eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology
Cholestasis
Updated: Jun 23, 2009
Introduction
Background
Cholestasis is not a disease; rather, it is a symptom of many diseases. It is defined as a pathologic state of reduced bile formation or flow. This definition applies more to the experimental situation, where the rates of bile formation and flow can be measured, than to human cholestasis, where neither can be assessed. 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.
Pathophysiology
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.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. This subject was recently reviewed in depth.
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, often by a stone or tumor. 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.
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. Bile salts may be a mediator of hepatic fibrosis as well. Injury to RBCs can result in spur-cell hemolytic anemia.
Many patients with chronic cholestasis have an asthmalike syndrome, which may be quite severe and unresponsive to conventional asthma therapy. Wheezing disappears with effective therapy of cholestasis, which suggests that it is a secondary event. The authors' opinion is that retention of bile salts results in irritation of respiratory membranes and the asthmalike picture. Patients with chronic cholestasis also have frequent nosebleeds, probably from the same mechanism. These patients may have life-threatening nosebleeds without abnormal coagulation parameters and with no clinically apparent anatomic problem in the nasal airway.
The differential diagnosis of cholestasis in neonates and infants is 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. This is better termed physiologic hypercholemia and is characterized by the elevation of serum bile salt concentrations in healthy infants to a level equal to many adults with pathologic cholestasis. This developmental condition probably helps to establish the infant's sensitivity to various insults that would not produce cholestasis in adults, such as gram-negative sepsis, heart failure, metabolic disease, and exposure to minimally toxic substances.
Because of this, looking beyond the liver for the cause of cholestasis in newborns or young infants is wise. If no other cause is found and liver disease is suspected, a more focused diagnostic investigation can be undertaken.
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. The retention of bile constituents results in 6 clinically important events.
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.1 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. This complex is formed in plasma by a nonenzymatic process that involves acyl migration of bilirubin from its glucuronide ester with the formation of an amide linkage between 1 propionic acid side chain and a lysine residue of plasma albumin. The presence of large quantities of delta bilirubin indicates long-standing cholestasis. Any amount of delta bilirubin in cord blood or the blood of a newborn is an important sign indicating cholestasis that antedates birth.
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.
Reduced flux of bile salts into bile results in reduced delivery into the intestine and reduced enterohepatic recirculation. Because the movement of bile salts in the enterohepatic circulation represents the major driving force for bile formation, the degree of cholestasis is amplified by these events.
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. 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.
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. Scratching leads to abrasions and skin mutilation in some patients. Secondary skin infections can occur. Constantly "scratching the unscratchable itch" has serious consequences. These children experience loss of sleep, attention deficits, poor school performance, and a form of hyperkinesis that may have importance regarding energy balance. The psychological ramifications have not been reported, but older children express helplessness and can become suicidal. Unremitting and untreatable pruritus can be an indication for liver transplantation.
The effects of pruritus are age-dependent. The authors are often asked why young infants with cholestasis do not itch. Confidently, the response is that they do itch but are developmentally incapable of scratching. Scratching involves the use of arms, forearms, and fingers in a coordinated motion that occurs at a typical frequency. The ability to scratch is not yet developed in young infants.
The cutaneous signs of scratching begin to appear, usually around the ears or the nasal bridge, in infants aged 6-7 months. From there, they expand over the head, then the trunk, and finally to the limbs by the time the baby reaches age 12-14 months. The mutilating scratching observed in older patients does not appear until well after the first birthday. The fact that young infants do not scratch does not mean that they do not itch. Cholestatic babies are often irritable and do not socialize well. Young infants with those signs almost invariably proceed to scratching as they age, and irritability probably represents their response to pruritus.
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. Its centrifugation density is similar to a low-density lipoprotein, but the structure is very different. It has a high phospholipid and albumin content and a platelike rouleau structure when viewed under the electron microscope.
The marked elevation of serum cholesterol observed in children with cholestasis, which often exceeds 1,000 mg/dL and sometimes can be as high as 4,000 mg/dL, probably does not have as great an effect on the cardiovascular system as a similar elevation of low-density lipoprotein in familial hypercholesterolemia. This may be because of the packaging of cholesterol into lipoprotein-X, which lacks the surface protein constituents necessary to interact with vascular endothelium. Although it should be considered in a therapeutic strategy, the potential for cardiovascular disease is probably low. Few studies of children with chronic cholestasis have demonstrated accelerated cardiovascular disease.
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.
Eruptive xanthomas. Courtesy of Duke University Medical Center.
Planar xanthomas that occur first around the eyes but also in the creases of the palms and soles and on the neck develop more slowly and are principally observed in chronic cholestasis syndromes. Finally, tuberous xanthomas are associated with very long duration of cholestasis and develop over the extensor surfaces, such as the elbows, Achilles tendons, and knees. These are unusual in pediatric patients.
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 in 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. 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.
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.2 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, 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.
Clinical
History
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 maddening pruritus in which patients are unable to sleep or concentrate and may resort to cutaneous mutilation for relief.
- Infants who are unable to scratch may become very irritable in response to the pruritus. In chronic cholestasis, cholesterol deposits called xanthomas may form in the skin. This may be a visible signal of severe cholestasis. Because of the poor bile flow in patients with cholestasis, they may also have inefficient digestion and absorption of dietary fats. These patients often demonstrate failure to thrive and have problems with fat-soluble vitamin deficiency and steatorrhea.
Physical
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
- Obstructive cholestasis
- Biliary atresia
- Congenital bile duct anomalies (choledochal cysts)
- Cholelithiasis
- Primary sclerosing cholangitis
- Infectious cholangitis (cholangitis)
- Cholangitis associated with Langerhans cell histiocytosis
- Cholestasis with ductal paucity
- Alagille syndrome
- Nonsyndromic ductal paucity
- Ductopenic allograft rejection
- 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 cholestasis3,4,5
More on Cholestasis |
 Overview: Cholestasis |
| Differential Diagnoses & Workup: Cholestasis |
| Treatment & Medication: Cholestasis |
| Follow-up: Cholestasis |
| Multimedia: Cholestasis |
| References |
| Further Reading |
| Next Page » |
References
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Strople J, Lovell G, Heubi J. Prevalence of Subclinical Vitamin K Deficiency in Cholestatic Liver Disease. J Pediatr Gastroenterol Nutr. Jun 3 2009;[Medline].
Hutchin T, Preece MA, Hendriksz C, et al. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) as a cause of liver disease in infants in the UK. J Inherit Metab Dis. Jun 11 2009;[Medline].
Mathias A, Wax JR, Pinette MG, Cartin A, Blackstone J. Progressive familial intrahepatic cholestasis complicating pregnancy. J Matern Fetal Neonatal Med. Jun 1 2009;1-3. [Medline].
Shneider BL. Liver transplantation for progressive familial intrahepatic cholestasis: the evolving role of genotyping. Liver Transpl. Jun 2009;15(6):565-6. [Medline].
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[Guideline] Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. Aug 2004;39(2):115-28. [Medline]. [Full Text].
[Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline]. [Full Text].
Balistreri WF. Neonatal cholestasis. J Pediatr. Feb 1985;106(2):171-84. [Medline].
Elferink RP, Groen AK. The mechanism of biliary lipid secretion and its defects. Gastroenterol Clin North Am. Mar 1999;28(1):59-74, vi. [Medline].
Jones EA, Bergasa NV. The pruritus of cholestasis and the opioid system. JAMA. Dec 16 1992;268(23):3359-62. [Medline].
Kaufman SS, Murray ND, Wood RP. Nutritional support for the infant with extrahepatic biliary atresia. J Pediatr. May 1987;110(5):679-86. [Medline].
Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology. Mar 2006;130(3):908-25. [Medline].
Sabesin SM. Cholestatic lipoproteins--their pathogenesis and significance. Gastroenterology. Sep 1982;83(3):704-9. [Medline].
Suchy FJ. Approach to the infant with cholestasis. In: Liver Disease in Children. 1st ed. St. Louis, Mo:. Mosby;1994:349-355.
Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med. Oct 22 1998;339(17):1217-27. [Medline].
Whitington PF. Chronic cholestasis of infancy. Pediatr Clin North Am. Feb 1996;43(1):1-26. [Medline].
Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. Jul 1988;95(1):130-6. [Medline].
Further Reading
- Relevant clinical guidelines include the following:
- Relevant clinical trials include the following:
- Related eMedicine topics include the following:
- Progressive Familial Intrahepatic Cholestasis
- Primary Sclerosing Cholangitis (Gastroenterology)
- Primary Sclerosing Cholangitis (Pediatrics: General Medicine)
- Biliary Atresia
- Biliary Obstruction
Keywords
cholestasis, reduced bile formation, reduced bile flow, bile duct obstruction, cholestatic disorders, Dubin-Johnson syndrome, Rotor syndrome, Alagille syndrome, hyperchloremia, gram-negative sepsis, heart failure, metabolic disease, pruritus, itching, scratching, hyperlipidemia, xanthomas, xanthoma, failure to thrive, cholestatic liver disease, vitamin E deficiency, vitamin D deficiency, osteomalacia, rickets, biliary atresia, steatorrhea, scleral icterus, cutaneous jaundice, choledochal cyst, choledochal cyst, cholelithiasis, primary sclerosing cholangitis, hepatitis A, hepatitis B, hepatitis C, progressive familial intrahepatic cholestasis, treatment, diagnosis
