Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Hyperbilirubinemic and cholestatic syndromes Norman B. Javitt To cite this article: Norman B. Javitt (1979) Hyperbilirubinemic and cholestatic syndromes, Postgraduate Medicine, 65:1, 120-130, DOI: 10.1080/00325481.1979.11715028 To link to this article: https://doi.org/10.1080/00325481.1979.11715028
Published online: 07 Jul 2016.
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Citing articles: 1 View citing articles
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Hyperbilirubinemic and cholestatic syndromes New concepts aiding recognition and management Norman B. Javitt, MD, PhD
Consider When serum bilirubin concentration is elevated, what tests are most critical for evaluating the mechanism of the increase? What syndromes are associated with conjugation defects? With uptake defects? With storage defects? With excretion defects? What findings characterize hyperbilirubinemic syndromes? How is mechanical extrahepatic obstruction most reliably distinguished from intrahepatic cholestasis?
An elevated bilirubin level can be classified as hyperbilirubinemia only if results of all other liver function tests are normal. In contrast, cholestatic syndromes are characterized by elevations in various measurements ofliverfunction, particularly alkaline phosphatase, bile acid, gammaglutamyl transferase, and 5'-nucleotidase.
Advances in the understanding of hepatic excretory function permit a new classification of hyperbilirubinemic and cholestatic syndromes. The former refer specifically to disturbances in bilirubin transport, and the latter affect specifically bile acid transport (figure 1). Without laboratory evidence that one of these two pathways is involved, the diagnosis of either hyperbilirubinemia or cholestasis is in doubt.
Hyperbilirubinemia When serum bilirubin concentration is elevated, differential diagnosis must begin with an evaluation to determine the mechanism of the increase. The most critical tests for evaluation are measurement of serum levels of ( 1) bile acid two hours postprandially, (2) transaminases (SGOT and SGP1), and (3) alkaline phosphatase or preferably gammaglutamyl transferase or 5'-nucleotidase. If results of these tests are normal, it is reasonable to assume that hyperbilirubinemia is related either to overproduction I of bilirubin or to a specific defect in bilirubin transport or metabolism. A hematologic evaluation will usually identify an increase in bilirubin production if such is present; normal results indicate that the problem is con-
120
fined to some defect in the bilirubin pathway.2 I do not believe it is necessary to do a liver biopsy. For discussion purposes, the bilirubin pathway may be divided into hepatic uptake, conjugation, storage, and excretion. Defects in uptake and conjugation are associated with unconjugated hyperbilirubinemia. Defects in storage and excretion are associated with conjugated plus a variable degree of unconjugated hyperbilirubinemia. Most routine analytical methods overestimate the amount of conjugated (direct-reacting) bilirubin; therefore, if I 0% or less of the total bilirubin is direct-reacting, the condition is best classified as unconjugated hyperbilirubinemia. Conjugation defect- The most frequent and probably the most clearly identifiable cause of unconjugated hyperbilirubinemia (not related to hemolytic disease) is a decrease in bilirubin conjugation, which can be attributed to a decrease in the activity of the hepatic enzyme bilirubin glucuronyl transferase. This defect probably accounts for many cases of neonatal hyperbilirubinemia, Gilbert's syndrome,3,4 and Crigler-Na.ijar syndrome (types I and 11). The apparent activity of glucuro-
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
Illustration: John A. deCesare
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
nyl transferase can be increased by administration of phenobarbital, a known inducer of many hepatic enzymes, except in type I CriglerNajjar syndrome. In this autosomal recessive defect, it is likely that the template for synthesis of a protein with enzyme activity is absent; therefore, synthesis of the gene product cannot be stimulated by phenobarbital. Many infants with this disorder die of kernicterus in early life. A few may survive to adult life, particularly with the judicious use of phototherapy, but the threat of kernicterus may always be present. Gilbert's and type 11 CriglerNajjar syndromes are benign disorders, and patients should be reassured as to this fact. Fasting for 24 hours or more can cause a diagnostically useful elevation in serum bilirubin level. Gallstones are sometimes present, perhaps coincidentally, since cholelithiasis is a common disorder. If icterus is socially embarrassing, phenobarbital can be used to reduce the hyperbilirubinemia. Uptake defect-Unconjugated hyperbilirubinemia associated with abnormal sulfobromophthalein (Bromsulphalein, or BSP) clearance has also been describedJ and classified as a form of Gilbert's syndrome. Since results of other liver function tests are ~ormal in such cases (although serum bile acids have not been measured) and histologic findings are said to be normal, there is no evidence for underlying liver disease. However, because bilirubin continued 121
Defects in hepatic uptake or conjugation of bilirubin are associated with unconjugated hyperbilirubinemia; defects in storage or excretion are associated with conjugated plus a variable amount of unconjugated hyperbilirubinemia.
Figure 1. Hyperbilirubinemic and cholestatic syndromes.
and BSP are conjugated by different enzymes, the defect cannot be attributed to a decrease in glucuronyl transferase activity. The alternative is a defect in either uptake or storage. A defect in uptake at the molecular level5· 6 implies the presence of a mobile protein (carrier) in the sinusoidal membrane
122
of the hepatocyte to which bilirubin binds as it enters the sinusoidal circulation and the space of Disse and is then transported across the membrane to be delivered to the interior of the hepatocyte. A decrease in either the number of carrier protein molecules or their affinity for bilirubin would reduce the rate at which
uptake occurs and account for unconjugated hyperbilirubinemia. BSP and bilirubin probably bind to the same membrane carrier, which would explain the possible association between an increase in serum bilirubin level and a decrease in BSP excretion. The term "Gilbert's syndrome" is
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
Physicians are not attuned to early diagnosis of cholestatic liver dis· ease; hence, it may go unrecognized until jaundice occurs, unless the patient complains of pruritus.
not used as precisely to designate this entity as to designate the entity attributable to a decrease in glucuronyl transferase activity. Storage defect- The concept of a storage defect in regard to bilirubin transport is relatively new and stems from the work of Dhumeaux and Berthelot. 7 A person with conjugated hyperbilirubinemia was found to have a marked defect in BSP storage with a normal capacity to excrete BSP. All other liver function values, including serum bile acid concentration, were normal, as were histologic findings. Although initially one might expect that a decrease in storage capacity would be associated with unconjugated hyperbilirubinemia, it is possible to postulate that either type or both types of hyperbilirubinemia can occur. The hepatocyte is known to contain proteins that bind a variety of anionic molecules, such as bilirubin, BSP, and indocyanine green. Chief among these proteins are the glutathione transferase enzymes8 (ligandins) in the cytosol, although binding to other proteins also occurs. The molecules may remain bound to these proteins until they enter the biliary excretory pathway. A decrease in binding would permit greater flux of the molecules across the sinusoidal membrane and an elevation in serum level. Flux of molecules already conjugated and awaiting excretion would lead to conjugated hyperbilirubinemia. Speculatively, a storage defect may be the molecular basis for Ro-
tor's syndrome, which contrary to previous suggestions is not DubinJohnson syndrome without the pathognomonic pigment in liver cells. The initial report of Rotor's syndrome indicated a marked elevation of BSP level in the serum sample taken at 45 minutes, in contrast to normal or slightly elevated levels in Dubin-Johnson syndrome. In addition, in Rotor's syndrome no increase in BSP level is seen in samples taken after 45 minutes, whereas in Dubin-Johnson syndrome increases may be seen in samples taken at 90 and 120 minutes. Failure to clearly specify these differences led to some confusion between the two syndromes. The recent description of the storage defect provides a basis for tentatively classifying Rotor's syndrome as a defect in bilirubin storage.
Excretion defect-Dubin-Johnson syndrome9 is a well-defined defect in the excretion of conjugated bilirubin and other organic anions. The accumulation of pigment in the hepatocyte may represent polymerized epinephrine glucuronide (melanins) and be a consequence ofthe excretory defect. A requirement for diagnosis is the demonstration of an increase in BSP level in serum samples taken subsequent to the 45-minute specimen. The defect is believed to be inherited as an autosomal recessive trait, but the decrease in BSP transport maximum that is present in the homozygous state cannot be found in carriers. However, an increase in urinary ex-
cretion of coproporphyrin I occurs in both the heterozygous and the homozygous state and probably reflects, in part, the defect in biliary excretion. Dubin-Johnson syndrome is benign, and patients need reassurance as to this fact. Occasionally they may have abdominal pain and also gallstones. Because of the defect in organic anion excretion, it is not possible to visualize the gallbladder. An elevated level of alkaline phosphatase or a typical episode of cholecystitis would be evidence of biliary tract disease independent of coexisting Dubin-Johnson syndrome. Alternatively, sonography may detect the presence of unsuspected cholelithiasis. Intercurrent acute renal or urinary tract disease may result in temporary marked elevation in the serum level of conjugated bilirubin and obscure the correct diagnosis.
Cholestatic liver disease In contrast to hyperbilirubinemic syndromes, cholestatic syndromes to are characterized by elevated values on several liver function tests, particularly serum levels of alkaline phosphatase, bile acid, gammaglutamyl transferase, and 5'-nucleotidase. Such elevations may occur before serum bilirubin level rises.ll However, physicians are not attuned to the early diagnosis of cholestatic disease, and it may go unrecognized until jaundice occurs, unless the patient complains of pruritus.
continued VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
123
The initial choices for diagnosis of extrahepatic cholestasis in anicteric patients are oral cholecystography and intravenous cholangio· graphy, because they are the least invasive.
Mechanical extrahepatic obstruction is most reliably distinguished from intrahepatic cholestasis by visualization of the entire biliary tree. Techniques used for differentiation include sonography, percutaneous cholangiography, endoscopic retrograde cholangiopancreatography, or a combination of these. Cholestasis attributable to disturbances in hepatocyte function or to disease of the intrahepatic bile ductules can be further subdivided into generalized or specific dysfunction. Cholestasis associated with disturbances which are part of a generalized disruption in hepatocyte function, as occurs in viral hepatitis, has no special significance and may improve together with other hepatocyte functions. Occasionally, for unknown reasons, interference with the capacity to excrete bile acids is not associated with liver cell necrosis or other evidence of a generalized impairment of cell function. These instances represent a selective defect in hepatocyte function and can occur at any age. Extrahepatic cho/estasis-Oral cholecystography and intravenous cholangiography are the initial choices for diagnosing extrahepatic cholestasis in anicteric patients, because they are the least invasive. Nonvisualization of the gallbladder on two occasions, with normal visualization of the biliary tree by cholangiography, indicates cholelithiasis, probably with cystic duct obstruction.
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Intravenous cholangiography unfortunately fails to provide completely adequate visualization of the biliary tree. Small stones that do not distend the duct system may cause pain and recurrent cholangitis but may not be seen. Therefore, retrograde cholangiography may be indicated. In a patient who has had a previous cholecystectomy because of cholelithiasis, recurrence of unexplained symptoms warrants endoscopic retrograde cannulation even if a normal intravenous cholangiogram has been obtained. In a patient with jaundice, percutaneous thin-needle cholangiography (0. 75 mm external diameter) may be preferable to retrograde cannulation, s.ince there is less discomfort and a higher rate of duct visualization. Depending on their size and location, stones in the common duct may also be identified and treated by retrograde cholangiography with or without sphincterotomy for extraction of the stones. Adequate visualization of the biliary tree is also important after an unexplained episode of pancreatitis. In the absence of choledocholithiasis, an anomaly of the duct system, such as choledochal cyst, must be considered. Anomalies of the biliary tree may not cause symptoms until adult life. Intrahepatic cho/estasis in neonates-Cholestasis may be present at birth, but the presence of hyperbilirubinemia, which may be unconjugated or mixed (unconjugated
and conjugated), detracts from its recognition in the neonate. 12 A pitfall in the care of these infants is to assume that when the jaundice disappears the cholestasis is also gone, whereas the disease may have entered the anicteric phase of a persistent cholestatic syndrome. To distinguish the anicteric phase from complete resolution of cholestasis, serum levels of bile acid and 5'-nucleotidase should be measured in every neonate with hyperbilirubinemia at some time after the disappearance of jaundice. As these tests become more widely available, their use will become standard. Persistence of cholestasis, as occurs in Byler's disease, can lead to the development of cirrhosis in early life. In some instances, marked retention of copper in the liver occurs as part of the prolonged cholestasis and depends to some extent on the copper content of the diet. Prevention of cirrhosis is dependent on early recognition. It is possible that long-term treatment with cholestyramine, an ionexchange resin that lowers bile acid concentration in the hepatocyte, may prevent progression to cirrhosis,13 but not all infants respond to such therapy. Phenobarbital, alone or in combination with cholestyramine, may facilitate bile acid excretion, with a lowering of serum and hepatocyte concentration. Response to therapy is best indicated by a decrease in serum bile acid levels or by an increase in fecal bile acid excretion, rather than by a decrease continued
VOL 65/NO 1/JANUARY 1979/POSTGRAOUATE MEDICINE
In neonates, lt Is a pitfall to aaume that cholestasls Is gone when Jaundice disappears; the di-H may have entered the anicteric phaH of a persistent cholestatlc syndrome.
in pruritus or serum bilirubin level. Cholestasis is associated with malabsorption of fats. Adequate nutrition should be maintained with a relatively high carbohydrate diet; supplemental vitamins A, D, and K; calcium lactate or glucuronate; and if necessary, supplemental mediumchain triglycerides. 14 A diet low in copper would be a wise precaution. Another cholestatic syndrome presenting early in life is benign recurrent cholestasis. I have not found that therapy alters the frequency of attacks or shortens their duration, but some observers have stated that phenobarbital may be useful. Drug-induced cho/estasis- In adults, intrahepatic cholestatic syndromes occur mostly as a consequence of drug therapy, particularly with synthetic estrogens and androgens. Cholestasis of pregnancy is probably related to estrogens, since this disorder usually develops in women who have received ethinyl estradiol or similar anovulatory agents. Cholestasis secondary to drug therapy can be difficult to recognize, since the patient may forget to report in the history a medication used for many years and considered part of the life-style. When the patient is elderly, especially if living alone, it is wise to have a member of the family bring the contents of the medicine chest to the office. Drugs recognized as causing cholestasis are easy to eliminate, but all medications are suspect as possible offenders. Any medication capa-
ble of causing a hypersensitivity reaction or containing organically bound chlorine or bromine atoms (eg, chlorpropamide, chlorothiazide, halothane) can be suspected of occasionally causing cholestasis. Ideally, in practice it would be wise to monitor liver function when starting therapy with any medication that will be used for a prolonged period. The tests that would be most sensitive and most acceptable to the patient are measurement of serum levels of bile acid two hours postprandially, gammaglutamyl transferase, and SG PT, all of which can be done with a few milliliters of serum. Certainly in monitoring isoniazid or methyldopa therapy, SG PT level should be measured. Jaundice should not be used as the criterion for discontinuing therapy, because it is a late manifestation of drug toxicity. Se/erasing cholangitis and pericholangitis-Hepatocellular function is normal early in these cholestatic syndromes which occur in adult life, but a progressive inflammatory reaction in the biliary tree eventually leads to cirrhosis. Sclerosing cholangitis and pericholangitis may be associated with chronic inflammatory disease elsewhere, particularly in the intestine. Occasionally thyroiditis may also be associated with chronic biliary tract inflammation, which implies a lymphocyte-mediated pathogenesis. In contrast to primary biliary cirrhosis, in sclerosing cholangitis and pericholangitis circulating antibodcontinued
VOL85/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
Nonnan B. Javitt Dr Javitt is professor of medicine and head of the division of gastroenterology, New York Hospital-Comell Medical Center, New York.
127
See important product information including warnings, adverse reactions. patient selection and prescribing and precautionary recommendations.
Because virtually any drug is capable of inducing cholestasis, liver function should be monitored whenever long-term therapy is started.
ies to mitochondria are not found and men and women are affected with equal frequency. The diagnosis of sclerosing cholangitis is made by cholangiography showing narrowing of the lumina of the biliary tree. Pericholangitis is suspected from liver biopsy findings, from typical clinical manifestations (particularly when associated with disease of other organs), and from characteristic laboratory data. Primary biliary cirrhosis- This disease, like cholangitis, occurs in adults. Causes are probably diverse, but in each instance the inflammatory reaction is directed at the bile ductules. Early in the disease the characteristic dense lymphocytic infiltrates in the portal areas, together with bile duct necrosis, may not be seen in tissue obtained by percutaneous liver biopsy but will be seen in tissue containing larger bile ductules, such as is obtained by open biopsy. Clinically, there is a tendency to diagnose primary biliary cirrhosis on insufficient evidence. Thus, when routine biochemical analysis (SMA-12) shows an asymptomatic patient to have an elevated alkaline phosphatase level, an investigation is initiated to determine the source of the abnormality. An elevated level of 5'-nucleotidase or of gammaglutamyl transferase confirms the source as the liver, and a positive test for antimitochondrial antibodies is accepted as sufficient evidence for the diagnosis of biliary cirrhosis. However, the absence of pruritus, of
128
The Beta 2 metered aerosol
BRONKOMETERe (ISOETHARINE MESYLATE)
hyperbilirubinemia, or of an elevated level of serum bile acid should indicate that hepatic excretory function is not decreased. In my experience, progressive disease does not always develop in persons in this category. I believe the abnormalities represent a type of hepatitis that can have a favorable prognosis. Similar findings have been reported by other physicians. 15 Classically, primary biliary cirrhosis presents in the postmenopausal woman with darkening of the skin, pruritus, and a bitter taste sensation. The skin pigmentation results from deposition of melanin, but the relationship to the disease is unexplained. Experience indicates that azathioprine is ineffective in suppressing the inflammatory reaction in the portal areas and that steroids accelerate the osteoporosis and other complications of the illness without providing any benefits. Patients 'with early disease have a relatively normal level of serum bile acid after an overnight fast; pruritus is least severe in the morning.B Administration of large doses of cholestyramine with breakfast prevents the postprandial elevation in serum bile acid level and effectively relieves the pruritus. I have not seen further progression of the liver disease in patients treated with cholestyramine at this phase. In addition to a bile-acidsequestering agent, fat-soluble vitamins and calcium should be given to avoid the progressive osteoporosis associated with primary biliary cirrhosis. continued
DESCRIPTION: Bronkomeler is a complete pocket nebulizer containing lsoetharine mesylate 0.61% (W/W) with saccharin, menthol, alcohol 30% (W/W). and fluorochlorohydrocarbons as gaseous propellants. Preserved with ascorbic acid 0.1% (W/W) ''As originally marketed, Bronkometer contained thenyldiamine hydrochloride 0.05% and phenyl· ephrine hydrochloride 0.125%. The presentformu· lation has been revised to delete these ingredients. I soethari ne is I· ( 3, 4 di hydroxyphenyl)·2·iso· propylamino·l·butanol. The Bronkometer unit delivers approximately 20 metered doses per ml. of solution. Each average 56 mg. delivery contains 340 mcg. isoetharine. ACTION: lsoetharine is a sympathomimetic amine w1th preferential affinity for Beta,adrenergic recep· tor sites of bronchial and certain arteriolar mus· culature. and a lower order of affinity for Beta 1 adrenergic receptors. Its activity in symptomatiC relief of bronchospasm is rap1d and of relatively long duration. By relieving bronchospasm, Bronkometer helps give prompt relief and signif· icantly increases v1tal capacity. INDICATIONS: Bronkometer is indicated for the acute relief of bronchial asthma and other condi· tions in wh1ch bronchospasm is a complicatmg factor. such as chronic bronchitiS or emphysema. CONTRAINDICATION: Bronkometer should not be admmistered to pat1ents who are hypersensitive to any of 1ts ingredients. WARNINGS: Excessive use of an adrenergic aerosol should be discouraged as 11 may lose its effective· ness. Occas1onal patients have been reported to develop severe paradoxical airway resistance with repeated excess1ve use of an aerosol adrenergic inhalatiOn preparation. The cause of this refractory state IS unknown. lt is advisable that 1n such In· stances the use of the aerosol adrenergic be discontmued Immediately and alternative therapy mst1tuted. since 1n the reported cases the patients d1d not respond to other forms of therapy until the drug was withdrawn. Cardiac arrest has been noted in several instances. Bronkometer should not be administered along with epinephrine or other sympathomimetic amines. since these drugs are direct card1ac stimulants and may cause excessive tachycardia. They may, how· ever. be alternated if desired. Usage in PreRnancy: Although there has been no ev1dence of teratogenic effects with this drug, use of any drug 1n pregnancy, lactat1on, or 1n women of childbearing potential requireS that the potential benefit of the drug be weighed against its poss1ble hazard to the mother or child PRECAUTIONS: Dosage must be carefully adjusted 1n pat1ents w1th hyperthyroidism, hypertension, acute coronary disease. cardiac asthma. lim1ted cardiac reserve, and in individuals sensitive to sympathomimetiC ammes. smce overdosage may result in tachycardia. palpitatiOn, nausea. head· ache. or epmephrine·like side effects. ADVERSE REACTIONS: Although Bronkometer is relatively free of tox1c side effects. too frequent use may cause tachycardia, palpitation. nausea. headache. changes 1n blood pressure.anxiety, ten· si on. restlessness. insomnia, tremor. weakness. dizzmess. and excitement, as IS the case w1th other sympathomimetic amines. DOSAGE AND ADMINISTRATION: The average adult dose is one or two inhalations. Occasionally, more may be required. it is 1mportant. however. to wait one full minute after the Initial one or two inhalations 1n order to be certain whether another 1s necessary. In most cases. inhalations need not be repeated more often than every four hours. although more frequent admmistrat1on may be neces-
sary rn severe cases. HOW SUPPLIED: Bronkometer' 10 mI. Vial w1th Oral Nebul1zer. Code No. 1740. Bronkometer• 20 ml. V1al with Oral Nebulizer. Code No. 1742. Bronkometer' 10 ml. refill only, Code No. 1743 Bronkometer' 20 ml. refill only, Code No. 1741
l:l;IJ•UI Breon Laboratories Inc. 90 Pari< Avenue. New Yorl
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Hyperbilirubinemic and cholestatic syndromes Norman B. Javitt To cite this article: Norman B. Javitt (1979) Hyperbilirubinemic and cholestatic syndromes, Postgraduate Medicine, 65:1, 120-130, DOI: 10.1080/00325481.1979.11715028 To link to this article: https://doi.org/10.1080/00325481.1979.11715028
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20
Hyperbilirubinemic and cholestatic syndromes New concepts aiding recognition and management Norman B. Javitt, MD, PhD
Consider When serum bilirubin concentration is elevated, what tests are most critical for evaluating the mechanism of the increase? What syndromes are associated with conjugation defects? With uptake defects? With storage defects? With excretion defects? What findings characterize hyperbilirubinemic syndromes? How is mechanical extrahepatic obstruction most reliably distinguished from intrahepatic cholestasis?
An elevated bilirubin level can be classified as hyperbilirubinemia only if results of all other liver function tests are normal. In contrast, cholestatic syndromes are characterized by elevations in various measurements ofliverfunction, particularly alkaline phosphatase, bile acid, gammaglutamyl transferase, and 5'-nucleotidase.
Advances in the understanding of hepatic excretory function permit a new classification of hyperbilirubinemic and cholestatic syndromes. The former refer specifically to disturbances in bilirubin transport, and the latter affect specifically bile acid transport (figure 1). Without laboratory evidence that one of these two pathways is involved, the diagnosis of either hyperbilirubinemia or cholestasis is in doubt.
Hyperbilirubinemia When serum bilirubin concentration is elevated, differential diagnosis must begin with an evaluation to determine the mechanism of the increase. The most critical tests for evaluation are measurement of serum levels of ( 1) bile acid two hours postprandially, (2) transaminases (SGOT and SGP1), and (3) alkaline phosphatase or preferably gammaglutamyl transferase or 5'-nucleotidase. If results of these tests are normal, it is reasonable to assume that hyperbilirubinemia is related either to overproduction I of bilirubin or to a specific defect in bilirubin transport or metabolism. A hematologic evaluation will usually identify an increase in bilirubin production if such is present; normal results indicate that the problem is con-
120
fined to some defect in the bilirubin pathway.2 I do not believe it is necessary to do a liver biopsy. For discussion purposes, the bilirubin pathway may be divided into hepatic uptake, conjugation, storage, and excretion. Defects in uptake and conjugation are associated with unconjugated hyperbilirubinemia. Defects in storage and excretion are associated with conjugated plus a variable degree of unconjugated hyperbilirubinemia. Most routine analytical methods overestimate the amount of conjugated (direct-reacting) bilirubin; therefore, if I 0% or less of the total bilirubin is direct-reacting, the condition is best classified as unconjugated hyperbilirubinemia. Conjugation defect- The most frequent and probably the most clearly identifiable cause of unconjugated hyperbilirubinemia (not related to hemolytic disease) is a decrease in bilirubin conjugation, which can be attributed to a decrease in the activity of the hepatic enzyme bilirubin glucuronyl transferase. This defect probably accounts for many cases of neonatal hyperbilirubinemia, Gilbert's syndrome,3,4 and Crigler-Na.ijar syndrome (types I and 11). The apparent activity of glucuro-
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
Illustration: John A. deCesare
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
nyl transferase can be increased by administration of phenobarbital, a known inducer of many hepatic enzymes, except in type I CriglerNajjar syndrome. In this autosomal recessive defect, it is likely that the template for synthesis of a protein with enzyme activity is absent; therefore, synthesis of the gene product cannot be stimulated by phenobarbital. Many infants with this disorder die of kernicterus in early life. A few may survive to adult life, particularly with the judicious use of phototherapy, but the threat of kernicterus may always be present. Gilbert's and type 11 CriglerNajjar syndromes are benign disorders, and patients should be reassured as to this fact. Fasting for 24 hours or more can cause a diagnostically useful elevation in serum bilirubin level. Gallstones are sometimes present, perhaps coincidentally, since cholelithiasis is a common disorder. If icterus is socially embarrassing, phenobarbital can be used to reduce the hyperbilirubinemia. Uptake defect-Unconjugated hyperbilirubinemia associated with abnormal sulfobromophthalein (Bromsulphalein, or BSP) clearance has also been describedJ and classified as a form of Gilbert's syndrome. Since results of other liver function tests are ~ormal in such cases (although serum bile acids have not been measured) and histologic findings are said to be normal, there is no evidence for underlying liver disease. However, because bilirubin continued 121
Defects in hepatic uptake or conjugation of bilirubin are associated with unconjugated hyperbilirubinemia; defects in storage or excretion are associated with conjugated plus a variable amount of unconjugated hyperbilirubinemia.
Figure 1. Hyperbilirubinemic and cholestatic syndromes.
and BSP are conjugated by different enzymes, the defect cannot be attributed to a decrease in glucuronyl transferase activity. The alternative is a defect in either uptake or storage. A defect in uptake at the molecular level5· 6 implies the presence of a mobile protein (carrier) in the sinusoidal membrane
122
of the hepatocyte to which bilirubin binds as it enters the sinusoidal circulation and the space of Disse and is then transported across the membrane to be delivered to the interior of the hepatocyte. A decrease in either the number of carrier protein molecules or their affinity for bilirubin would reduce the rate at which
uptake occurs and account for unconjugated hyperbilirubinemia. BSP and bilirubin probably bind to the same membrane carrier, which would explain the possible association between an increase in serum bilirubin level and a decrease in BSP excretion. The term "Gilbert's syndrome" is
VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
Physicians are not attuned to early diagnosis of cholestatic liver dis· ease; hence, it may go unrecognized until jaundice occurs, unless the patient complains of pruritus.
not used as precisely to designate this entity as to designate the entity attributable to a decrease in glucuronyl transferase activity. Storage defect- The concept of a storage defect in regard to bilirubin transport is relatively new and stems from the work of Dhumeaux and Berthelot. 7 A person with conjugated hyperbilirubinemia was found to have a marked defect in BSP storage with a normal capacity to excrete BSP. All other liver function values, including serum bile acid concentration, were normal, as were histologic findings. Although initially one might expect that a decrease in storage capacity would be associated with unconjugated hyperbilirubinemia, it is possible to postulate that either type or both types of hyperbilirubinemia can occur. The hepatocyte is known to contain proteins that bind a variety of anionic molecules, such as bilirubin, BSP, and indocyanine green. Chief among these proteins are the glutathione transferase enzymes8 (ligandins) in the cytosol, although binding to other proteins also occurs. The molecules may remain bound to these proteins until they enter the biliary excretory pathway. A decrease in binding would permit greater flux of the molecules across the sinusoidal membrane and an elevation in serum level. Flux of molecules already conjugated and awaiting excretion would lead to conjugated hyperbilirubinemia. Speculatively, a storage defect may be the molecular basis for Ro-
tor's syndrome, which contrary to previous suggestions is not DubinJohnson syndrome without the pathognomonic pigment in liver cells. The initial report of Rotor's syndrome indicated a marked elevation of BSP level in the serum sample taken at 45 minutes, in contrast to normal or slightly elevated levels in Dubin-Johnson syndrome. In addition, in Rotor's syndrome no increase in BSP level is seen in samples taken after 45 minutes, whereas in Dubin-Johnson syndrome increases may be seen in samples taken at 90 and 120 minutes. Failure to clearly specify these differences led to some confusion between the two syndromes. The recent description of the storage defect provides a basis for tentatively classifying Rotor's syndrome as a defect in bilirubin storage.
Excretion defect-Dubin-Johnson syndrome9 is a well-defined defect in the excretion of conjugated bilirubin and other organic anions. The accumulation of pigment in the hepatocyte may represent polymerized epinephrine glucuronide (melanins) and be a consequence ofthe excretory defect. A requirement for diagnosis is the demonstration of an increase in BSP level in serum samples taken subsequent to the 45-minute specimen. The defect is believed to be inherited as an autosomal recessive trait, but the decrease in BSP transport maximum that is present in the homozygous state cannot be found in carriers. However, an increase in urinary ex-
cretion of coproporphyrin I occurs in both the heterozygous and the homozygous state and probably reflects, in part, the defect in biliary excretion. Dubin-Johnson syndrome is benign, and patients need reassurance as to this fact. Occasionally they may have abdominal pain and also gallstones. Because of the defect in organic anion excretion, it is not possible to visualize the gallbladder. An elevated level of alkaline phosphatase or a typical episode of cholecystitis would be evidence of biliary tract disease independent of coexisting Dubin-Johnson syndrome. Alternatively, sonography may detect the presence of unsuspected cholelithiasis. Intercurrent acute renal or urinary tract disease may result in temporary marked elevation in the serum level of conjugated bilirubin and obscure the correct diagnosis.
Cholestatic liver disease In contrast to hyperbilirubinemic syndromes, cholestatic syndromes to are characterized by elevated values on several liver function tests, particularly serum levels of alkaline phosphatase, bile acid, gammaglutamyl transferase, and 5'-nucleotidase. Such elevations may occur before serum bilirubin level rises.ll However, physicians are not attuned to the early diagnosis of cholestatic disease, and it may go unrecognized until jaundice occurs, unless the patient complains of pruritus.
continued VOL 65/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
123
The initial choices for diagnosis of extrahepatic cholestasis in anicteric patients are oral cholecystography and intravenous cholangio· graphy, because they are the least invasive.
Mechanical extrahepatic obstruction is most reliably distinguished from intrahepatic cholestasis by visualization of the entire biliary tree. Techniques used for differentiation include sonography, percutaneous cholangiography, endoscopic retrograde cholangiopancreatography, or a combination of these. Cholestasis attributable to disturbances in hepatocyte function or to disease of the intrahepatic bile ductules can be further subdivided into generalized or specific dysfunction. Cholestasis associated with disturbances which are part of a generalized disruption in hepatocyte function, as occurs in viral hepatitis, has no special significance and may improve together with other hepatocyte functions. Occasionally, for unknown reasons, interference with the capacity to excrete bile acids is not associated with liver cell necrosis or other evidence of a generalized impairment of cell function. These instances represent a selective defect in hepatocyte function and can occur at any age. Extrahepatic cho/estasis-Oral cholecystography and intravenous cholangiography are the initial choices for diagnosing extrahepatic cholestasis in anicteric patients, because they are the least invasive. Nonvisualization of the gallbladder on two occasions, with normal visualization of the biliary tree by cholangiography, indicates cholelithiasis, probably with cystic duct obstruction.
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Intravenous cholangiography unfortunately fails to provide completely adequate visualization of the biliary tree. Small stones that do not distend the duct system may cause pain and recurrent cholangitis but may not be seen. Therefore, retrograde cholangiography may be indicated. In a patient who has had a previous cholecystectomy because of cholelithiasis, recurrence of unexplained symptoms warrants endoscopic retrograde cannulation even if a normal intravenous cholangiogram has been obtained. In a patient with jaundice, percutaneous thin-needle cholangiography (0. 75 mm external diameter) may be preferable to retrograde cannulation, s.ince there is less discomfort and a higher rate of duct visualization. Depending on their size and location, stones in the common duct may also be identified and treated by retrograde cholangiography with or without sphincterotomy for extraction of the stones. Adequate visualization of the biliary tree is also important after an unexplained episode of pancreatitis. In the absence of choledocholithiasis, an anomaly of the duct system, such as choledochal cyst, must be considered. Anomalies of the biliary tree may not cause symptoms until adult life. Intrahepatic cho/estasis in neonates-Cholestasis may be present at birth, but the presence of hyperbilirubinemia, which may be unconjugated or mixed (unconjugated
and conjugated), detracts from its recognition in the neonate. 12 A pitfall in the care of these infants is to assume that when the jaundice disappears the cholestasis is also gone, whereas the disease may have entered the anicteric phase of a persistent cholestatic syndrome. To distinguish the anicteric phase from complete resolution of cholestasis, serum levels of bile acid and 5'-nucleotidase should be measured in every neonate with hyperbilirubinemia at some time after the disappearance of jaundice. As these tests become more widely available, their use will become standard. Persistence of cholestasis, as occurs in Byler's disease, can lead to the development of cirrhosis in early life. In some instances, marked retention of copper in the liver occurs as part of the prolonged cholestasis and depends to some extent on the copper content of the diet. Prevention of cirrhosis is dependent on early recognition. It is possible that long-term treatment with cholestyramine, an ionexchange resin that lowers bile acid concentration in the hepatocyte, may prevent progression to cirrhosis,13 but not all infants respond to such therapy. Phenobarbital, alone or in combination with cholestyramine, may facilitate bile acid excretion, with a lowering of serum and hepatocyte concentration. Response to therapy is best indicated by a decrease in serum bile acid levels or by an increase in fecal bile acid excretion, rather than by a decrease continued
VOL 65/NO 1/JANUARY 1979/POSTGRAOUATE MEDICINE
In neonates, lt Is a pitfall to aaume that cholestasls Is gone when Jaundice disappears; the di-H may have entered the anicteric phaH of a persistent cholestatlc syndrome.
in pruritus or serum bilirubin level. Cholestasis is associated with malabsorption of fats. Adequate nutrition should be maintained with a relatively high carbohydrate diet; supplemental vitamins A, D, and K; calcium lactate or glucuronate; and if necessary, supplemental mediumchain triglycerides. 14 A diet low in copper would be a wise precaution. Another cholestatic syndrome presenting early in life is benign recurrent cholestasis. I have not found that therapy alters the frequency of attacks or shortens their duration, but some observers have stated that phenobarbital may be useful. Drug-induced cho/estasis- In adults, intrahepatic cholestatic syndromes occur mostly as a consequence of drug therapy, particularly with synthetic estrogens and androgens. Cholestasis of pregnancy is probably related to estrogens, since this disorder usually develops in women who have received ethinyl estradiol or similar anovulatory agents. Cholestasis secondary to drug therapy can be difficult to recognize, since the patient may forget to report in the history a medication used for many years and considered part of the life-style. When the patient is elderly, especially if living alone, it is wise to have a member of the family bring the contents of the medicine chest to the office. Drugs recognized as causing cholestasis are easy to eliminate, but all medications are suspect as possible offenders. Any medication capa-
ble of causing a hypersensitivity reaction or containing organically bound chlorine or bromine atoms (eg, chlorpropamide, chlorothiazide, halothane) can be suspected of occasionally causing cholestasis. Ideally, in practice it would be wise to monitor liver function when starting therapy with any medication that will be used for a prolonged period. The tests that would be most sensitive and most acceptable to the patient are measurement of serum levels of bile acid two hours postprandially, gammaglutamyl transferase, and SG PT, all of which can be done with a few milliliters of serum. Certainly in monitoring isoniazid or methyldopa therapy, SG PT level should be measured. Jaundice should not be used as the criterion for discontinuing therapy, because it is a late manifestation of drug toxicity. Se/erasing cholangitis and pericholangitis-Hepatocellular function is normal early in these cholestatic syndromes which occur in adult life, but a progressive inflammatory reaction in the biliary tree eventually leads to cirrhosis. Sclerosing cholangitis and pericholangitis may be associated with chronic inflammatory disease elsewhere, particularly in the intestine. Occasionally thyroiditis may also be associated with chronic biliary tract inflammation, which implies a lymphocyte-mediated pathogenesis. In contrast to primary biliary cirrhosis, in sclerosing cholangitis and pericholangitis circulating antibodcontinued
VOL85/NO 1/JANUARY 1979/POSTGRADUATE MEDICINE
Nonnan B. Javitt Dr Javitt is professor of medicine and head of the division of gastroenterology, New York Hospital-Comell Medical Center, New York.
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See important product information including warnings, adverse reactions. patient selection and prescribing and precautionary recommendations.
Because virtually any drug is capable of inducing cholestasis, liver function should be monitored whenever long-term therapy is started.
ies to mitochondria are not found and men and women are affected with equal frequency. The diagnosis of sclerosing cholangitis is made by cholangiography showing narrowing of the lumina of the biliary tree. Pericholangitis is suspected from liver biopsy findings, from typical clinical manifestations (particularly when associated with disease of other organs), and from characteristic laboratory data. Primary biliary cirrhosis- This disease, like cholangitis, occurs in adults. Causes are probably diverse, but in each instance the inflammatory reaction is directed at the bile ductules. Early in the disease the characteristic dense lymphocytic infiltrates in the portal areas, together with bile duct necrosis, may not be seen in tissue obtained by percutaneous liver biopsy but will be seen in tissue containing larger bile ductules, such as is obtained by open biopsy. Clinically, there is a tendency to diagnose primary biliary cirrhosis on insufficient evidence. Thus, when routine biochemical analysis (SMA-12) shows an asymptomatic patient to have an elevated alkaline phosphatase level, an investigation is initiated to determine the source of the abnormality. An elevated level of 5'-nucleotidase or of gammaglutamyl transferase confirms the source as the liver, and a positive test for antimitochondrial antibodies is accepted as sufficient evidence for the diagnosis of biliary cirrhosis. However, the absence of pruritus, of
128
The Beta 2 metered aerosol
BRONKOMETERe (ISOETHARINE MESYLATE)
hyperbilirubinemia, or of an elevated level of serum bile acid should indicate that hepatic excretory function is not decreased. In my experience, progressive disease does not always develop in persons in this category. I believe the abnormalities represent a type of hepatitis that can have a favorable prognosis. Similar findings have been reported by other physicians. 15 Classically, primary biliary cirrhosis presents in the postmenopausal woman with darkening of the skin, pruritus, and a bitter taste sensation. The skin pigmentation results from deposition of melanin, but the relationship to the disease is unexplained. Experience indicates that azathioprine is ineffective in suppressing the inflammatory reaction in the portal areas and that steroids accelerate the osteoporosis and other complications of the illness without providing any benefits. Patients 'with early disease have a relatively normal level of serum bile acid after an overnight fast; pruritus is least severe in the morning.B Administration of large doses of cholestyramine with breakfast prevents the postprandial elevation in serum bile acid level and effectively relieves the pruritus. I have not seen further progression of the liver disease in patients treated with cholestyramine at this phase. In addition to a bile-acidsequestering agent, fat-soluble vitamins and calcium should be given to avoid the progressive osteoporosis associated with primary biliary cirrhosis. continued
DESCRIPTION: Bronkomeler is a complete pocket nebulizer containing lsoetharine mesylate 0.61% (W/W) with saccharin, menthol, alcohol 30% (W/W). and fluorochlorohydrocarbons as gaseous propellants. Preserved with ascorbic acid 0.1% (W/W) ''As originally marketed, Bronkometer contained thenyldiamine hydrochloride 0.05% and phenyl· ephrine hydrochloride 0.125%. The presentformu· lation has been revised to delete these ingredients. I soethari ne is I· ( 3, 4 di hydroxyphenyl)·2·iso· propylamino·l·butanol. The Bronkometer unit delivers approximately 20 metered doses per ml. of solution. Each average 56 mg. delivery contains 340 mcg. isoetharine. ACTION: lsoetharine is a sympathomimetic amine w1th preferential affinity for Beta,adrenergic recep· tor sites of bronchial and certain arteriolar mus· culature. and a lower order of affinity for Beta 1 adrenergic receptors. Its activity in symptomatiC relief of bronchospasm is rap1d and of relatively long duration. By relieving bronchospasm, Bronkometer helps give prompt relief and signif· icantly increases v1tal capacity. INDICATIONS: Bronkometer is indicated for the acute relief of bronchial asthma and other condi· tions in wh1ch bronchospasm is a complicatmg factor. such as chronic bronchitiS or emphysema. CONTRAINDICATION: Bronkometer should not be admmistered to pat1ents who are hypersensitive to any of 1ts ingredients. WARNINGS: Excessive use of an adrenergic aerosol should be discouraged as 11 may lose its effective· ness. Occas1onal patients have been reported to develop severe paradoxical airway resistance with repeated excess1ve use of an aerosol adrenergic inhalatiOn preparation. The cause of this refractory state IS unknown. lt is advisable that 1n such In· stances the use of the aerosol adrenergic be discontmued Immediately and alternative therapy mst1tuted. since 1n the reported cases the patients d1d not respond to other forms of therapy until the drug was withdrawn. Cardiac arrest has been noted in several instances. Bronkometer should not be administered along with epinephrine or other sympathomimetic amines. since these drugs are direct card1ac stimulants and may cause excessive tachycardia. They may, how· ever. be alternated if desired. Usage in PreRnancy: Although there has been no ev1dence of teratogenic effects with this drug, use of any drug 1n pregnancy, lactat1on, or 1n women of childbearing potential requireS that the potential benefit of the drug be weighed against its poss1ble hazard to the mother or child PRECAUTIONS: Dosage must be carefully adjusted 1n pat1ents w1th hyperthyroidism, hypertension, acute coronary disease. cardiac asthma. lim1ted cardiac reserve, and in individuals sensitive to sympathomimetiC ammes. smce overdosage may result in tachycardia. palpitatiOn, nausea. head· ache. or epmephrine·like side effects. ADVERSE REACTIONS: Although Bronkometer is relatively free of tox1c side effects. too frequent use may cause tachycardia, palpitation. nausea. headache. changes 1n blood pressure.anxiety, ten· si on. restlessness. insomnia, tremor. weakness. dizzmess. and excitement, as IS the case w1th other sympathomimetic amines. DOSAGE AND ADMINISTRATION: The average adult dose is one or two inhalations. Occasionally, more may be required. it is 1mportant. however. to wait one full minute after the Initial one or two inhalations 1n order to be certain whether another 1s necessary. In most cases. inhalations need not be repeated more often than every four hours. although more frequent admmistrat1on may be neces-
sary rn severe cases. HOW SUPPLIED: Bronkometer' 10 mI. Vial w1th Oral Nebul1zer. Code No. 1740. Bronkometer• 20 ml. V1al with Oral Nebulizer. Code No. 1742. Bronkometer' 10 ml. refill only, Code No. 1743 Bronkometer' 20 ml. refill only, Code No. 1741
l:l;IJ•UI Breon Laboratories Inc. 90 Pari< Avenue. New Yorl
