Symposium on Diseases of the Liver
Cholestatic Jaundice Norman B. Javitt, M.D., Ph.D.*
Probably by the year 2000 (which is only 25 years from now) physicians will have learned that there is a fundamental difference between cholestasis and jaundice. Ey that time, chapters will be headed with only the single word, cholestasis, and physicians will know that for more than 90 per cent of his patients with hepatic disease the presence of jaundice automatically means the patient has cholestasis. It is to the care of the anicteric patient that this article will be mostly devoted. Specifically, indications will be given as to when estimation of the serum bile acid will provide a better guide for management of the patient and manipulation of the bile acid pool a better approach to therapy. Many years ago when ESP (phenoltetrabromphthalein disulfonate) was introduced for the evaluation of liver function, it was learned 5 that when jaundice was present, and related to underlying liver disease, the test was always abnormal. Therefore, as a practical guide to management the test was unnecessary in a jaundiced patient. During the "ESP years" the test proved to be extremely sensitive for detecting liver disease and often was included as part of an annual evaluation of a patient with previously known liver disease. A rationale, parallel to that used for ESP, can be used to introduce the subject of cholestasis since we are still focused on the excretory function of the hepatocyte but must shift our attention from synthetic ESP to the natural bile acids.
PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE ENTEROHEPATIC CIRCULATION The bile acids are the major hepatic excretory load presented to the liver. In man, following an overnight fast, the bile acid pool of 2500 to 3500 mg of conjugated bile acids will have accumulated in the gallbladder and the serum bile acid will be at its lowest level. With breakfast, the gallbladder empties about two thirds of the pool into the duodenum. The glycine conjugated bile acids will begin to diffuse into portal vein blood from the jejunum in about 1 hour but most of the bile acids will pass into the ileum between 90 and 180 minutes. At about 120 minutes the active transport system of the ileum will be re':'Professor of Medicine and Head, Division of Gastroenterology, New York Hospital-CorneU Medical Center, New York, New York
Medical Clinics of North America- Vo!. 59, No. 4, July 1975
817
818
NORMAN
B.
]AVITT
turning the bile acids at rates of 35 mg per min or more. Despite this high rate of return, the very high extraction capacity of the liver prevents bile acids from entering the systemic circulation so that there is virtually no rise in the postprandial serum bile acid level. Thus, with each meal, man gives himself an intraintestinal infusion of 2500 mg of bile salts that are actively reabsorbed from the ileum, over a relatively brief period of time. A serum bile acid taken 2 hours postprandially can reflect this load, and is a most sensitive way of detecting decreased hepatic excretory function. 4 Evidence is accumulating that one of the earliest manifestations of hepatocellular dysfunction is a reduction in the capacity to transport bile acids. The hepatocyte can no longer keep pace with the bile acids returning from the intestines and the level rises in serum. The best known example is anicteric hepatitisl in which data has been obtained indicating that the serum concentration of bile acids rises abnormally at about the same time as a rise in the serum glutamic-oxalacetic transaminase occurs. Unlike slight elevations in transaminases which can occur from injury to organs other than the liver an elevation in serum bile acid always indicates ~ disturbance in either the hepatocyte or biliary tree. In the evaluation of biliary tract disease, it has been noted that hyperphosphatasemia without hyperbilirubinemia occurs early in the course of the disease. The serum bile acid levels become abnormal before hyperbilirubinemia occurs but can be normal even when there is hyperphosphatasemia. In biliary tract disease, therefore, an elevation of serum bile acid is a more sensitive estimate of severity and localizes the source of the phosphatasemia. CHOLEST ASIS IN LIVER DISEASE Viral Hepatitis Serum bile acid levels are increased in anicteric viral hepatitis attributable to either the A or B virus. In a series of hepatitis B carriers, with morphologic evidence of persistent hepatitis, elevations in the 2 hour postprandial level were found. 6 In acute viral hepatitis elevated postprandial levels of bile acid in serum can persist even after transaminase levels and BSP retention have returned to normal. Thus in judging the extent of recovery from hepatitis an elevated level is evidence for persistent disease and a return to normal is a sensitive indication of recovery. Chronic Active Hepatitis Serum bile acid levels are elevated in all patients found to have chronic active hepatitis. The degree of elevation appears related to the severity of the illness as judged by other clinical and biochemical parameters. Patients who respond to prednisolone and azathioprine therapy, or both, show return of serum bile acid values to normal. Biliary Tract Disease Gallstones and related problems account for most of the biliary tract disease seen in practice. A variety of situations can occur following
CHOLESTATIC JAUNDICE
819
cholecystectomy and usually present with a clinical picture suggestive of recurrent episodes of choledochitis attributable to either "sludge" or the passage of small stones. Relatively little consideration has been given to the possibility that at peak bile flow rates occurring after meals, previous injury or scarring to the sphincter may cause a pressure gradient to develop with distention of the common bile duct. Although occasionally the clinical episodes are clearly associated with elevations in alkaline phosphatase and bilirubinuria (when sought for), biochemical confirmation is often lacking. In this situation, the serum bile acid will elevate promptly during the acute episode and establish the presence of biliary tract disease. Although sufficient data have not been accumulated to evaluate the relative merit of ascertaining the serum bile acid and/or alkaline phosphatase as part of the evaluation of biliary tract disease, it seems clear that any decision to administer bile acid preparations in an attempt to manage these problems must be rationally based on a knowledge of the serum bile acid concentration. The feeding of bile acids to patients with persistently elevated concentrations in plasma may result only in further increased levels with pruritus and no therapeutic effect. Cryptogenic Cholestasis and Cirrhosis The physician is well aware that the appearance of liver disease in a child or young adult is a signal for evaluation of a number of metabolic errors such as Wilson's disease and a-I antitrypsin deficiency. Often an explanation is not found. In the last several years it has become increasingly more apparent that cholestatic syndromes beginning in the neonatal period may persist into adult life. Typically, but not invariably, these patients have a history of neonatal jaundice or perhaps have been explored for the possibility of biliary atresia. The jaundice often disappears by the fourth month of life and the infant is thought to be entirely well. About the first year of life, the child may be noted to scratch frequently but the significance usually is not noted. Often the child is treated for "eczema," or "dry skin," or may be considered to have a behavior disorder. We have recently seen a patient aged 26 with cirrhosis and portal hypertension who had pruritus all her life, the significance of which was unrecognized. At the present time, in the absence of the technical capacity to routinely screen for serum bile acid levels, the only hope we have of detecting these cholestatic syndromes that lead to cirrhosis is the inquiry as to the presence of pruritus and a biochemical confirmation that there is an elevated bile acid level. The pathogenesis of neonatal cholestatic syndromes is unknown. 3 From a functional point of view it is clear that the reduction in the capacity to excrete bile acids is the most profound defect. Because there is no associated defect in bilirubin excretion, the patients develop conjugated hyperbilirubinemia only when the cholestasis is most severe and there is virtually no bile flow. It is not clear whether the current therapeutic approach to persistent cholestasis can prevent the progression to cirrhosis. The basis of therapy has been the reduction of the bile salt load on the liver by the use of anion-exchange resins such as cholestyramine that prevent the reabsorption of bile acids from the intestines. Hopefully, this type of
820
NORMAN
B.
jAVITT
therapy will reduce the high intracellular concentration of bile acids in the hepatocyte that play a role in the progression to cirrhosis. The longest period of treatment thus far has been 3 years, and although results thus far are encouraging, it is too short a period to evaluate if there has been a change in the natural history of the disease. Phenobarbital therapy can reduce the hyperbilirubinemia if present, and reduce pruritus, but does not appear to beneficially affect the underlying cholestasis.
Primary Biliary Cirrhosis The two prominent features of this disease occurring early in its course and before there is cirrhosis are (1) an inflammatory reaction in the portal areas having the bile ductules as the apparent target with necrosis of biliary epithelium and (2) severe cholestasis associated with pruritus. The pathogenesis of the inflammatory reaction is not understood and possible immunotherapeutic agents such as prednisolone and azathioprine are not usually helpful. In contrast, it is possible to treat successfully the cholestasis, provided that both the patient and the physician work together and do not discourage easily.2 The physician must explain to the patient that the basis of therapy is to give a medication that must mechanically mix with the bile and prevent reabsorption of the bile acids. The best time to do this is when the gallbladder is rich in bile salt and discharges during a meal. The physician should understand that because the patient has cholestasis it may take the liver 12 hours or more to accomplish what the normal liver can do in 2 hours or less. Thus once the bile acids flow freely to the ileum they will be reabsorbed and be distributed wherever the plasma carries them. The liver will work incessantly to retrieve the bile acids and restore them to the gallbladder. Given enough time, the bile salts will accumulate in the gallbladder. One of the time limitations is the emptying of the gallbladder with the next meal. U sing these principles it is possible to design a rational therapeutic regimen. The patient is cautioned not to have late snacks and to allow a long interval between the evening meal and breakfast. With the morning meal 8 gm of cholestyramine are given, half before the meal and half after. Often this is sufficient therapy to reduce serum bile acid levels and pruritus. However, in the initial phase of treatment it may be necessary to administer more cholestyramine. This is done best by giving an additional 8 gm at the evening meal, provided the patient is told to have little or no lunch so that the gallbladder will not empty between breakfast and dinner. After a period of time, perhaps months, there will be relief from pruritus and a feeling of well-being. Objective evidence that therapy will be successful, before symptomatic improvement is obtained, can be derived from following fasting serum bile acid levels during treatment. Supportive therapy in the form of vitamins A, D, and K and supplemental calcium (such as calcium lactate) should also be given either at lunch time when twice daily therapy is used, or in the evening when cholestyramine is given only at breakfast. In addition to these positive therapeutic measures, the patient must be cautioned against taking any and all medications. So many drugs are, at least in part, metabolized and excreted in bile, that one can almost predict a "relapse" in the patient's condition when a medication is
821
CHOLESTATIC JAUNDICE
taken. If some therapy is urgently needed, then the physician must try and choose one that theoretically at least will not affect bilirubin and bile acid excretion. Should the medication be required and produce an exacerbation of symptoms, the patient may be reassured that it is probably only temporary and in time there will be return to the previous status.
SUMMARY Cholestasis is best detected by an increase in serum bile acid concentration and is a feature of most, if not all, diseases of the liver and biliary tract. In acute and chronic inflammatory disease affecting primarily the hepatocyte, the cholestasis provides a sensitive estimate of the severity of the disease and is prognostically helpful. The cholestasis subsides with treatment of the underlying hepatitis. In diseases affecting primarily bile acid excretion, cholestasis is the most prominent feature of the disease and accounts for the major symptoms. In these instances, therapy directed at the enterohepatic circulation of bile salts is effective in providing symptomatic relief and may favorably affect the long-term prognosis. Division of Gastroenterology New York Hospital-Comell Medical Center New York, New York 10021
Cholestatic Jaundice Norman B. Javitt, M.D., Ph.D.*
Probably by the year 2000 (which is only 25 years from now) physicians will have learned that there is a fundamental difference between cholestasis and jaundice. Ey that time, chapters will be headed with only the single word, cholestasis, and physicians will know that for more than 90 per cent of his patients with hepatic disease the presence of jaundice automatically means the patient has cholestasis. It is to the care of the anicteric patient that this article will be mostly devoted. Specifically, indications will be given as to when estimation of the serum bile acid will provide a better guide for management of the patient and manipulation of the bile acid pool a better approach to therapy. Many years ago when ESP (phenoltetrabromphthalein disulfonate) was introduced for the evaluation of liver function, it was learned 5 that when jaundice was present, and related to underlying liver disease, the test was always abnormal. Therefore, as a practical guide to management the test was unnecessary in a jaundiced patient. During the "ESP years" the test proved to be extremely sensitive for detecting liver disease and often was included as part of an annual evaluation of a patient with previously known liver disease. A rationale, parallel to that used for ESP, can be used to introduce the subject of cholestasis since we are still focused on the excretory function of the hepatocyte but must shift our attention from synthetic ESP to the natural bile acids.
PHYSIOLOGY AND PATHOPHYSIOLOGY OF THE ENTEROHEPATIC CIRCULATION The bile acids are the major hepatic excretory load presented to the liver. In man, following an overnight fast, the bile acid pool of 2500 to 3500 mg of conjugated bile acids will have accumulated in the gallbladder and the serum bile acid will be at its lowest level. With breakfast, the gallbladder empties about two thirds of the pool into the duodenum. The glycine conjugated bile acids will begin to diffuse into portal vein blood from the jejunum in about 1 hour but most of the bile acids will pass into the ileum between 90 and 180 minutes. At about 120 minutes the active transport system of the ileum will be re':'Professor of Medicine and Head, Division of Gastroenterology, New York Hospital-CorneU Medical Center, New York, New York
Medical Clinics of North America- Vo!. 59, No. 4, July 1975
817
818
NORMAN
B.
]AVITT
turning the bile acids at rates of 35 mg per min or more. Despite this high rate of return, the very high extraction capacity of the liver prevents bile acids from entering the systemic circulation so that there is virtually no rise in the postprandial serum bile acid level. Thus, with each meal, man gives himself an intraintestinal infusion of 2500 mg of bile salts that are actively reabsorbed from the ileum, over a relatively brief period of time. A serum bile acid taken 2 hours postprandially can reflect this load, and is a most sensitive way of detecting decreased hepatic excretory function. 4 Evidence is accumulating that one of the earliest manifestations of hepatocellular dysfunction is a reduction in the capacity to transport bile acids. The hepatocyte can no longer keep pace with the bile acids returning from the intestines and the level rises in serum. The best known example is anicteric hepatitisl in which data has been obtained indicating that the serum concentration of bile acids rises abnormally at about the same time as a rise in the serum glutamic-oxalacetic transaminase occurs. Unlike slight elevations in transaminases which can occur from injury to organs other than the liver an elevation in serum bile acid always indicates ~ disturbance in either the hepatocyte or biliary tree. In the evaluation of biliary tract disease, it has been noted that hyperphosphatasemia without hyperbilirubinemia occurs early in the course of the disease. The serum bile acid levels become abnormal before hyperbilirubinemia occurs but can be normal even when there is hyperphosphatasemia. In biliary tract disease, therefore, an elevation of serum bile acid is a more sensitive estimate of severity and localizes the source of the phosphatasemia. CHOLEST ASIS IN LIVER DISEASE Viral Hepatitis Serum bile acid levels are increased in anicteric viral hepatitis attributable to either the A or B virus. In a series of hepatitis B carriers, with morphologic evidence of persistent hepatitis, elevations in the 2 hour postprandial level were found. 6 In acute viral hepatitis elevated postprandial levels of bile acid in serum can persist even after transaminase levels and BSP retention have returned to normal. Thus in judging the extent of recovery from hepatitis an elevated level is evidence for persistent disease and a return to normal is a sensitive indication of recovery. Chronic Active Hepatitis Serum bile acid levels are elevated in all patients found to have chronic active hepatitis. The degree of elevation appears related to the severity of the illness as judged by other clinical and biochemical parameters. Patients who respond to prednisolone and azathioprine therapy, or both, show return of serum bile acid values to normal. Biliary Tract Disease Gallstones and related problems account for most of the biliary tract disease seen in practice. A variety of situations can occur following
CHOLESTATIC JAUNDICE
819
cholecystectomy and usually present with a clinical picture suggestive of recurrent episodes of choledochitis attributable to either "sludge" or the passage of small stones. Relatively little consideration has been given to the possibility that at peak bile flow rates occurring after meals, previous injury or scarring to the sphincter may cause a pressure gradient to develop with distention of the common bile duct. Although occasionally the clinical episodes are clearly associated with elevations in alkaline phosphatase and bilirubinuria (when sought for), biochemical confirmation is often lacking. In this situation, the serum bile acid will elevate promptly during the acute episode and establish the presence of biliary tract disease. Although sufficient data have not been accumulated to evaluate the relative merit of ascertaining the serum bile acid and/or alkaline phosphatase as part of the evaluation of biliary tract disease, it seems clear that any decision to administer bile acid preparations in an attempt to manage these problems must be rationally based on a knowledge of the serum bile acid concentration. The feeding of bile acids to patients with persistently elevated concentrations in plasma may result only in further increased levels with pruritus and no therapeutic effect. Cryptogenic Cholestasis and Cirrhosis The physician is well aware that the appearance of liver disease in a child or young adult is a signal for evaluation of a number of metabolic errors such as Wilson's disease and a-I antitrypsin deficiency. Often an explanation is not found. In the last several years it has become increasingly more apparent that cholestatic syndromes beginning in the neonatal period may persist into adult life. Typically, but not invariably, these patients have a history of neonatal jaundice or perhaps have been explored for the possibility of biliary atresia. The jaundice often disappears by the fourth month of life and the infant is thought to be entirely well. About the first year of life, the child may be noted to scratch frequently but the significance usually is not noted. Often the child is treated for "eczema," or "dry skin," or may be considered to have a behavior disorder. We have recently seen a patient aged 26 with cirrhosis and portal hypertension who had pruritus all her life, the significance of which was unrecognized. At the present time, in the absence of the technical capacity to routinely screen for serum bile acid levels, the only hope we have of detecting these cholestatic syndromes that lead to cirrhosis is the inquiry as to the presence of pruritus and a biochemical confirmation that there is an elevated bile acid level. The pathogenesis of neonatal cholestatic syndromes is unknown. 3 From a functional point of view it is clear that the reduction in the capacity to excrete bile acids is the most profound defect. Because there is no associated defect in bilirubin excretion, the patients develop conjugated hyperbilirubinemia only when the cholestasis is most severe and there is virtually no bile flow. It is not clear whether the current therapeutic approach to persistent cholestasis can prevent the progression to cirrhosis. The basis of therapy has been the reduction of the bile salt load on the liver by the use of anion-exchange resins such as cholestyramine that prevent the reabsorption of bile acids from the intestines. Hopefully, this type of
820
NORMAN
B.
jAVITT
therapy will reduce the high intracellular concentration of bile acids in the hepatocyte that play a role in the progression to cirrhosis. The longest period of treatment thus far has been 3 years, and although results thus far are encouraging, it is too short a period to evaluate if there has been a change in the natural history of the disease. Phenobarbital therapy can reduce the hyperbilirubinemia if present, and reduce pruritus, but does not appear to beneficially affect the underlying cholestasis.
Primary Biliary Cirrhosis The two prominent features of this disease occurring early in its course and before there is cirrhosis are (1) an inflammatory reaction in the portal areas having the bile ductules as the apparent target with necrosis of biliary epithelium and (2) severe cholestasis associated with pruritus. The pathogenesis of the inflammatory reaction is not understood and possible immunotherapeutic agents such as prednisolone and azathioprine are not usually helpful. In contrast, it is possible to treat successfully the cholestasis, provided that both the patient and the physician work together and do not discourage easily.2 The physician must explain to the patient that the basis of therapy is to give a medication that must mechanically mix with the bile and prevent reabsorption of the bile acids. The best time to do this is when the gallbladder is rich in bile salt and discharges during a meal. The physician should understand that because the patient has cholestasis it may take the liver 12 hours or more to accomplish what the normal liver can do in 2 hours or less. Thus once the bile acids flow freely to the ileum they will be reabsorbed and be distributed wherever the plasma carries them. The liver will work incessantly to retrieve the bile acids and restore them to the gallbladder. Given enough time, the bile salts will accumulate in the gallbladder. One of the time limitations is the emptying of the gallbladder with the next meal. U sing these principles it is possible to design a rational therapeutic regimen. The patient is cautioned not to have late snacks and to allow a long interval between the evening meal and breakfast. With the morning meal 8 gm of cholestyramine are given, half before the meal and half after. Often this is sufficient therapy to reduce serum bile acid levels and pruritus. However, in the initial phase of treatment it may be necessary to administer more cholestyramine. This is done best by giving an additional 8 gm at the evening meal, provided the patient is told to have little or no lunch so that the gallbladder will not empty between breakfast and dinner. After a period of time, perhaps months, there will be relief from pruritus and a feeling of well-being. Objective evidence that therapy will be successful, before symptomatic improvement is obtained, can be derived from following fasting serum bile acid levels during treatment. Supportive therapy in the form of vitamins A, D, and K and supplemental calcium (such as calcium lactate) should also be given either at lunch time when twice daily therapy is used, or in the evening when cholestyramine is given only at breakfast. In addition to these positive therapeutic measures, the patient must be cautioned against taking any and all medications. So many drugs are, at least in part, metabolized and excreted in bile, that one can almost predict a "relapse" in the patient's condition when a medication is
821
CHOLESTATIC JAUNDICE
taken. If some therapy is urgently needed, then the physician must try and choose one that theoretically at least will not affect bilirubin and bile acid excretion. Should the medication be required and produce an exacerbation of symptoms, the patient may be reassured that it is probably only temporary and in time there will be return to the previous status.
SUMMARY Cholestasis is best detected by an increase in serum bile acid concentration and is a feature of most, if not all, diseases of the liver and biliary tract. In acute and chronic inflammatory disease affecting primarily the hepatocyte, the cholestasis provides a sensitive estimate of the severity of the disease and is prognostically helpful. The cholestasis subsides with treatment of the underlying hepatitis. In diseases affecting primarily bile acid excretion, cholestasis is the most prominent feature of the disease and accounts for the major symptoms. In these instances, therapy directed at the enterohepatic circulation of bile salts is effective in providing symptomatic relief and may favorably affect the long-term prognosis. Division of Gastroenterology New York Hospital-Comell Medical Center New York, New York 10021
