Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Jaundice and cholestasis Stuart C. Gordon MD To cite this article: Stuart C. Gordon MD (1991) Jaundice and cholestasis, Postgraduate Medicine, 90:4, 65-71, DOI: 10.1080/00325481.1991.11701060 To link to this article: http://dx.doi.org/10.1080/00325481.1991.11701060
Published online: 17 May 2016.
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Date: 24 July 2016, At: 15:30
--@CME credit article
Jaundice and cholestasis Some common and uncommon causes
Stuart C. Gordon, MD
Downloaded by [University of Technology Sydney] at 15:30 24 July 2016
Preview Jaundiced patients may not always be as sick as they look, and cholestatic patients may be quite ill but not yet jaundiced. There is variability in presentation of cholestasis, and jaundice may be intrahepatic or extrahepatic and acute or chronic. Even though the diagnosis of jaundice can be elusive, an unnecessarily exhaustive search for a cause should be avoided, because some tests are not without dangers. Dr Gordon describes many possible causes, some of which are rare but are still worth consideration.
Jaundiced patients can pose a great clinical challenge. Nowadays, with the combination of modern laboratories, viral serologic assays, sophisticated imaging studies, and cholangiography; the cause is usually established easily. In an occasional patient, however, jaundice is unexplained or the cause of cholestasis is unclear despite all of these technological advances.
Jaundice versus cholestasis Not all cholestatic patients are jaundiced and vice versa. Cholestasis (ie, impaired secretion of bile) has different clinical definitions to different specialists. To pathologists, it represents the plugging of bile ducts. To physiologists, it represents a defect in biliary transpon mechanisms. To clinicians, however, cholestasis usually implies an elevated alkaline phosphatase level, pruritus, and possibly, but not always, jaundice. Patients with primary biliary cirrhosis, for example, may be profoundly cholestatic but have a normal serum bilirubin level.
Jaundice (ie, hyperbilirubinemia) may accompany almost any liver disorder. It may also result from hemolysis, but in hemolytic syndromes, bilirubin is primarily unconjugated, scleral icterus is rare, and the serum bilirubin level rarely exceeds 5 mg/dL. Disorders ofbilirubin metabolism (eg, Gilben syndrome, CriglerNajjar syndrome) also can produce hyperbilirubinemia but not cholestasis. Disorders unrelated to the liver (eg, sepsis, lymphoma) may produce both deep jaundice and clinical cholestasis. With these ambiguities in mind, investigators classifY cholestatic jaundice as intrahepatic or extrahepatic. Syndromes of intrahepatic (ie, nonobstructive) cholestasis can mimic obstructive jaundice clinically. However, cholestatic disorders may also be completely asymptomatic. Most cases of extrahepatic (ie, obstructive) jaundice are easily diagnosed with ultrasound or endoscopic retrograde cholangiopancreatography, yet confusion still exists in some cases. Although some of these conditions are
VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE • JAUNDICE AND CHOLESTASIS
uncommon, their prompt recognition may help guide diagnosis and treatment.
Intrahepatic causes of cholestatic jaundice Causes of cholestatic jaundice are summarized in table 1. Some common and uncommon intrahepatic sources are discussed in the following text. HEPATITIS A-Acutely jaundiced patients represent an urgent diagnostic challenge. In general, if ultrasound examination shows normal bile ducts, a nonmechanical cause should be sought. Probably the most common cause of acute jaundice is acute viral hepatitis. Patients with acute hepatitis B may present with deep jaundice, but most are anicteric. In a small percentage of patients, the acute episode may progress to chronic hepatitis B. Persistent jaundice in these patients is unusual. Acute hepatitis A may also present with deep jaundice. Hepatitis A does not progress to the chronic carrier state, but jaundice may persist for a prolonged period after the acute episode. Hepatitis A is usually a benign disorder of childhood. However, it runs a more severe and protracted course (perhaps for weeks or months) if acquired in adulthood. Jaundice is more common in adults than in children. Biphasic and even triphasic courses, in which symptoms abate only to flare up again and again, may continued 65
Downloaded by [University of Technology Sydney] at 15:30 24 July 2016
Probably the most common cause of acute jaundice is acute viral hepatitis.
Table 1. Causes of cholestatic jaundice Acute intrahepatic disorders Alcoholic hepatitis Amyloidosis Benign recurrent intrahepatic cholestasis Cholestasis of pregnancy Drug use Amoxicillin-clavulanate potassium (Augmentin) Anabolic steroids Chlorpropamide (Diabinese) Contraceptive steroids Danazol (Danocrine) Erythromycin Injectable gold compounds lnterleukin-2 Megestrol acetate (Megace) Phenothiazine derivatives Trimethoprim-sulfamethoxazole Hodgkin's disease Postoperative cholestasis Sarcoidosis Sepsis Sickle cell anemia Total parenteral nutrition Toxic shock syndrome Viral hepatitis (especially type A) Chronic cholestatic syndromes Drug use Ajmaline* Chlorpromazine HCI (Thorazine) Chlorpropamide Floxacillin (Fioxapen) Haloperidol (Haldol) Imipramine HCI (Janimine, Tofranil) Phenytoin sodium (Dilantin) Tolbutamide (Orinase) Trimethoprim-sulfamethoxazole Idiopathic adulthood ductopenia Primary biliary cirrhosis Primary sclerosing cholangitis Sarcoidosis
occur. Ultimately, recovery is the
rule. An unusual form of hepatitis A is the cholestatic variant. These patients generally recover completely from hepatitis (ie, aminotransferase levels return to normal), but they have prolonged jaundice. The serum bilirubin level may reach 30 mg!d.L, pruritus may be intense, and patients are miserable. In one series of such patients, 1 clinicians were not aware that hepatitis A could behave in this manner, so many patients were unnecessarily hospitalized for extensive investigations. Cholestatic variants of acute viral hepatitis are not unique to hepatitis A Prolonged jaundice may occur as a sequela of acute hepatitis B as well. Presumably, other viral hepatitis agents may also cause protracted jaundice, but less is known about these entities. Because ours is a highly mobile society, practitioners are likely to see adults who have contracted hepatitis A infection during travel to an endemic region (eg, South or Central America, India). Development of jaundice is not a cause for concern, bur practitioners should be aware of this unusual but benign cholestatic syndrome. POSTOPERATIVE JAUNDICE-The appearance of jaundice afrer surgery is alarming to patients, families, and surgeons alike. Often, however, fears are unfounded. The critical issue in such cases is to differentiate liver fail-
ure from jaundice and to realize that these two conditions are not synonymous. Soon afrer the introduction of chloroform in the 1800s came reports of liver failure associated with its use. Fatal halothane hepatitis was recognized in the 1950s. Nevertheless, oven liver failure (coagulopathy, encephalopathy, and renal failure) after surgery is unusual under ordinary circumstances. If cirrhosis is present, however, surgery may be risky. Before the decision to operate is made, risk-benefit factors should be assessed. By definition, benign postoperative cholestasis implies that hepatocellular injury is not severe and that the liver was normal preoperatively. Typically, in patients with benign postoperative cholestasis, jaundice appears 2 to 10 days afrer surgery. Although aminotransferase levels are not significantly elevated, jaundice may be deep and the serum bilirubin level may reach as high as 40 mgld.L. Patients are otherwise healthy, and jaundice usually resolves by the third postoperative week The absence of the stigmata of chronic liver disease and the presence of nondilated bile ducts on ultrasound suppon the diagnosis of benign postoperative cholestasis. The cause of jaundice is usually multifactorial in these patients. 2 Since these patients are often in an intensive care unit, it is difficult to son out individual pathophysiologic
*Not available in the United States.
66
JAUNDICE AND CHOLESTASIS • VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE
Downloaded by [University of Technology Sydney] at 15:30 24 July 2016
Recognition of septic jaundice is a true "clinical pearl," because the liver is actually normal.
mechanisms. The pigment load of multiple blood transfusions, renal insufficiency with decreased bilirubin clearance, resorption of extravasated blood, hypoxemia and hypotension, use of drugs and anesthetic agents, and concurrent infection may all contribute to postoperative jaundice. Recognition ofbenign postoperative cholestasis may help avert unnecessary invasive procedures and reassure the patient, family, and medical team.
SEPSis--Patients with sepsis may become deeply jaundiced.1 However, the liver is actually normal (ie, withour parenchymal disease), and the source of sepsis may be far removed from the biliary tree. Thus, recognition of septic jaundice is a true "clinical pearl." Although mild hyperbilirubinemia is common in adults with extrahepatic bacterial infection, overt jaundice is not; in fact, jaundice occurs in less than 1o/o of all bacteremic patients. 1 Therefore, the presence of jaundice in these patients confuses manv clinicians. Typically, patients present with overwhelming (usually gram-negative) sepsis. The pathogenesis of the jaundice may be related to the resultant endotoxemia. The syndrome has been reported in association with many organisms, however, including Streptococcus and Staphylococcus. Hyperbilirubinemia (usually of conjugated bilirubin) may be profound, and the serum bilirubin level
may reach 30 mg!dl. Serum aminotransferase and alkaline phosphatase levels may be slightly elevated, but much less so than they are in hepatocellular or extrahepatic obstructive jaundice. The crucial entity to be differentiated in patients with septic jaundice is cholangitis. The combination of fever, leukocytosis, and jaundice strongly mimics biliary infection, and clues to the correct diagnosis often come from the history, physical examination, and biochemical profile. For example, jaundice in the presence of urosepsis, pyelonephritis, or pneumonia (especially pneumococcal) suggests septic jaundice. This diagnosis would be supported by the absence of right-upper-quadrant pain and by normal results on biliary ultrasound. If doubt remains, direct cholangiography (eg, endoscopic retrograde cholangiopancreatography) may be helpful. Differentiation is critical because laparotomy performed to treat a nonexistent biliary obstruction may be hazardous. HODGKIN'S DISEASE-An unusual cause of intrahepatic jaundice is Hodgkin's disease. Lymphomas can cause cholestasis by various mechanisms. Most commonly, lymphomatous cells infiltrate the portal tracts. The alkaline phosphatase level is raised, bur jaundice is mild. Fever is common. The diagnosis of this condition is established by liver biopsy, Lymphoma has a patchy distribution in the
VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE • JAUNDICE AND CHOLESTASIS
liver, so laparoscopically guided biopsy may increase the diagnostic yield. Occasionally, extrahepatic jaundice may result from lymph node obstruction at the porta hepatis. Computed tomography is helpful in making this diagnosis. An extremely rare form of intrahepatic jaundice may occur in Hodgkin's disease in the absence of any liver involvement. Deep and protracted jaundice may be seen, with intense pruritus and high fever. In some cases, jaundice may actually predate the appearance of systemic lymphoma. The pathogenesis of this very obscure jaundice is unknown, bur it may be humorally mediated. DRUG USE-Although all clinicians are aware of drug-induced jaundice, it can masquerade as one of several clinical syndromes and remain undiagnosed. A detailed clinical history is necessary, since patients often do not think to volunteer the fact that they use oral contraceptives and can easily overlook a recently prescribed antibiotic. The use of anabolic steroids, even months earlier,' should be questioned. In the elderly, polypharmacy must be scrupulously examined. It is often helpful to have patients bring all drugs from their home medicine cabinet to an office appointment. Drug-induced cholestatic reactions may be divided into two categories: bland and exudative.1' An example of bland cholestasis is the reaction caused by contraceptive continued
67
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Drug-induced cholestasis is usually mild, but jaundice may be prolonged.
steroids. Infrequently, these estrogen compounds can produce deep jaundice; liver biopsy specimens show little inflammation, however. Exudative cholestatic hepatitis can result from use of such drugs as erythromycin and chlorpromazine hydrochloride (Thorazine). In these cases, jaundice may have a hepatitic component as well. A variety of drugs can cause acute cholestatic reactions (table 1), some of which may run a protracted course. Whether drug use can actually cause a chronic cholestatic syndrome is not well documented, but some drugs have been implicated. Drug-induced cholestasis is usually mild, but jaundice may be prolonged, occasionally launching a search for extrahepatic obstruction. The associated abdominal pain, increased alkaline phosphatase level, and weight loss can strongly suggest pancreatic neoplasm, particularly in elderly patients. As a result, endoscopic retrograde cholangiopancreatography or even exploratory laparotomy may be done unnecessarily. The diagnosis of drug-induced jaundice is usually one of exclusion. The presence of deep jaundice in a
Stuart C. Gordon, MD Dr Gordon is clinical assistant professor of medicine, Wayne State University School of Medicine, Detroit, and chief, division of gastroenterology-hepatology, William Beaumont Hospital, Royal Oak, Michigan.
patient who is otherwise reasonably healthy and has nondilated bile ducts on ultrasound suggests a druginduced process. Such jaundice may last for months. Corticosteroid therapy is often ineffective, but use of the bile acid-binding resin cholestyramine (Cholybar, Questran) may provide relief from pruritus. The popularity of confirming a drug reaction by rechallenge has waned in these litigious times.
Causes of chronic cholestatic syndromes The preceding discussion outlines various causes of intrahepatic jaundice, which is characterized by acute bilirubin elevation. It must be distinguished from so-called chronic cholestatic syndromes in adults. Traditionally, these latter conditions are characterized by prolonged alkaline phosphatase elevation, often without jaundice. Elevated levels of alkaline phosphatase can be a source of frustration for clinicians and raise many questions. How high is too high? What tests are appropriate? Which medications must be stopped? Should the patient see a specialist? In general, alkaline phosphatase elevation ofless than twice the upper limit of normal m an asymptomatic patient is not cause for concern. With progressive elevation, however, a reason should be sought. Occasionally, even with extensive investigation, no obvious cause is found. A search for the usual
causes of chronic cholestasis, however, is imperative. PRIMARY BIUARY CIRRHOSis--
This condition is not as rare as was once thought. It predominantly affects middle-aged women, but women of all ages, and occasionally men as well, may be affected. Thus, clinical suspicion of primary biliary cirrhosis must remain high in all cases of prolonged alkaline phosphatase elevation. All clinicians should recognize its clinical spectrum, since it is a disease with protean manifestations. Endocrinologists often see these patients because primary biliary cirrhosis accompanies hypothyroidism and autoimmune thyroiditis. Dermatologists should be aware that persistent, otherwise unexplained pruritus may indicate primary biliary cirrhosis. Often, rheumatologists are the first to see these patients because primary biliary cirrhosis is part of the spectrum of many rheumatologic and autoimmune conditions (eg, osteoporosis, rheumatoid and psoriatic arthritis, Sjogren's and sicca syndromes, scleroderma). In recent years, an increased association between primary biliary cirrhosis and breast cancer has been recognized. Fortunately, a diagnostic blood test is available. The presence of mitochondrial antibody in nearly 95% of patients with primary biliary cirrhosis usually facilitates a confident diagnosis." Liver biopsy results can help stage the disease process. In
continued 68
JAUNDICE AND CHOLESTASIS • VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE
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Diagnosis of hepatic sarcoidosis requires biopsy to establish the presence of hepatic granulomas.
many patients, the clisease has not yet progressed to cirrhosis at the time of diagnosis; thus, the term "primary biliary cirrhosis" is ofi:en a misnomer. Pruritus, which can be intense, is the most important symptom and is clearly these patients' main concern. Cholesryramine, in doses up to 16 g!day, can afford symptomatic relie£ Treatment of primary biliary cirrhosis is discussed elsewhere. 7 Despite profound cholestasis in these patients, jaundice is rare. If it occurs, it is a signal of impending liver failure. Some patients with primary biliary cirrhosis are entirely asymptomatic, and whether they have a better or worse prognosis than symptomatic patients is still being debated. Once persistent jaundice evolves, liver transplantation should be considered. PRIMARY SCLEROSING CHOLAN-
GITis--This condition is characterized by diffuse scarring and narrowing of the bile ducts. In the 1950s and 1960s, it was rarely if ever diagnosed, bur this changed with the advent of endoscopic cholangiography in the 1970s. Today, primary sclerosing cholangitis ranks as a major cause of chronic cholestasis, especially among young men with underlying ulcerative colitis. Like primary biliary cirrhosis, however, primary sclerosing cholangitis can affiict anyone, and medical practitioners should be aware of the clinical features of this disease.
70
It can present insidiously. For reasons that are not clear, nearly half of patients with primary sclerosing cholangitis have underlying ulcerative colitis. Some are asymptomatic and identified only by the incidental finding of alkaline phosphatase elevation. As more and more asymptomatic patients undergo endoscopic retrograde cholangiopancreatography, the incidence of primary sclerosing cholangitis is likely to increase. More typically, though, these patients present with pruritus and sometimes abdominal pain and fever. If the constricted bile ducts close off, obstructive jaundice may develop. Diagnosis of primary sclerosing cholangitis requires endoscopic cholangiography. In a patient with prolonged and unexplained significant elevations of alkaline phosphatase levels (ofliver origin) without mitochondrial antibody, endoscopic retrograde cholangiopancreatography is indicated. This study can both detect primary sclerosing cholangitis and exclude the presence of other diseases (eg, cholangiocarcinoma, choledocholithiasis). As is the case with primary biliary cirrhosis, debate focuses on whether asymptomatic patients with primary sclerosing cholangitis have a better or worse prognosis than symptomatic ones. There is also controversy about whether all patients should be entered into treatment trials at tertiary
JAUNDICE AND CHOLESTASIS • VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE
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medical centers. The definitive therapy for primary sclerosing cholangitis is not known; its natural history and medical and surgical management are discussed elsewhere. 8 Ultimately; "secondary'' biliary cirrhosis develops, and in some centers, primary sclerosing cholangitis is the major indication for liver transplantation. SARCOIDOSis-Differential diagnosis of prolonged alkaline phosphatase elevation should always include granulomatous disorders. Sarcoidosis, a systemic disorder, ofi:en involves the liver and is probably the most common cause of hepatic granulomas. 9 Unlike primary biliary cirrhosis, which is diagnosed by the presence of mitochondrial antibody, or primary sclerosing cholangitis, which is diagnosed with endoscopy, hepatic sarcoidosis can be diagnosed only by liver biopsy. Even then, the finding of hepatic granulomas can sometimes create more questions than answers. Nevertheless, if granulomas are found in two or more organ systems, the diagnosis of sarcoidosis can be made with some confidence. Symptoms of hepatic sarcoidosis are variable. This condition is ofi:en asymptomatic, but marked fatigue may be present. Although the biochemical profile usually indicates cholesrasis, pruritus is not a dominant feature. Jaundice is not common but can occur. Rarely, a prolonged
cholesratic syndrome resembling primary biliary cirrhosis is seen. In some patients, especially young black men, primary biliary cirrhosis and sarcoidosis are indistinguishable. Treatment of hepatic sarcoidosis is not mandatory. In symptomatic patients, a brief course of corticosteroids may be efficacious. Potentially infectious causes of hepatic granuloma (bacterial, viral, or fungal) must be excluded.
Conclusion
mary biliary cirrhosis, primary sclerosing cholangitis, and sarcoidosis, among others. Recently publishedguidelines10 provide a useful algorithm fur clinical evaluation of jaundice. Yet, despite all that has been written on this topic, individual patients often do not confurm to textbook definitions, and the diagnosis of cholestatic jaundice remains elusive. Multiple mechanisms may play a role. Therapeutic interventions fur jaundice are not without risk, so clinical judgment is critical: primum non nocere. PCN
Evaluation of jaundiced patients can be a diagnostic challenge. Some intrahepatic causes of cholestatic jaundice seen on medical wards include viral hepatitis, sepsis, postoperative mechanism, Hodgkin's disease, and use of certain drugs. Chronic cholestatic syndromes may result from pri-
References l. Gordon SC, Reddy KR, Schiff L, et al. Prolonged intrahepatic cholestasis secondary to acute hepatitis A. Ann Intern Med 1984;101 (5):635-7 2. Becker SD, Lamont JT. Postoperative jaundice. Semin Liver Dis 1988:8(2): 183-90 3. Bravo-Fernandez EF, SchiffER. How to pin down a septic cause of jaundice. J Crit Illness 1987; 2(9):24-41 4. Zimmerman HJ, Fang M, Utili R, et al. Jaundice due to bacterial infection. Gastroenterology 1979:77(2):362-74 5. Veneri RJ, Gordon SC. Anabolic steroidinduced cholestasis: choleretic response to corticosteroids. (Letter) J Clin Gastroenterol1988;10(4): 467-8 6. Kaplowitz N, Aw TY, Simon FR, et al. Drug-
VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE • JAUNDICE AND CHOLESTASIS
--®
Earn credit on this article. See CME Quiz.
Address for correspondence: Stuart C. Gordon, MD, Division of Gastroenterology-Hepatology, William Beaumont Hospital, 3601 W 13 Mile Rd, Royal Oak, MI 48073.
induced hepatotoxicity. Ann Intern Med 1986; 104(6):826-39 7. Kaplan MM. Primary biliary cirrhosis. N Eng! J Med 1987;316(9):521-8 8. LaRusso NF, Wiesner RH, LudwigJ.Is primary sclerosing cholangitis a bad disease' (Editorial) Gastroenterology 1987;92(6):2031-3 9. Maddrey WC. Granulomatous liver disease: clinical aspects. In: Seeff LB, Lewis JH, eds. Current perspectives in hepatology. New York: Plenum, 1989:309-26 10. Frank BB. Clinical evaluation of jaundice: a guideline of the Patient Care Commitree of the American Gastroenterological Association. JAMA 1989;262(21 ):3031-4
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ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Jaundice and cholestasis Stuart C. Gordon MD To cite this article: Stuart C. Gordon MD (1991) Jaundice and cholestasis, Postgraduate Medicine, 90:4, 65-71, DOI: 10.1080/00325481.1991.11701060 To link to this article: http://dx.doi.org/10.1080/00325481.1991.11701060
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Technology Sydney]
Date: 24 July 2016, At: 15:30
--@CME credit article
Jaundice and cholestasis Some common and uncommon causes
Stuart C. Gordon, MD
Downloaded by [University of Technology Sydney] at 15:30 24 July 2016
Preview Jaundiced patients may not always be as sick as they look, and cholestatic patients may be quite ill but not yet jaundiced. There is variability in presentation of cholestasis, and jaundice may be intrahepatic or extrahepatic and acute or chronic. Even though the diagnosis of jaundice can be elusive, an unnecessarily exhaustive search for a cause should be avoided, because some tests are not without dangers. Dr Gordon describes many possible causes, some of which are rare but are still worth consideration.
Jaundiced patients can pose a great clinical challenge. Nowadays, with the combination of modern laboratories, viral serologic assays, sophisticated imaging studies, and cholangiography; the cause is usually established easily. In an occasional patient, however, jaundice is unexplained or the cause of cholestasis is unclear despite all of these technological advances.
Jaundice versus cholestasis Not all cholestatic patients are jaundiced and vice versa. Cholestasis (ie, impaired secretion of bile) has different clinical definitions to different specialists. To pathologists, it represents the plugging of bile ducts. To physiologists, it represents a defect in biliary transpon mechanisms. To clinicians, however, cholestasis usually implies an elevated alkaline phosphatase level, pruritus, and possibly, but not always, jaundice. Patients with primary biliary cirrhosis, for example, may be profoundly cholestatic but have a normal serum bilirubin level.
Jaundice (ie, hyperbilirubinemia) may accompany almost any liver disorder. It may also result from hemolysis, but in hemolytic syndromes, bilirubin is primarily unconjugated, scleral icterus is rare, and the serum bilirubin level rarely exceeds 5 mg/dL. Disorders ofbilirubin metabolism (eg, Gilben syndrome, CriglerNajjar syndrome) also can produce hyperbilirubinemia but not cholestasis. Disorders unrelated to the liver (eg, sepsis, lymphoma) may produce both deep jaundice and clinical cholestasis. With these ambiguities in mind, investigators classifY cholestatic jaundice as intrahepatic or extrahepatic. Syndromes of intrahepatic (ie, nonobstructive) cholestasis can mimic obstructive jaundice clinically. However, cholestatic disorders may also be completely asymptomatic. Most cases of extrahepatic (ie, obstructive) jaundice are easily diagnosed with ultrasound or endoscopic retrograde cholangiopancreatography, yet confusion still exists in some cases. Although some of these conditions are
VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE • JAUNDICE AND CHOLESTASIS
uncommon, their prompt recognition may help guide diagnosis and treatment.
Intrahepatic causes of cholestatic jaundice Causes of cholestatic jaundice are summarized in table 1. Some common and uncommon intrahepatic sources are discussed in the following text. HEPATITIS A-Acutely jaundiced patients represent an urgent diagnostic challenge. In general, if ultrasound examination shows normal bile ducts, a nonmechanical cause should be sought. Probably the most common cause of acute jaundice is acute viral hepatitis. Patients with acute hepatitis B may present with deep jaundice, but most are anicteric. In a small percentage of patients, the acute episode may progress to chronic hepatitis B. Persistent jaundice in these patients is unusual. Acute hepatitis A may also present with deep jaundice. Hepatitis A does not progress to the chronic carrier state, but jaundice may persist for a prolonged period after the acute episode. Hepatitis A is usually a benign disorder of childhood. However, it runs a more severe and protracted course (perhaps for weeks or months) if acquired in adulthood. Jaundice is more common in adults than in children. Biphasic and even triphasic courses, in which symptoms abate only to flare up again and again, may continued 65
Downloaded by [University of Technology Sydney] at 15:30 24 July 2016
Probably the most common cause of acute jaundice is acute viral hepatitis.
Table 1. Causes of cholestatic jaundice Acute intrahepatic disorders Alcoholic hepatitis Amyloidosis Benign recurrent intrahepatic cholestasis Cholestasis of pregnancy Drug use Amoxicillin-clavulanate potassium (Augmentin) Anabolic steroids Chlorpropamide (Diabinese) Contraceptive steroids Danazol (Danocrine) Erythromycin Injectable gold compounds lnterleukin-2 Megestrol acetate (Megace) Phenothiazine derivatives Trimethoprim-sulfamethoxazole Hodgkin's disease Postoperative cholestasis Sarcoidosis Sepsis Sickle cell anemia Total parenteral nutrition Toxic shock syndrome Viral hepatitis (especially type A) Chronic cholestatic syndromes Drug use Ajmaline* Chlorpromazine HCI (Thorazine) Chlorpropamide Floxacillin (Fioxapen) Haloperidol (Haldol) Imipramine HCI (Janimine, Tofranil) Phenytoin sodium (Dilantin) Tolbutamide (Orinase) Trimethoprim-sulfamethoxazole Idiopathic adulthood ductopenia Primary biliary cirrhosis Primary sclerosing cholangitis Sarcoidosis
occur. Ultimately, recovery is the
rule. An unusual form of hepatitis A is the cholestatic variant. These patients generally recover completely from hepatitis (ie, aminotransferase levels return to normal), but they have prolonged jaundice. The serum bilirubin level may reach 30 mg!d.L, pruritus may be intense, and patients are miserable. In one series of such patients, 1 clinicians were not aware that hepatitis A could behave in this manner, so many patients were unnecessarily hospitalized for extensive investigations. Cholestatic variants of acute viral hepatitis are not unique to hepatitis A Prolonged jaundice may occur as a sequela of acute hepatitis B as well. Presumably, other viral hepatitis agents may also cause protracted jaundice, but less is known about these entities. Because ours is a highly mobile society, practitioners are likely to see adults who have contracted hepatitis A infection during travel to an endemic region (eg, South or Central America, India). Development of jaundice is not a cause for concern, bur practitioners should be aware of this unusual but benign cholestatic syndrome. POSTOPERATIVE JAUNDICE-The appearance of jaundice afrer surgery is alarming to patients, families, and surgeons alike. Often, however, fears are unfounded. The critical issue in such cases is to differentiate liver fail-
ure from jaundice and to realize that these two conditions are not synonymous. Soon afrer the introduction of chloroform in the 1800s came reports of liver failure associated with its use. Fatal halothane hepatitis was recognized in the 1950s. Nevertheless, oven liver failure (coagulopathy, encephalopathy, and renal failure) after surgery is unusual under ordinary circumstances. If cirrhosis is present, however, surgery may be risky. Before the decision to operate is made, risk-benefit factors should be assessed. By definition, benign postoperative cholestasis implies that hepatocellular injury is not severe and that the liver was normal preoperatively. Typically, in patients with benign postoperative cholestasis, jaundice appears 2 to 10 days afrer surgery. Although aminotransferase levels are not significantly elevated, jaundice may be deep and the serum bilirubin level may reach as high as 40 mgld.L. Patients are otherwise healthy, and jaundice usually resolves by the third postoperative week The absence of the stigmata of chronic liver disease and the presence of nondilated bile ducts on ultrasound suppon the diagnosis of benign postoperative cholestasis. The cause of jaundice is usually multifactorial in these patients. 2 Since these patients are often in an intensive care unit, it is difficult to son out individual pathophysiologic
*Not available in the United States.
66
JAUNDICE AND CHOLESTASIS • VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE
Downloaded by [University of Technology Sydney] at 15:30 24 July 2016
Recognition of septic jaundice is a true "clinical pearl," because the liver is actually normal.
mechanisms. The pigment load of multiple blood transfusions, renal insufficiency with decreased bilirubin clearance, resorption of extravasated blood, hypoxemia and hypotension, use of drugs and anesthetic agents, and concurrent infection may all contribute to postoperative jaundice. Recognition ofbenign postoperative cholestasis may help avert unnecessary invasive procedures and reassure the patient, family, and medical team.
SEPSis--Patients with sepsis may become deeply jaundiced.1 However, the liver is actually normal (ie, withour parenchymal disease), and the source of sepsis may be far removed from the biliary tree. Thus, recognition of septic jaundice is a true "clinical pearl." Although mild hyperbilirubinemia is common in adults with extrahepatic bacterial infection, overt jaundice is not; in fact, jaundice occurs in less than 1o/o of all bacteremic patients. 1 Therefore, the presence of jaundice in these patients confuses manv clinicians. Typically, patients present with overwhelming (usually gram-negative) sepsis. The pathogenesis of the jaundice may be related to the resultant endotoxemia. The syndrome has been reported in association with many organisms, however, including Streptococcus and Staphylococcus. Hyperbilirubinemia (usually of conjugated bilirubin) may be profound, and the serum bilirubin level
may reach 30 mg!dl. Serum aminotransferase and alkaline phosphatase levels may be slightly elevated, but much less so than they are in hepatocellular or extrahepatic obstructive jaundice. The crucial entity to be differentiated in patients with septic jaundice is cholangitis. The combination of fever, leukocytosis, and jaundice strongly mimics biliary infection, and clues to the correct diagnosis often come from the history, physical examination, and biochemical profile. For example, jaundice in the presence of urosepsis, pyelonephritis, or pneumonia (especially pneumococcal) suggests septic jaundice. This diagnosis would be supported by the absence of right-upper-quadrant pain and by normal results on biliary ultrasound. If doubt remains, direct cholangiography (eg, endoscopic retrograde cholangiopancreatography) may be helpful. Differentiation is critical because laparotomy performed to treat a nonexistent biliary obstruction may be hazardous. HODGKIN'S DISEASE-An unusual cause of intrahepatic jaundice is Hodgkin's disease. Lymphomas can cause cholestasis by various mechanisms. Most commonly, lymphomatous cells infiltrate the portal tracts. The alkaline phosphatase level is raised, bur jaundice is mild. Fever is common. The diagnosis of this condition is established by liver biopsy, Lymphoma has a patchy distribution in the
VOL 90/NO 4/SEPTEMBER 15, 1991/POSTGRADUATE MEDICINE • JAUNDICE AND CHOLESTASIS
liver, so laparoscopically guided biopsy may increase the diagnostic yield. Occasionally, extrahepatic jaundice may result from lymph node obstruction at the porta hepatis. Computed tomography is helpful in making this diagnosis. An extremely rare form of intrahepatic jaundice may occur in Hodgkin's disease in the absence of any liver involvement. Deep and protracted jaundice may be seen, with intense pruritus and high fever. In some cases, jaundice may actually predate the appearance of systemic lymphoma. The pathogenesis of this very obscure jaundice is unknown, bur it may be humorally mediated. DRUG USE-Although all clinicians are aware of drug-induced jaundice, it can masquerade as one of several clinical syndromes and remain undiagnosed. A detailed clinical history is necessary, since patients often do not think to volunteer the fact that they use oral contraceptives and can easily overlook a recently prescribed antibiotic. The use of anabolic steroids, even months earlier,' should be questioned. In the elderly, polypharmacy must be scrupulously examined. It is often helpful to have patients bring all drugs from their home medicine cabinet to an office appointment. Drug-induced cholestatic reactions may be divided into two categories: bland and exudative.1' An example of bland cholestasis is the reaction caused by contraceptive continued
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Drug-induced cholestasis is usually mild, but jaundice may be prolonged.
steroids. Infrequently, these estrogen compounds can produce deep jaundice; liver biopsy specimens show little inflammation, however. Exudative cholestatic hepatitis can result from use of such drugs as erythromycin and chlorpromazine hydrochloride (Thorazine). In these cases, jaundice may have a hepatitic component as well. A variety of drugs can cause acute cholestatic reactions (table 1), some of which may run a protracted course. Whether drug use can actually cause a chronic cholestatic syndrome is not well documented, but some drugs have been implicated. Drug-induced cholestasis is usually mild, but jaundice may be prolonged, occasionally launching a search for extrahepatic obstruction. The associated abdominal pain, increased alkaline phosphatase level, and weight loss can strongly suggest pancreatic neoplasm, particularly in elderly patients. As a result, endoscopic retrograde cholangiopancreatography or even exploratory laparotomy may be done unnecessarily. The diagnosis of drug-induced jaundice is usually one of exclusion. The presence of deep jaundice in a
Stuart C. Gordon, MD Dr Gordon is clinical assistant professor of medicine, Wayne State University School of Medicine, Detroit, and chief, division of gastroenterology-hepatology, William Beaumont Hospital, Royal Oak, Michigan.
patient who is otherwise reasonably healthy and has nondilated bile ducts on ultrasound suggests a druginduced process. Such jaundice may last for months. Corticosteroid therapy is often ineffective, but use of the bile acid-binding resin cholestyramine (Cholybar, Questran) may provide relief from pruritus. The popularity of confirming a drug reaction by rechallenge has waned in these litigious times.
Causes of chronic cholestatic syndromes The preceding discussion outlines various causes of intrahepatic jaundice, which is characterized by acute bilirubin elevation. It must be distinguished from so-called chronic cholestatic syndromes in adults. Traditionally, these latter conditions are characterized by prolonged alkaline phosphatase elevation, often without jaundice. Elevated levels of alkaline phosphatase can be a source of frustration for clinicians and raise many questions. How high is too high? What tests are appropriate? Which medications must be stopped? Should the patient see a specialist? In general, alkaline phosphatase elevation ofless than twice the upper limit of normal m an asymptomatic patient is not cause for concern. With progressive elevation, however, a reason should be sought. Occasionally, even with extensive investigation, no obvious cause is found. A search for the usual
causes of chronic cholestasis, however, is imperative. PRIMARY BIUARY CIRRHOSis--
This condition is not as rare as was once thought. It predominantly affects middle-aged women, but women of all ages, and occasionally men as well, may be affected. Thus, clinical suspicion of primary biliary cirrhosis must remain high in all cases of prolonged alkaline phosphatase elevation. All clinicians should recognize its clinical spectrum, since it is a disease with protean manifestations. Endocrinologists often see these patients because primary biliary cirrhosis accompanies hypothyroidism and autoimmune thyroiditis. Dermatologists should be aware that persistent, otherwise unexplained pruritus may indicate primary biliary cirrhosis. Often, rheumatologists are the first to see these patients because primary biliary cirrhosis is part of the spectrum of many rheumatologic and autoimmune conditions (eg, osteoporosis, rheumatoid and psoriatic arthritis, Sjogren's and sicca syndromes, scleroderma). In recent years, an increased association between primary biliary cirrhosis and breast cancer has been recognized. Fortunately, a diagnostic blood test is available. The presence of mitochondrial antibody in nearly 95% of patients with primary biliary cirrhosis usually facilitates a confident diagnosis." Liver biopsy results can help stage the disease process. In
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Diagnosis of hepatic sarcoidosis requires biopsy to establish the presence of hepatic granulomas.
many patients, the clisease has not yet progressed to cirrhosis at the time of diagnosis; thus, the term "primary biliary cirrhosis" is ofi:en a misnomer. Pruritus, which can be intense, is the most important symptom and is clearly these patients' main concern. Cholesryramine, in doses up to 16 g!day, can afford symptomatic relie£ Treatment of primary biliary cirrhosis is discussed elsewhere. 7 Despite profound cholestasis in these patients, jaundice is rare. If it occurs, it is a signal of impending liver failure. Some patients with primary biliary cirrhosis are entirely asymptomatic, and whether they have a better or worse prognosis than symptomatic patients is still being debated. Once persistent jaundice evolves, liver transplantation should be considered. PRIMARY SCLEROSING CHOLAN-
GITis--This condition is characterized by diffuse scarring and narrowing of the bile ducts. In the 1950s and 1960s, it was rarely if ever diagnosed, bur this changed with the advent of endoscopic cholangiography in the 1970s. Today, primary sclerosing cholangitis ranks as a major cause of chronic cholestasis, especially among young men with underlying ulcerative colitis. Like primary biliary cirrhosis, however, primary sclerosing cholangitis can affiict anyone, and medical practitioners should be aware of the clinical features of this disease.
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It can present insidiously. For reasons that are not clear, nearly half of patients with primary sclerosing cholangitis have underlying ulcerative colitis. Some are asymptomatic and identified only by the incidental finding of alkaline phosphatase elevation. As more and more asymptomatic patients undergo endoscopic retrograde cholangiopancreatography, the incidence of primary sclerosing cholangitis is likely to increase. More typically, though, these patients present with pruritus and sometimes abdominal pain and fever. If the constricted bile ducts close off, obstructive jaundice may develop. Diagnosis of primary sclerosing cholangitis requires endoscopic cholangiography. In a patient with prolonged and unexplained significant elevations of alkaline phosphatase levels (ofliver origin) without mitochondrial antibody, endoscopic retrograde cholangiopancreatography is indicated. This study can both detect primary sclerosing cholangitis and exclude the presence of other diseases (eg, cholangiocarcinoma, choledocholithiasis). As is the case with primary biliary cirrhosis, debate focuses on whether asymptomatic patients with primary sclerosing cholangitis have a better or worse prognosis than symptomatic ones. There is also controversy about whether all patients should be entered into treatment trials at tertiary
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medical centers. The definitive therapy for primary sclerosing cholangitis is not known; its natural history and medical and surgical management are discussed elsewhere. 8 Ultimately; "secondary'' biliary cirrhosis develops, and in some centers, primary sclerosing cholangitis is the major indication for liver transplantation. SARCOIDOSis-Differential diagnosis of prolonged alkaline phosphatase elevation should always include granulomatous disorders. Sarcoidosis, a systemic disorder, ofi:en involves the liver and is probably the most common cause of hepatic granulomas. 9 Unlike primary biliary cirrhosis, which is diagnosed by the presence of mitochondrial antibody, or primary sclerosing cholangitis, which is diagnosed with endoscopy, hepatic sarcoidosis can be diagnosed only by liver biopsy. Even then, the finding of hepatic granulomas can sometimes create more questions than answers. Nevertheless, if granulomas are found in two or more organ systems, the diagnosis of sarcoidosis can be made with some confidence. Symptoms of hepatic sarcoidosis are variable. This condition is ofi:en asymptomatic, but marked fatigue may be present. Although the biochemical profile usually indicates cholesrasis, pruritus is not a dominant feature. Jaundice is not common but can occur. Rarely, a prolonged
cholesratic syndrome resembling primary biliary cirrhosis is seen. In some patients, especially young black men, primary biliary cirrhosis and sarcoidosis are indistinguishable. Treatment of hepatic sarcoidosis is not mandatory. In symptomatic patients, a brief course of corticosteroids may be efficacious. Potentially infectious causes of hepatic granuloma (bacterial, viral, or fungal) must be excluded.
Conclusion
mary biliary cirrhosis, primary sclerosing cholangitis, and sarcoidosis, among others. Recently publishedguidelines10 provide a useful algorithm fur clinical evaluation of jaundice. Yet, despite all that has been written on this topic, individual patients often do not confurm to textbook definitions, and the diagnosis of cholestatic jaundice remains elusive. Multiple mechanisms may play a role. Therapeutic interventions fur jaundice are not without risk, so clinical judgment is critical: primum non nocere. PCN
Evaluation of jaundiced patients can be a diagnostic challenge. Some intrahepatic causes of cholestatic jaundice seen on medical wards include viral hepatitis, sepsis, postoperative mechanism, Hodgkin's disease, and use of certain drugs. Chronic cholestatic syndromes may result from pri-
References l. Gordon SC, Reddy KR, Schiff L, et al. Prolonged intrahepatic cholestasis secondary to acute hepatitis A. Ann Intern Med 1984;101 (5):635-7 2. Becker SD, Lamont JT. Postoperative jaundice. Semin Liver Dis 1988:8(2): 183-90 3. Bravo-Fernandez EF, SchiffER. How to pin down a septic cause of jaundice. J Crit Illness 1987; 2(9):24-41 4. Zimmerman HJ, Fang M, Utili R, et al. Jaundice due to bacterial infection. Gastroenterology 1979:77(2):362-74 5. Veneri RJ, Gordon SC. Anabolic steroidinduced cholestasis: choleretic response to corticosteroids. (Letter) J Clin Gastroenterol1988;10(4): 467-8 6. Kaplowitz N, Aw TY, Simon FR, et al. Drug-
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Earn credit on this article. See CME Quiz.
Address for correspondence: Stuart C. Gordon, MD, Division of Gastroenterology-Hepatology, William Beaumont Hospital, 3601 W 13 Mile Rd, Royal Oak, MI 48073.
induced hepatotoxicity. Ann Intern Med 1986; 104(6):826-39 7. Kaplan MM. Primary biliary cirrhosis. N Eng! J Med 1987;316(9):521-8 8. LaRusso NF, Wiesner RH, LudwigJ.Is primary sclerosing cholangitis a bad disease' (Editorial) Gastroenterology 1987;92(6):2031-3 9. Maddrey WC. Granulomatous liver disease: clinical aspects. In: Seeff LB, Lewis JH, eds. Current perspectives in hepatology. New York: Plenum, 1989:309-26 10. Frank BB. Clinical evaluation of jaundice: a guideline of the Patient Care Commitree of the American Gastroenterological Association. JAMA 1989;262(21 ):3031-4
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