7 for women and men, respectively.

Pathobiology

PBC is thought to be an autoimmune disorder, but the mechanism of progressive destruction of the small interlobular ducts is unknown. The disease is slowly progressive and can eventually lead to biliary cirrhosis with portal hypertension and liver failure. The classic histologic finding is the presence of noncaseating granulomas associated with small bile ducts and an overall paucity of bile ducts in the portal tracts. The presence of significant bridging fibrosis or cirrhosis carries a worse prognosis.

Clinical Manifestations

Almost 60% of patients with PBC are asymptomatic at the time of initial diagnosis. The most common symptoms are fatigue (50%) and pruritus (30%). Fatigue is unrelated to the degree of underlying liver injury or cholestasis and can be extremely debilitating. Pruritus is often first noticed in pregnancy but persists after delivery, and many patients are initially referred for dermatologic evaluation.

In addition to the features of cholestasis, multiple clinical syndromes are associated with PBC and are suggestive of an autoimmune origin. Autoimmune thyroid dysfunction ( Chapter 244 ), sicca syndrome ( Chapter 289 ), Raynaud's phenomenon ( Chapter 288 ), and celiac disease ( Chapter 143 ) have all been associated with PBC. Metabolic bone disease can be particularly troublesome because of the long duration of cholestasis; bone density studies are mandatory every 2 years to guide and monitor therapy.

Diagnosis

The most common biochemical abnormality is an elevation in serum alkaline phosphatase, which should be confirmed by an elevated γ-glutamyl transpeptidase and indicates cholestasis. The bilirubin level is not elevated until late in the course of disease, and most of the elevation is usually of conjugated bilirubin. US should be performed to image the biliary tree and confirm the absence of extrahepatic disease. AMA, which has a sensitivity and specificity higher than 95% when the titer is greater than 1:40, can be positive before there is any clinical or biochemical evidence of PBC. Total immunoglobulins are generally normal, but the IgM fraction can be elevated. Liver biopsy is performed to stage the disease and occasionally to confirm the diagnosis, particularly in AMA-negative patients.

Treatment

UDCA therapy reduces intracellular hydrophobic bile acids and may have a cytoprotective effect on cell membranes. Randomized trials show a significant increase in survival after up to 4 years of therapy with UDCA (12 to 15 mg/kg),[2] as judged by time to liver transplantation. The greatest benefit is seen in patients with the most severe disease. Serum bilirubin, alkaline phosphatase, and cholesterol levels improve with UDCA therapy, but treatment does not benefit the fatigue and has a variable effect on pruritus. Side effects are rare, the most common being diarrhea.

There is no definite benefit to steroids, colchicine, or azathioprine. Low-dose methotrexate (2.5 mg three times per week) has been tried, but data are insufficient to support its routine use at this time. PBC is a common indication for liver transplantation ( Chapter 158 ), but there is considerable debate regarding the timing of transplantation.

Prognosis

PBC is a progressive disease, with up to two thirds of asymptomatic patients becoming symptomatic in 2 to 4 years. Median survival is 9.3 years from diagnosis, and the most reliable determinants of prognosis are the height of the serum bilirubin level and the Mayo risk score, a composite score that predicts clinical outcomes and is calculated as R = 0.871 log(e) (bilirubin in mg/dL) + 2.53 log(e) (albumin in g/dL) + 0.039 (age in years) + 2.38 log(e) (prothrombin time in seconds) + 0.859 (edema score of 0, 0.5, or 1). Liver failure develops in 26% of patients by 10 years after diagnosis.

   Vanishing Bile Duct Syndromes

Vanishing bile duct syndromes are characterized by a paucity of intrahepatic bile ducts and by eventual cholestasis and biliary cirrhosis. Causes include PBC, primary sclerosing cholangitis, autoimmune hepatitis ( Chapter 152 ), graft-versus-host disease, chronic liver allograft rejection ( Chapter 158 ), ischemia, intrahepatic chemotherapy, drug toxicity (e.g., ampicillin, amoxicillin, flucloxacillin, erythromycin, tetracycline, doxycycline, cotrimoxazole), human immunodeficiency virus infection ( Chapter 413 ), sarcoidosis ( Chapter 95 ), idiopathic or paraneoplastic bile duct paucity, and histiocytosis. Almost all these conditions are accompanied by chronic cholestasis and elevated alkaline phosphatase levels. Treatment is for the complications of cholestasis, and UDCA (15 mg/kg) is given to increase bile flow. Most of these conditions are slowly progressive and result in biliary cirrhosis, which ultimately requires liver transplantation.

   GALLSTONE DISEASE

Definition

There are three different types of gallstones: cholesterol gallstones, mixed gallstones, and pigment stones, which can be further divided into black and brown stones. Cholesterol and mixed stones account for 80% of gallstone disease in the United States. Cholesterol stones contain more than 70% cholesterol, whereas mixed stones also contain significant amounts of pigments such as bilirubin. Black pigment stones, which are generally associated with hemolytic diseases, contain calcium salts, bilirubin, and proteins. Brown pigment stones are more common in Asia, where they are associated with intrahepatic cholangitis and infection; in the United States, brown stones are seen after cholecystectomy, especially when manifested as choledocholithiasis.

Epidemiology

Approximately 30 million people in the United States have gallstones, and the estimated annual cost of gallstone disease is $15 billion. In Europe, large ultrasound studies in subjects between 30 and 65 years of age have shown gallstones in 18.8% of women and 9.5% of men. In a study in which 1930 subjects were monitored for 10 years, the cumulative incidence of new stones was 4.6%.

Age is a major risk factor for gallstone disease ( Table 159-6 ); less than 2% of cholecystectomies for gallstones are performed in children, usually because of hemolytic diseases. However, the increased prevalence of obesity in children may result in an earlier incidence of gallstone disease.

TABLE 159-6   -- RISK FACTORS FOR GALLSTONE DISEASE

   Age
   Female gender
   Parity
   Obesity
   Rapid weight loss
   Hypertriglyceridemia
   Genetic (e.g., Pima Indians, Chileans)
   Medications: estrogen, clofibrate, ceftriaxone, Sandostatin
   Terminal ileal resection
   Gallbladder hypomotility: pregnancy, diabetes, after vagotomy
   Somatostatinoma
   Total parenteral nutrition
   Spinal cord injury

The age-adjusted female-to-male ratio for gallstone disease is 2.9 between the ages of 30 and 39 years, but it decreases to 1.2 between the ages of 50 and 59 years. Women with gallstone disease also appear to be more likely than men to undergo cholecystectomy. Pregnancy appears to be the major risk factor for the increased prevalence of gallstones in younger women, with a prevalence of 1.3% in nulliparous women versus 13% in multiparous women. Estrogen use is also associated with a higher risk for symptomatic gallstones and cholecystectomy: a relative risk of 2.1 to 3.7 versus no estrogen use. The mechanisms of increased risk include activation of estrogen α-receptor–mediated hepatic cholesterol secretion, a progesterone-induced reduction in gallbladder contraction, and a pregnancy-induced alteration in hydrophobic/hydrophilic bile salt balance.

Obesity increases the risk for gallstones as a result of enhanced cholesterol absorption, synthesis, and secretion. The risk is higher in women and in the morbidly obese, but rapid weight reduction by very low calorie diets is also associated with gallstones. Diets high in polyunsaturated and monounsaturated fats may reduce the risk for gallstone disease.

Pathobiology

Gallstone disease is predominantly an inability to maintain free cholesterol in solution in bile. As canalicular bile passes down the bile duct system, cholangiocytes maintain bile flow and volume by secreting chloride, bicarbonate, and water into bile. In cystic fibrosis ( Chapter 89 ), defects in the cystic fibrosis transmembrane conductance regulator, which in the liver is found only on cholangiocytes, reduces choleresis and results in the formation of mucous plugs with subsequent focal biliary cirrhosis and gallstone disease.

The gallbladder, which acts as the final storage reservoir for bile, concentrates bile by removing water and thereby increasing the lipid concentration from 3 g/dL in hepatic bile to 10 g/dL in gallbladder bile. Bile salt concentrations can be as high as 300 mM and would digest the biliary epithelium if the gallbladder did not secrete mucin for protection. The gallbladder mucosa also secretes hydrogen ions to prevent calcium salt deposition and maintain a bile pH of about 6.5. A normal gallbladder ejects 10 to 20% of its contents in response to duodenal-gallbladder enteric nervous stimulation. Postprandially, duodenal lipids cause about a 70% contraction of the gallbladder mediated by both the enteric nervous system and cholecystokinin. Impaired contractility is one of the critical steps in the pathogenesis of gallstones.

Genetics

Family history studies have shown that gallstones are twice as common in first-degree relatives of gallstone patients as in age- and sex-matched control subjects. In the United States, descendants of the original Amerindians have a markedly increased prevalence of gallstones, with the highest rates in female Pima Indians older than 25 years, who have a 75% prevalence of cholesterol gallstones. Amerindians in South America and Mexico also have a very high prevalence of gallstones, and these populations have the highest rate of complications of gallstone disease, such as gallbladder cancer, in the world. South Americans of Hispanic origin have much lower rates of gallstone disease.

No specific gallstone genes have been found in humans, but lithogenic genes, including the bile salt export pump gene, have been described in gallstone-susceptible mice. Human gallstone disease is probably a combination of complex multigene susceptibility and environmental factors.

Cholesterol Gallstones

Cholesterol gallstones contain 50 to 90% cholesterol and are the most common form of stones in countries with a Western diet that is high in protein and fat. Cholesterol is an intensely hydrophobic molecule that can remain soluble in aqueous solution only as saturated micelles and vesicles in conjunction with bile salts and lecithin. Cholesterol in gallbladder bile is found in multiple phases; in the presence of cholesterol supersaturation, unstable cholesterol vesicles nucleate to form cholesterol crystals ( Fig. 159-4 ). Nucleation is promoted by a variety of factors, including proteins and lipids.

Equilibrium phase diagram for a lithogenic model bile system with a total lipid content of 10 g/dL.

FIGURE 159-4  Equilibrium phase diagram for a lithogenic model bile system with a total lipid content of 10 g/dL.

Increased biliary secretion of cholesterol results in cholesterol supersaturation of bile. The result is excess secretion of mucus into the gallbladder, formation of a gel layer, and stasis, which causes cholesterol to nucleate and cholesterol crystals to be deposited.

Cholesterol monohydrate crystals are only several hundred micrometers in size and should easily be expelled through the cystic duct. However, the mucous sludge containing calcium salts, bilirubin, mucin, and crystals is not easily expelled by contraction of the gallbladder. Biliary sludge, also known as microlithiasis, can be seen as an echogenic, freely mobile mass in the gallbladder on US. Biliary sludge can cause the symptoms of gallstone disease, including cholecystitis, cholangitis, and pancreatitis.

Biliary sludge can resolve, persist, or progress to stones when its crystals grow to form plates, in part because of an impairment in gallbladder contractility. Cholesterol supersaturation of bile is associated with increased absorption of cholesterol by the gallbladder smooth muscle, a process that impairs smooth muscle contractility and reduces the response of the gallbladder to cholecystokinin.

Pigment Gallstones

Black pigment stones contain 10 to 90% calcium bilirubinate in combination with a variety of other calcium salts, such as hydroxyapatite and carbonate. These stones are common in India (40%) but rare in Minnesota (5%). Older age is associated with a higher incidence of pigment stones, as are total parenteral nutrition and hemolytic diseases.

Brown pigment stones represent 30% of gallstones in Japan and up to 90% of gallstones in rural China. They are related to low-calorie, high-vegetable diets, occur in both the biliary tract and the liver, and have a strong association with recurrent pyogenic cholangitis and cholangiohepatitis. In the United States, these stones are seen as postcholecystectomy cholelithiasis, presumably secondary to stasis and infection. Bacterial enzymes deconjugate bilirubin from its glucuronide and hydrolyze phospholipids, thereby leading to precipitation of calcium, bilirubin, and free fatty acids. These stones, which are often soft and easy to crush endoscopically, are commonly treated by endoscopic extraction.

Clinical Manifestations

The symptoms caused by gallstones are often nonspecific and include nausea, bloating, and right upper quadrant pain. Biliary pain, which is described as an intermittent right upper quadrant or epigastric pain occurring 15 to 30 minutes after a meal, often with radiation to the back, is unpredictable, severe, and usually constant rather than a true colic. The pain persists for 3 to 4 hours and may be associated with nausea and vomiting. In uncomplicated cholecystitis, fever and leukocytosis are absent, the pain can usually be adequately treated with a single dose of narcotic analgesics or nonsteroidal anti-inflammatory agents (NSAIDs), and the pain generally subsides within 6 hours. Attacks of colic may be separated by days or months.

Diagnosis

Asymptomatic Gallstones

Asymptomatic gallstones, which are frequently diagnosed by US performed for other indications, account for about 85% of gallstones. Patients with asymptomatic stones have a similar incidence of nonspecific symptoms of nausea and bloating as the general population, and complications of gallstone disease rarely develop. Biliary colic, however, is more predictive of gallstones, and it is an indicator of increased risk for cholecystitis or other complications. Because the current standard of care is to treat only symptomatic stones, it is critically important to determine whether any symptoms are related to gallbladder stones.

Among patients with asymptomatic stones, biliary colic develops in about 2 to 3% annually. In the absence of antecedent symptoms, complications of gallstone disease, such as acute cholecystitis, develop at a rate of less than 1% per year. As a result, the recommendation is to reserve cholecystectomy until after biliary colic develops, with prophylactic or incidental cholecystectomy recommended only for Amerindians, transplant recipients, or patients with sickle cell anemia, morbid obesity, an anomalous pancreatic ductal junction, a porcelain gallbladder, or gallbladder polyps larger than 1 cm (see Cholecystectomy).

Acute Calculous Cholecystitis

Acute cholecystitis, which is the most common serious complication of gallstone disease, can lead to a variety of complications, including perforation of the gallbladder, peritonitis, fistula into the intestine or duodenum with gallstone ileus or obstruction, and abscesses in the liver or abdominal cavity. Acute cholecystitis is caused by obstruction of the cystic duct, and the ensuing increased intraluminal pressure can lead to vascular compromise of the gallbladder. Salmonella and other less common microorganisms such as Vibrio cholerae, Leptospira, and Listeria can cause primary cholecystitis. Clinical differentiation of biliary colic from acute cholecystitis is difficult but can usually be made from clinical and radiologic findings ( Table 159-7 ).

TABLE 159-7   -- CLINICAL FEATURES OF BILIARY COLIC COMPARED WITH ACUTE CHOLECYSTITIS

Clinical Findings Biliary Colic Acute Cholecystitis
Right upper quadrant pain Present Present
Abdominal tenderness Absent or mild Moderate to severe, especially over the liver and/or gallbladder (Murphy's sign)
Fever Absent Usually present
Leukocytosis Absent Usually >11,000/μL
Duration of symptoms <4 hr > 6 hr
Ultrasound Gallstones Gallstones, thickening of the gallbladder wall
HIDA scan Gallbladder visualized within 4 hr No filling of the gallbladder

HIDA = hepatobiliary iminodiacetic acid.

Blood Tests

In uncomplicated acute cholecystitis, laboratory testing usually shows leukocytosis but otherwise is not very helpful. Elevated liver enzyme levels, hyperbilirubinemia, and elevated amylase or lipase levels are not common in cholecystitis and suggest other complications of gallstone disease, such as cholangitis or pancreatitis. When acute cholecystitis is accompanied by an inflammatory mass, the gallbladder can compress the common duct and lead to bile duct obstruction (Mirrizzi's syndrome).

Imaging Studies

Right upper quadrant US noninvasively diagnoses gallstones in 95% of patients with cholecystitis ( Fig. 159-5 ). US can also exclude common bile duct obstruction and may occasionally show bile duct stones. In cholecystitis, the gallbladder wall may be thickened, and free pericholecystic fluid may be present. Murphy's sign is also useful and can be elicited by the ultrasonographer or on physical examination. Gentle pressure is placed by the probe or hand at the border of the rectus sheath in the right upper quadrant, and the patient is asked to inspire. The gallbladder moves down with inspiration onto the examiner's hand or ultrasound probe, and the patient complains of pain when the inflamed gallbladder comes into contact with the examining hand. US can also exclude gangrenous cholecystitis with free air in the gallbladder wall, perforation, and abscess. The most specific test for acute cholecystitis is a technetium-labeled hepatobiliary iminodiacetic acid (HIDA) scan. Intravenously, HIDA is normally taken up by the liver, excreted into the biliary tract, and concentrated in the gallbladder. When a stone obstructs the cystic duct, the gallbladder fails to fill with HIDA; the sensitivity of HIDA scan is 95%, but the specificity varies markedly and can be as poor as 50% in critically ill or jaundiced patients.

 Ultrasound showing a gallstone

FIGURE 159-5  Ultrasound showing a gallstone.

Treatment
Medical Stabilization of Acute Cholecystitis

Treatment of uncomplicated acute cholecystitis is intravenous fluids, antibiotics for 7 to 10 days, and bowel rest. Antibiotic choices include ampicillin (2 g intravenously every 6 hours) and an aminoglycoside (gentamicin, 5.1 mg/kg every 24 hours), but cephalosporins (ceftriaxone, 1 to 2 g once daily) and ampicillin-sulbactam (1.5 to 3 g every 6 hours) can also be used. Broader coverage should be used in immunosuppressed patients, including the addition of metronidazole (500 mg every 8 hours), piperacillin-tazobactam (3.375 g every 6 hours), and levofloxacin (500 mg to 1 g once daily). Early cholecystectomy (at the time of first admission) is generally recommended.[3]

Cholecystectomy

Indications for cholecystectomy include biliary colic, acute and chronic cholecystitis, and acalculous cholecystitis. Diabetic patients may have fewer symptoms because of their neuropathy, so their cholecystitis may more frequently be complicated by gangrene and perforation; however, prophylactic cholecystectomy is not recommended in patients with diabetes.

Laparoscopic cholecystectomy has now all but replaced conventional open cholecystectomy as the procedure of choice for gallstones. Advantages of laparoscopic cholecystectomy include less pain, early discharge (usually 1 day after the procedure), fewer wound infections, earlier return to work, and lower cost. A planned laparoscopic approach is changed to open cholecystectomy in only 3% of cases, usually because of difficulty identifying critical anatomic structures such as the cystic or common bile ducts.

Operative cholangiography can be performed during laparoscopic cholecystectomy, and bile duct stones can be removed concurrently or subsequently by ERCP. The incidence of unsuspected, retained common bile duct stones after laparoscopic cholecystectomy is about 2.3%.

The most serious complication of laparoscopic cholecystectomy is bile duct injury, which now occurs in 0.25% of cases, is more common when the indication for surgery is acute cholecystitis, and is less common after a surgeon has performed more than 25 laparoscopic surgeries. Bile duct injuries include cystic duct leak, laceration of the duct, complete transection of the duct, and thermal injuries to the duct. Early recognition permits primary open bile duct repair. Leakage from the cystic duct is usually recognized as jaundice, fever, and abdominal pain several days after the procedure; it can be treated successfully by ERCP with insertion of an endoscopic stent or by sphincterotomy.

Gallstone Dissolution Therapies

In patients who have relative or absolute contraindications to laparoscopic cholecystectomy, such as concomitant advanced cardiopulmonary or liver disease, a combination of chenodeoxycholic acid (10 mg/kg/day) with UDCA (7 to 15 mg/kg/day) or UDCA alone (15 mg/kg/day) can dissolve multiple small (<5 mm) stones in up to 60% of patients with a functioning gallbladder. If CT shows the stones to be calcified, the efficacy is lower, and complete dissolution occurs in only about 10% of patients. Gallstones generally dissolve at a rate of 1 mm/mo. After dissolution, gallstones recur at a rate of 10% per year for 5 years, but recurrence is unusual after that time. Continuous therapy may be necessary, thereby making this therapy unattractive except in selected patients in whom cholecystectomy cannot be performed safely.

Extracorporeal shock wave lithotripsy, which uses a focused ultrasound beam, can fragment larger stones. The fragmented stones can be passed through the cystic duct and expelled into the common bile duct. The fragments that remain behind in the gallbladder should be treated with UDCA for dissolution. Gallstones disappear in more than 50% of patients, but they recur in 50% of successfully treated patients, particularly those with multiple stones and poorly functioning gallbladders.

Topical dissolution therapy involves the insertion of a catheter into the gallbladder under ultrasound guidance; stones are dissolved with methyl terbutyl ether or ethyl propionate. The technique is still experimental but may soon be ready for widespread testing.

    Choledocholithiasis

Common bile duct stones can descend from the gallbladder or arise de novo in a tortuous, dilated common bile duct as a result of infection and biliary stasis (usually cholesterol stones), or they can occur in a postcholecystectomy patient (usually brown stones), in whom they are frequently missed at surgery (2% of cholecystectomies). The clinical findings are cholangitis, pancreatitis, or biliary obstruction; large, obstructing stones can cause jaundice.

Acute bacterial cholangitis, which is most frequently caused by common duct stones that obstruct the common bile duct and raise intrabiliary pressure, is a medical emergency. The bile in these patients is generally infected with Escherichia coli, Bacteroides, Klebsiella, or Clostridium species, and the increase in pressure results in transient bacteremia.

Diagnosis

Patients with bacterial cholangitis have Charcot's triad of jaundice, abdominal pain, and fever with rigors. Severe renal dysfunction and disseminated intravascular coagulation can complicate severe cholangitis. Aminotransferase, bilirubin, and alkaline phosphatase levels are usually increased. The diagnosis of common bile duct stones can be made with US, which generally shows dilated bile ducts and occasionally identifies a stone. MRCP can identify 95% of stones larger than 1 cm ( Fig. 159-6 ). ERCP remains the “gold standard” for the diagnosis and treatment of common bile duct stones. If cholangitis is suspected, ERCP should be performed.