Cholestasis

Cholestasis is defined as a decrease in bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow through intra-or extrahepatic bile ducts. Therefore, the clinical definition of cholestasis is any condition in which substances normally excreted into bile are retained. The serum concentrations of conjugated bilirubin and bile salts are the most commonly measured.

Not all substances normally excreted into bile are retained to the same extent in various cholestatic disorders. In some conditions, serum bile salts may be markedly elevated while bilirubin is only modestly elevated and vice versa. However, demonstrable retention of several substances is needed to establish a diagnosis of cholestasis. Only in rare disorders of bilirubin metabolism (eg, Dubin-Johnson syndrome, Rotor syndrome) does an isolated increase in the serum concentration of conjugated bilirubin appear, so increased serum conjugated bilirubin indicates cholestasis. The histopathologic definition of cholestasis is the appearance of bile within the elements of the liver, usually associated with secondary cell injury.

The mechanisms of cholestasis can be broadly classified into hepatocellular, where an impairment of bile formation occurs, and obstructive, where impedance to bile flow occurs after it is formed. The typical histopathologic features of hepatocellular cholestasis include the presence of bile within hepatocytes and canalicular spaces, in association with generalized cholate injury. Typical of obstructive cholestasis is bile plugging of the interlobular bile ducts, portal expansion, and bile duct proliferation in association with centrilobular cholate injury.[1]

Bile is a highly complex water-based medium containing inorganic ions and many classes of organic amphiphiles, the formation of which involves multiple mechanisms and levels of regulation. The transport of solute into the canaliculus by specific transporters creates chemical and osmotic gradients and promotes water flow by a paracellular pathway. Several of these specific transporters have been identified, and their function has been characterized. The identification of defective transporters in some familial cholestatic disorders has led to improved understanding of the molecular mechanisms of human cholestasis.[2, 3, 4]

Redundancies in the mechanisms of solute transport that result in bile formation are noted. From what is currently known about the process, seemingly few, if any, of the known transporters are absolutely essential in the process. Therefore, the absence or impairment of a single transporter is not expected to result in failure of bile formation. Instead, a process of amplification is required to produce clinical cholestasis. A primary mechanism of amplification is the retention of hydrophobic bile salts, strong detergents that cause membrane injury and impairment of membrane function. Retained bile salts down-regulate new bile acid synthesis, which results in a reduction of the bile salt pool and in reduced enterohepatic recirculation.

Retention of cholesterol results in increased cholesterol content of membranes that reduces their fluidity and impairs the function of integral membrane proteins. These amplification mechanisms result in further retention of damaging substances, accelerated membrane injury and dysfunction, and ultimately, generalized failure of the excretory mechanism for bile. This converging pathway makes the differentiation of cholestatic diseases on clinical grounds very difficult.

Obstructive cholestasis is usually the result of physical obstruction of the biliary system at the level of the extrahepatic bile ducts. However, obstruction or paucity of small bile ducts can result in functional obstruction of the entire biliary system. This may be the mechanism involved in the cholestasis observed in Alagille syndrome, which is associated with heart, skeleton, eye, kidney, and facial manifestations. The prognosis mainly depends on the severity of the liver and heart diseases.

Retention of bile salts results in injury to biological membranes throughout the body. The liver is most affected. The retention of hydrophobic bile salts results in their incorporation into membranes, which alters membrane fluidity and function. Bile salt injury of hepatocyte membranes is an important amplifier of cholestasis. The retention of secondary cholestatic bile acids, such as lithocholic acid, results in further membrane injury. 

Owing to an immaturity of hepatobiliary function, the number of distinct disorders presenting with cholestatic jaundice may be greater during the neonatal period than at any other period. The differential diagnosis of cholestasis in neonates and infants is therefore much broader than in older children and adults. This is because the immature liver is relatively sensitive to injury, and the response of the immature liver is more limited. Cholestasis develops in response to a wide variety of insults. Although the reasons for this are not entirely clear, it is considered the result of immaturity of several critical mechanisms of bile formation. So-called physiologic cholestasis of infancy results from immaturity of these mechanisms. Early enteral feedings as tolerated is the best way to prevent and manage cholestasis in preterm infants.[5]

The effects of cholestasis are profound and widespread. Although the principal effects involve the function of the liver and intestine, secondary effects can involve every organ system. The primary effects are bile retention, regurgitation of bile into serum, and reduction in bile delivery to the intestine. These result in secondary effects that lead to worsening liver disease and systemic illness.

Retention of Conjugated Bilirubin and Its Regurgitation Into Serum

Excretion of conjugated bilirubin is the rate-limiting step of bilirubin clearance. During cholestasis, conjugation of bilirubin continues but excretion is reduced. The mechanism by which conjugated bilirubin regurgitates into serum is unclear, but it may differ according to the disease etiology. In hepatocellular cholestasis, where bile formation is reduced, conjugated bilirubin is likely to efflux directly from the hepatocyte via diffusion or vesicular exocytosis. On the other hand, in obstructive cholestasis, conjugated bilirubin possibly enters the canalicular space and effluxes back through a weakened tight junction.

The presence of elevated serum concentration of conjugated bilirubin is a principal sign of cholestasis. It results in jaundice, which can be detected by scleral icterus at a concentration as low as 2 mg/dL, and by dark urine. The concentration of conjugated bilirubin is affected by the rate of production of bilirubin, the degree of cholestasis, and alternate pathways of elimination, principally renal excretion. The magnitude of elevation is not diagnostically important because it does not reflect the type or degree of cholestasis. For example, whereas other investigations clearly indicate that patients with neonatal giant cell hepatitis typically have more bile flow than patients with biliary atresia, the serum conjugated bilirubin concentration is usually higher in neonatal giant cell hepatitis. This probably reflects an increase in bilirubin production.

Alternate elimination pathways, principally by way of the kidneys, limit the absolute elevation of conjugated bilirubin. Conjugated bilirubin concentration rarely exceeds 30 mg/dL, although such elevated levels can occur. Because conjugated bilirubin is relatively weakly bound to albumin, it can dissociate relatively easily and be filtered into the urine. The parents of children with cholestasis frequently report dark urine or a stained diaper, and examination of the urine is a useful starting point in the evaluation of an infant with jaundice.

Increased Serum Concentration of Nonconjugated Bilirubin

Increased serum concentration of nonconjugated bilirubin is present in most patients with cholestasis. The rate of bilirubin conjugation is probably reduced by end-product inhibition or as the result of hepatocyte injury. The rate of bilirubin production may also be increased as the result of hemolysis that can accompany cholestasis.

Newer methods of measuring bilirubin in serum have resulted in the discovery of a fraction of serum bilirubin that is covalently bound to albumin, known as delta bilirubin or biliprotein. This fraction may account for a large proportion of total bilirubin in patients with cholestatic jaundice but is absent in patients with nonconjugated hyperbilirubinemia.

Hypercholemia

Hypercholemia, or increased serum bile salt concentration, is a universal consequence of cholestasis. The transport of bile salts from plasma to bile is the principal driving force for bile formation. Failure to transport bile salts may be a principal mechanism of cholestasis or may be a consequence of the effects of cholestasis on hepatocyte function. In either case, the liver cell retains bile salts, resulting in down-regulation of new bile acid synthesis and in an overall reduction in the total pool size. Bile salts are regurgitated from the hepatocyte, which results in an increase in the concentration of bile salts in the peripheral circulation. Furthermore, the uptake of bile salts entering the liver in portal vein blood is inefficient, which results in spillage of bile salts into the peripheral circulation.

Overall, patients with cholestasis have an increase in serum concentration of bile salts, an increase in hepatocyte concentration of bile salts, a decrease of bile salts in the enterohepatic circulation, and a decrease in the total bile salt pool size.

Pruritus

One very common clinical consequence of cholestasis is pruritus. Several links to its pathogenesis have been proposed, including the role of bile acids, endogenous opioid and serotonins, and lysophosphatidic acid. The mechanism of pruritus in liver disease is not entirely understood, and major debate concerns its relationship to the retention of bile salts. The serum or tissue concentrations of bile salts do not correlate well with the degree of pruritus, although all patients with pruritus related to liver disease have significant elevations of serum bile salts. Therapeutic approaches that reduce pruritus generally also reduce serum bile salt concentrations.

Newer theories suggest that patients have differing sensitivities to elevated bile salt concentrations, which act on peripheral pain afferent nerves to produce the sensation of itching. This stimulation involves opiate-mediated pathways, and opiate antagonists can block cholestasis-associated itching. Itching does not appear to be associated with histamine release, and antihistamine therapy is generally ineffective. Ultraviolet B phototherapy has been successfully used to treat pruritus.

Decock et al have reported that ultraviolet B phototherapy appears to be a promising and well-tolerated treatment for cholestasis-associated pruritus.[6]

For patients with cholestasis, pruritus may be a minimal problem, or it may seriously impair the quality of life. Scratching is the most measurable effect of pruritus. The degree of pruritus can be quantitated by clinical findings related to scratching, which has been useful in monitoring patient response to therapy.

Hyperlipidemia

Hyperlipidemia is characteristic of some but not all cholestatic diseases. Serum cholesterol is elevated in cholestasis because its metabolic degradation and excretion are impaired. Bile is the normal excretory pathway for cholesterol, and with reduced bile formation, cholesterol is retained. Cholesterol retention can cause an increase in membrane cholesterol content and a reduction in membrane fluidity and membrane function, thereby amplifying the cholestasis. Furthermore, bile salts are the metabolic products of cholesterol, and in cholestasis, synthesis of bile salts is reduced. Much of plasma cholesterol is in the form of lipoprotein-X, an abnormal lipoprotein observed only in the serum of patients with cholestasis.

The contribution of dietary cholesterol to the elevated serum cholesterol in patients with cholestasis is probably minimal, and limiting the diet in order to reduce serum cholesterol is not justified because that maneuver may have secondary effects on nutrition. Furthermore, the use of oral bile salt–binding agents, such as cholestyramine, has little effect on serum cholesterol in this setting. Agents that block the synthesis of cholesterol have been used sparingly in cholestasis and cannot be recommended at this time. The proper approach to treating hypercholesterolemia in cholestatic liver disease is to treat the liver disease itself.

Xanthomas

Xanthomas may result from the deposition of cholesterol into the dermis. The development of xanthomas is more characteristic of obstructive cholestasis than of hepatocellular cholestasis. Xanthomas may develop rapidly over a few months in acute extrahepatic biliary obstruction. Acutely developing xanthomas are usually the eruptive type, which are white pustular lesions pinpoint to 2 mm in diameter, that appear first on the trunk and in the diaper area. See the image below.

Failure to Thrive

One of the major clinical effects of cholestasis, particularly chronic cholestasis, is failure to thrive. The mechanisms of failure to thrive include malabsorption, anorexia, poor nutrient use, hormonal disturbances, and secondary tissue injury. Malabsorption in cholestatic liver disease results from reduced delivery of bile salts to the intestine, which results in inefficient digestion and absorption of fats. Digestion is affected because bile salts are important for the function of bile salt–dependent lipase activity and the stabilization of the lipase-colipase complex. In addition, bile salts are important in stabilization of lipid emulsions, which is important for increasing the surface area on which lipase works.

Absorption is inefficient because of reduced formation of intestinal micelles, which are important for removing the end products of lipolysis and effecting their absorption. The result of these events is the malabsorption of fat and fat-soluble vitamins.

Malabsorption of fat results in the loss of a source of calories that is important in infant nutrition. Furthermore, the delivery of fat into the colon can result in colonic secretion and diarrhea. Adults with fat malabsorption often experience anorexia. This may also occur in infants, but more often, infants take increased amounts of formula to compensate for loss of calories. Finally, the loss of fat into the stool also results in calcium wasting through the formation of calcium soaps of fatty acids. This may play an important role in bone disease in children and adults with chronic cholestasis.

The treatment of fat malabsorption principally involves dietary substitution. In older patients, a diet that is rich in carbohydrates and proteins can be substituted for a diet containing long-chain triglycerides. In infants, substitution may not be possible, and the substitution of a formula containing medium-chain triglycerides may improve fat absorption and nutrition.

The malabsorption of fat-soluble vitamins can result in vitamin deficiency states. Vitamins E, D, K, and A are all malabsorbed in cholestasis, and in that order.[7] Vitamin E deficiency can result in peripheral neuropathy and possibly hemolysis. Vitamin D deficiency results in osteomalacia and rickets. Vitamin K deficiency causes coagulopathy and possibly reduced brain development. Vitamin A deficiency does not result in clinical disease in cholestasis. In chronic cholestasis, careful attention must be paid to prevent fat-soluble vitamin deficiencies. This is accomplished by administering fat-soluble vitamins and monitoring the response to therapy.

Mortality/Morbidity

Cholestasis is not a primary cause of death. However, it is the cause of considerable morbidity as indicated above in Pathophysiology.

Sex

No clear difference in the incidence of cholestasis between males and females is observed. Incidence is equal in most genetic diseases leading to cholestasis. However, several conditions have a female dominance, including biliary atresia,[8] drug-induced cholestasis, and of course, cholestasis of pregnancy.

Age

Cholestasis is observed in people of every age group. However, newborns and infants are more susceptible and more likely to develop cholestasis as a consequence of immaturity of the liver.

Young gestational age, low birth body weight, more sepsis episodes, and long duration of parenteral nutrition are risk factors associated with parenteral nutrition-associated cholestasis.[9]

Patients with cholestasis may present clinically in many different ways depending on the disease process.

In most cases, scleral icterus is noted before any other sign; it may be apparent at conjugated bilirubin levels as low as 2 mg/dL.

At higher levels of conjugated bilirubin, dark urine may be noted secondary to the filtering of bilirubin into the urine. Cutaneous jaundice may not be noted until bilirubin levels reach 5 mg/dL or higher.

In patients with cholestasis, another common presentation is severe pruritus secondary to elevated bile acids. At high concentrations (5 times the reference range), retained bile acids can cause severe pruritus in which patients are unable to sleep or concentrate and may resort to cutaneous mutilation for relief.

As noted above, the physical signs of cholestasis are usually scleral icterus or cutaneous jaundice, or both. These patients may have physical evidence of scratching or excoriation if they also have severe bile acid retention.

Xanthomas look like small white papules or plaques and are usually found on the trunk and diaper area and in areas of friction (eg, diaper line, creases of hands, elbows, neck).

Another important physical finding in patients with cholestasis may be evidence of failure to thrive with altered anthropometrics, such as reduced height and reduced weight for height due to fat malabsorption.

Causes include the following:

• Obstructive cholestasis

  • Biliary atresia

  • Congenital bile duct anomalies (choledochal cysts)

  • Cholelithiasis

  • Primary sclerosing cholangitis

  • Infectious cholangitis (cholangitis)

  • Cholangitis associated with Langerhans cell histiocytosis

  • Alagille syndrome

  • Nonsyndromic ductal paucity

• Hepatocellular cholestasis

  • Hepatitis (hepatitis A, hepatitis B, hepatitis C)

  • Alpha1-antitrypsin deficiency

  • Inborn errors of bile acid synthesis

  • Drug-induced cholestasis

  • Total parenteral nutrition (TPN)–associated cholestasis

  • Progressive familial intrahepatic cholestasis[10, 11, 12, 13, 14]

Serum bilirubin levels are elevated in virtually all patients with cholestasis.

Total serum bile salt concentration levels are elevated in virtually all cholestatic diseases.

Qualitative serum and urine bile acids by mass spectroscopy are used to identify genetically determined errors in bile acid synthesis.

The total serum cholesterol level is elevated in virtually all obstructive cholestatic diseases, whereas the high-density lipoprotein (HDL) level is within the reference range or low. Total cholesterol is within the reference range in certain hepatocellular cholestatic diseases, whereas the HDL level is within the reference range or low.

Serum lipoprotein-X levels are elevated in virtually all obstructive cholestatic diseases.

Serum alkaline phosphatase levels, serum 5'-nucleotidase levels, and serum gamma-glutamyl transferase (GGT) levels are elevated in virtually all obstructive cholestatic diseases and most hepatocellular cholestatic diseases.

Ultrasonography of liver and bile ducts is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones).

Abdominal CT scanning is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones).

Biliary nuclear medicine study (ie, hepatoiminodiacetic acid [HIDA] scanning) is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones) and to differentiate between obstructive and hepatocellular cholestasis (ie, biliary atresia versus neonatal hepatitis).

Endoscopic retrograde cholangiography is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones).

Percutaneous transhepatic cholangiography is used to identify anatomic causes of obstructive cholestasis (eg, choledochal cyst, gallstones).

Liver biopsy is the single most useful test to determine the cause of cholestasis but requires a high degree of expertise in interpretation.

Exploratory surgery is a very useful tool for diagnosing neonatal cholestasis. Older literature suggested that exploratory surgery placed patients with neonatal hepatitis at risk, but this is not the case with modern anesthesia and surgical techniques. If surgical disease is in question, initiate exploratory surgery to provide a definitive demonstration of bile duct anatomy. In institutions with less experience and expertise, perform exploratory surgery more frequently, rather than less so.

Operative cholangiography is simple, straightforward, time-efficient, and definitive.

Many histologic findings are disease specific; therefore, refer to articles about disease states (see Causes). The typical histopathologic features of hepatocellular cholestasis include the presence of bile within hepatocytes and canalicular spaces, in association with generalized cholate injury. Typical of obstructive cholestasis is bile plugging of the interlobular bile ducts, portal expansion, and bile duct proliferation in association with centrilobular cholate injury.

Differentiating between idiopathic neonatal hepatitis and biliary atresia is a diagnostic challenge. With expert evaluation, nothing contributes as much to that differential diagnosis as the findings on percutaneous liver biopsy.

Much medical care in patients with cholestasis is disease specific.

Cholestasis often does not respond to medical therapy of any sort. Some reports indicate success in children with chronic cholestatic diseases with the use of ursodeoxycholic acid (20-30 mg/kg/d), which acts to increase bile formation and antagonizes the effect of hydrophobic bile acids on biological membranes. Phenobarbital (5 mg/kg/d) may also be useful in some children with chronic cholestasis.

Treatment of fat malabsorption principally involves dietary substitution. In older patients, a diet that is rich in carbohydrates and proteins can be substituted for a diet containing long-chain triglycerides. In infants, that may not be possible, and substitution of a formula containing medium-chain triglycerides may improve fat absorption and nutrition. This, however, has not clearly been proven, and therapeutic formulas containing medium-chain triglycerides may not be worth their expense. Bile salt therapy to replace missing bile salts is not practical. Ursodeoxycholic acid, which is used to treat some cholestatic conditions, does not form mixed micelles and has no effect on fat absorption.

In chronic cholestasis, careful attention must be paid to prevent fat-soluble vitamin deficiencies, which are common complications in pediatric patients with chronic cholestasis. This is accomplished by administering fat-soluble vitamins and monitoring the response to therapy. Oral absorbable, fat-soluble vitamin formulation A, D, E, and K supplementation is safe and potentially effective in pediatric patients with cholestasis.

Surgical care is disease specific; therefore, refer to articles about disease states (see Causes).

Referral to a specialist in gastroenterology or hepatology is indicated for any patient with cholestatic liver disease, particularly if it is severe or prolonged.

See Medical Care.

Class Summary

Ursodeoxycholic acid acts to increase bile formation and antagonizes the effect of hydrophobic bile acids on biological membranes.

Ursodeoxycholic acid (Actigall, Urso)

Shown to promote bile flow in cholestatic conditions associated with a patent extrahepatic biliary system. Decreases the cholesterol content of bile and therefore reduces bile stone and sludge formation.

Class Summary

These agents are used to induce hepatic enzyme metabolism in order to decrease serum bilirubin levels in some patients with cholestasis in order to improve function.

Phenobarbital (Luminal)

Mainly used as an anticonvulsant, which interferes with transmission of impulses from thalamus to cortex of brain, resulting in imbalance in central inhibitory and facilitatory mechanisms. Used in cholestasis to induce the CYP450 system in treatment of neonatal hyperbilirubinemia and lowering of bilirubin in chronic cholestasis.

Class Summary

Fat-soluble vitamins A, D, E, and K must be administered as individual supplements to assure proper absorption.

Phytonadione (AquaMEPHYTON)

Vitamin K. Fat-soluble vitamin absorbed by the gut and stored in the liver. Necessary for the function of clotting factors in the coagulation cascade. Used to replace essential vitamins not obtained in sufficient quantities in the diet or to further supplement levels.

Vitamin E (Liqui E)

Vitamin E. Prevention and treatment of hemolytic anemia secondary to vitamin deficiency or need for dietary supplementation. Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects RBC against hemolysis.

Vitamin A (Aquasol A)

Needed for bone development, growth, visual adaptation to darkness, testicular and ovarian function, and as a cofactor in many biochemical processes.

Ergocalciferol (Drisdol, Calciferol)

Vitamin D. Stimulates absorption of calcium and phosphate from small intestine and promotes release of calcium from bone into blood. PO solution comes as 8000 U/mL (200 mcg/mL, 40 U/mcg).

Class Summary

These agents are used to alleviate pruritus caused by cholestasis. They block opioid-mediated pathways of afferent nerves, which may be producing the itching sensation.

Naltrexone (ReVia)

Cyclopropyl derivative of oxymorphone that acts as a competitive antagonist at opioid receptors. Do not administer this medication until the patient is opioid-free for 7-10 d. Available as 50-mg tab.

Class Summary

Bile acid–binding resins form a nonabsorbable complex with bile acids in the intestine, which inhibits enterohepatic reuptake of intestinal bile salts and thereby increases the fecal losses of bile salt–bound low-density lipoprotein cholesterol.

Cholestyramine (Questran, Prevalite)

May use as adjunct in primary hypercholesterolemia. Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts. Dose based on resin content.

Class Summary

Antitubercular agents induce liver enzymes and ameliorate pruritus secondary to cholestasis.

Rifampin (Rimactane, Rifadin)

Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription.

Obeticholic acid (Ocaliva)

It is a framesoid X receptor (FXR) agonist is recommended for the treatment of primary biliary cirrhosis. It has been licensed by the FDA. 

Follow-up care in patients with cholestasis is disease specific; therefore, refer to articles about disease states (see Causes).