Hospital Practice

ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20

Cholestatic Liver Disease Neil Kaplowitz To cite this article: Neil Kaplowitz (1978) Cholestatic Liver Disease, Hospital Practice, 13:8, 83-92, DOI: 10.1080/21548331.1978.11707386 To link to this article: http://dx.doi.org/10.1080/21548331.1978.11707386

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Date: 30 January 2017, At: 08:13

Cholestatic Liver Disease NF: 1 1. KA J> L

o w 1T z University of California, Los Angeles

The ncwer diagnostic techniques, such as ultrasonography and cholangiography by the thin needle or retrograde endoscopie approach, simplify differentiation of extrafrom intrahepatic disease and open the way to more specifie management.

This is the second of four articles on liver disease. The lirst, "The Viral Hepatitides" by Robert H. Purcell, was publislJed in the July issue. "Drug-Induced Liver lnjury" by Jerry R. Mitchell and Bernhard H. Lauterburg of Baylor, and "Alcoholic Hepatitis" by Carroll Leevy, New Jersey College of Medicine and Dentistry, will follow in September and October respectively.

Dr. Karlowitz ls Associate Pro/essor of Medicine, Univer~lty of Califomia at Los Angeles, School of Medicine, and Chief of Hepatology, Wadsworth Veterans Ad· ministratlon Ho1p1tal.

For many years the major problem with a primarily cholestatic disease has been to decide whether it is intrahepatic or extrahepatic, the former being amenable to supportive treatment only, the latter to surgery as weil. While in most cases the definitive diagnosis still cannot be made without performing an invasive procedure, recent improvements in diagnostic techniques have made the task of differentiation Jess difficult. In this second article on clinical strategy for dealing with severa! major li ver conditions, I should like to discuss, first, the mechanisms of adult cholestasis as they are understood today, then the diagnosis of primary cholestasis and the differentiation between intra- and extrahepatic disease, and, finally, aspects of treatment. To the physiologist studying an animal model, cholestasis means a redùction in the volume of bile coming from the common bile duct. To the pathologist, the condition appears on liver biopsy as plugs of bile in canaliculi. To the clinician, cholestasis is a syndrome involving impairment of bile formation or bile flow, the result being the retention in the blood or body of products ordinarily excreted in bile. In dise ases that primarily produce hepatocellular destruction, su ch as acute or chronic hepatitis, cholestasis is only one of many hepatic dysfunctions (secondary cholestasis). For this reason I shall omit them from this discussion and focus instead on conditions th at primarily or predominantly decrease bile secretion or flow (primary cholestasis). Physiologically, there are two main forms of bile secretion, one generated at the leve! of the hepatocytic canaliculus, the other at the level of the bile ducts. From the standpoint that a major function of the liver is excretion, or elimination, of both exogenous and endogenous lipophilic waste products, the main excretory function occurs not in the ducts but through the portion of the hepatocyte membrane that surrounds the lumen of the canaliculus. ln the ducts, only a mechanical obstruction can influence hepatocyte excretion, and then only secondarily as the result of pressure built up in the duct and canalicular systems. At the level of the hepatocyte and canaliculus, two forms of bile secretion occur: bile acid dependent and bile acid independent, both initiated by osmotic water movement following active solute secretion. Bile flow is characterized by the fact that with increasing bile acid excretion in the bile there is increased canalicular flow of bile. When this relationship is graphed, with canalicular flow shown on the ordinate and bile acid secretion on the abscissa, the Y intercept of the extrapolation of the line that is produced indicatcs the independent fraction (bile flow at zero hile acid excretion). Whcn phenobarbital or theophylline is administcred to an experimental animal, the indcpendent fraction increascs and the intercept of the line rises without its slope changing, the slopc representing bile acid-depcndent flow. Administration of ouahain, on the other hand, decreases

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independent flow and moves the line down. These changes may relate to effects on Na+K+ ATPase and the active transport of sodium into the canaliculus. There is sorne argument as to whether the extrapolation that points to bile acidindependent flow is valid, but in general it is accepted that there is an independent flow. The bile acid-dependent bile flow is the predominant form, however, and in the clinical context no further discussion of the independent flow is necessary, since, based on experimental animal work, interference with it in man seems unlikely to produce clinical cholestasis. lt is now generally accepted that an impairmcnt of bile acid excretion is the primary event in cholestasis, sincc the excretion of the other substances in the bile is dependent upon the excretion of the bile acids. The current view is that there are two independent transport systems in the hepatocyte as shown in illustration at top of page 85. One is for organic anions, such as bilirubin, sulfobromophthalein (BSP), indocyanine green (ICG), iodinated contrast agents, etc.; the other is for bile acids. At the leve! of the canaliculus, the two systems interact because bile acids form micelles (either in the liver cell or in the canaliculus), i.e., macromolecules consisting of bile acids, cholesterol, and lecithin. Physiologically, the micelle employs the detergent properties of hile acids to solubilize lipid-soluble material. Micelles also scem to incorporate the bulk of the organic anions found in bile, such as conjugated bilirubin. This interaction removes conjugated bilirubin monomers from canalicular bile, thcreby favoring carrier-mediated transport of more conjugated bilirubin monomcrs into bile. Therefore, one can say th at the ·micelles serve as a "sink." The more bile acid excreted in the bile, the larger this sink becomes and the greater its ability to incorporate bilirubin and other substances found in the bile. This is one way in which bile acids are thought to enhance the excretion of bilirubin. In addition to micelle formation, bile acids enhance the flow of bile through "rccruitment" of liver cells. To understand this process, one must kcep in mind that liver cells differ in terms of what they handle or "sec." Nearly ali of the bile acids arc brought to the liver from the small intestine by the portal circulation (only a small quantity is synthcsized daily in the liver), and the blood carrying the bile acids flows through the hepatic lobule to the terminal hepatic venule. At low levels of input, during fasting when most of the bile acids are stored in the gallbladder, these small quantities of bile acids are efficiently removed from plasma by the periportal hepatocytes, while the more centrilobular liver cells receive, or "sec," progressively Jess bile acids (see illustration, bottom of page 85). But when a meal is eaten and the gallbladder empties, the large bolus of bile acids th at th en enters the intestine is reabsorbed in the ileum and passes via the portal vein to the liver. Traveling from portal to terminal hepatic venules, the quantity of hile acids is now sufficiently large to reach, enter, and thereby "recruit" the hcpatocytes in the centrilohular zone. These cells then increasc their excretion of bile acids and, concomitantly, other bile constitucnts. This recruitment is probably just as important as the micellar sink in controlling bile flow and hepatic excretory function.

Initial Diagnostic Steps As is weil known, a common clinical feature of a cholestatic illness is pruritus, with or without jaundice. Xanthoma, xanthelasma, and hyperpigmentation may also be observed, but usually only after cholestasis has persistcd for some time. Cholestasis can exist without any of these symptoms and signs, but if it does, it is much Jess likely to become clinically apparent. When cholestasis is a possibility, it is important to elicit a dctailed drug history because sorne drug-induced cholestatic reactions can mimic extrahepatic obstruction even to the point of producing fcver and right upper-quadrant pain. An

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llospital Practice AUBUII 1978

alcohol history is also essential. The characteristics of the pain and the presence of cholangitis, fever, and rigors are very important historical elues to biliary tract disease. It is helpful to know if there is a family history of jaundice or liver discase, which would point to the possibility of familial benign recurrent intrahepatic cholestasis, jaundice of pregnancy (which seems to be familial), or sorne Ç>f the congenital cystic diseases of the biliary tree. The finding of weight loss and wasting suggests malignancy. Physical examinatian may show excoriations as evidence of pruritus, and one should look for xanthoma and stigmata of chronic li ver disease. In addition, the most obvious manifestation of extrahepatic obstruction is a palpable, nontender gallbladder, the socalled Courvoisier's gallbladder, which usually indicates extrahepatic common bile duct obstruction from cancer. Many la bora tory tests are employed in the diagnosis of primary cholestasis. Biochemically the sine qua non of cholestasis is a fasting serum bile acid level above the upper limit of normal (1.5 JLg/ml). A normallevel excludes significant cholestasis as a diagnosis, while accumulation of bile acids in the blood reflects impairment in bile acid excretion, since (as noted above) bile acids are the major determinant of hepatic bile secretion and excretory function. Since retention of bile acids in the serum occurs in virtually ali hepatobiliary diseases, however, increased serum bile acid levels are not in themselves evidence that primary cholestasis is present, though the elevation does indicate that, biochemically, most hepatobiliary diseases are to sorne extent cholestatic. Since a rise in serum bile acids does not provide a definitive diagnosis of primary cholestasis, other tests must be employed. A useful one is determination of the ratio of cholic acid to chenodeoxycholic acid (the two primary bile acids). In most forms of chronic hepatocellular disease, such as chronic active hepatitis and Laënnec's cirrhosis, the ratio is < 1, and usually even < o. s. whereas in extrahepatic obstruction and many intrahepatic cholestatic conditions, like primary biliary cirrhosis, it is al most always > 1. The expia nations for these differences in primary bile acid ratio are not entirely clear; one hypothesis involves a possible deficiency of the enzyme that converts dihydroxy to trihydroxy bile acid intermediates in cirrhosis (accounting for the cholic/chenodeoxycholic acid ratio of 1). 1 should like to emphasize that jaundice and cholestasis are by no means synonymous, since clinically a patient can have either without the other. For example, there are severa! congenital defects of bilirubin transport: Cilbert's disease is an uptake defect; Crigler-Najjar syndrome is a conjugating defect; and DubinJohnson syndrome is an excretory defect. In ali of these conditions jaundice can occur, yet serum bile acids are normal, bile acid transport is normal, and bile flow is not reduced. The defects in bilirubin transport occur in a pathway that has no influence on bile acid excretion, and the patients do not have either biochemical or clinical cholestasis. Pruritus usually occurs in cholestasis before jaundice is seen. The serum bile acid leve) even in the fasting state is elevated in many patients who are not jaundiced as weil' as in every patient with jaundice and cholestasis. Thus, serum bile acids are a more sensitive index of cholestasis than is serum bilirubin. The rea son is that the size of the bilirubin "pool" is only a tenth the size of the bile acid pool in the body. Bilirubin simply passes once through the liver and then is excreted, whereas bile acids are recirculated frequently, and only a small portion is excreted each day. Bence, in a defect of transport affecting bath, measurable retention in plasma of bile acids occurs before - and always is quantitatively larger than that of bilirubin, and pruritus is experienced before jaundice. Another hallmark of cholestasis is a rise in serum alkaline phosphatase. The

Hile acids and organic anion.ç move independent/y. from ccli to canaliculus. There tlrcu combine in mixed micelles that enhance excretion of bile constituents.

At low blood levels, bile acids are removed by Jleriporlal heJJatocvtet (vellow). On eating, bile acld levels rise, cen· trilobular cells are recruited (tan and gray), and thev increase bile secretion. llospital Practice Augutt 1978

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Differentiation of Cholestatic Liver Disease INTRAHEPATIC

Can.;alicul;u

Microscopie Duels Primary biliary cirrhosis Sarcoidmis Drugs, e.g., phenothiazines Pericholangitis lnfihrative disease (carcinoma, granulorna, etc.)

Drugs, e.g., androgens and estrogens Pregnancy Benign re1:urrent familial Sep sis Postoperative Hodgkin's disease Alcohollc liver disease Sickle ce tl nisis

M;uroscoplc Duct1 Caroli's disease Cholilngiocarcinoma EXTRAHEPATIC

Choledocholithiasis Bile duct carcinoma Stric:tures lsurgic:al, sclerosing cholangltis, etr..)

Perlampullary carclnoma Acute and/or chronlc pancreatills Panc:reatic carclnoma

mechanism is not completely clear, but an increase in the production of alkaline phosphatase by the liver ccli appears to accompany the obstructive disease (in experimental obstruction, pretreatment with protein synthesis inhibitors prcvcnts the increase). As a result, an abnormal amount of alkaline phosphatase is released into the blood. ln addition, li ver alkaline phosphatase is normally secreted to sorne degree in bile, and the form found there migrates somewhat differcntly on polyacrylamide gel electrophoresis than the liver alkaline phosphatase normally present in the blood. A significant amount of the bile type appears in the blood in cholestasis, presumably having been regurgitated from the canaliculus into the blood. When only certain parts of the liver are obstructed by infiltrative processes (e.g., when small scattered tumor nodules are present), or when there is partial obstruction of the common bile duct, or perhaps complete obstruction of sorne small branch of the biliary trec, s~rum alkaline phosphatase rises while serum bilirubin does not. The reason is that the unobstructed portions of the liver can easily remove the excess bilirubin and excrete it in the bile (in experimental animais, it has been shown that jaundice does not occur until three quarters of the liver has been ablated, indicating tremcndous functional reserve for excreting the bile constituents). Liver cells cannot, however, take alkaline phosphatase out of the blood, and once it is in the blood, it disappears more slowly. Since a rise in serum alkaline phosphatase also characterizes diseases of other organs, it is necessary to do confirmatory studies to localize the problcm to the liver. Two highly specifie livcr enzymes are 5'-nuclcotidasc and leucine aminc>peptidasc, which in cholestasis will rise along with alkaline phosphatasc. Gamma-glutamyl transpcptidase is an exquisitely sensitive liver enzyme test. Howcver, the difficulties with it arc that 1) it rises in the blood of patients taking such drugs as phenobarbital and phenytoin (diphenylhydantoin), and even after drinking alcohol; and 2) it is not Jiver specifie. ln my opinion, a test for gammaglutamyl transpeptidase is mainly of value if this enzyme is not elevated when alkaline phosphatase is, which indicates that the alkaline phosph~tase elevation is al most certain! y of nonhepatic origin. The presence of hyperlipidemia is highly suggestive of cholestasis, though it is not an invariable finding. To be more specifie, a patient with hepatohiliary discase, with or without jaundice, who has hypercholestcrolemia and hyperphospholipidemia (but not hypertriglyceridemia) is quite likely to have cholestasis. Although the mechanisms arc not cntircly clcar, one explanation for cholestatic

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Hospital Practice Augud 1978

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hyperlipidemia is that the obstruction to bile flow augments cholesterol synthesis in the liver. Possibly, a reduction in the quantity of bile acid that enters the lumen of the bowelleads to reduced cholesterol absorption by the liver, which, in turn, Jowers the inhibitory effect of cholesterol feedback on its own synthesis, so that the liver synthesizes more than is normal. A second explanation is that biliary lipid regurgitates directly from bile to blood. The excess plasma li~id seen ~n cholestasis has the characteristics of "lipoprotein-X," an abnormal hpoprotem containing large amounts of unesterified cholesterol and phospholipid, albumin, and other apolipoproteins. Its immunologie and electrophoretic properties make specifie identification possible. Lipoprotein-X appears in the blood when hepatic or common bile duct bile is experimentally introduced into the blood in animais. Another explanation for Jipoprotein-X, unproved thus far, is that in cholestasis there may be a deficiency of lecithin cholesterol acy !transferase (LCAT)- the li ver enzyme that esterifies cholesterol in the blood- or that the available LCAT is either overwhelmed by the large amount of biliary lipids or inhibited by elevated serum bile acid levels. ln the rare congenital absence of LCAT, the plasma lipid is closely similar to lipoprotein-X. One other test should not be overlooked, the stool guaiac. If it indicates occult gastrointestinal bleeding, there may be a malignancy in association with obstructive jaundice.

Types of Cholestasis Bcfore wc consider the diffcrentiation of intrahepatic from extrahepatic cholestasis, it is necessary to discuss the various forms of the disease, and 1 shall first mention the intrahcpatic conditions and thcn those dcfined as extrahepatic. Fundamentally, the pathophysiology of canalicular cholestasis involves dysfunction of the hile acid secretory apparatus in sorne way related to changes in the membrane microenvironment, whereas cholcstasis arising from anatomically more distal processcs may be viewed as mechanical obstruction with secondary impairment in the canalicular secretory apparatus. Below is a clinical classification of cholestasis based on anatomie localization of the primary dcfect, from the canaliculus to the sphincter of Oddi. When the disease originales at the canalicular leve!, it may be associated with pregnancy or ingestion of hormonal substances, such as estrogens or C-17 alkylsnhstitnted androgens (e.g., methyl testosterone). ln animal model~. the substances rnentioned damage the canalicular membrane; for examplc, it is known that estrogens can incrcasc its porosity, permitting leakage of material back into the blood. Also, the C-17 alkyl-substituted androgens have bcen shawn cxperimcntally to damage a microfilamentous "network attached to the canalicular membrane. This nctwork, which contains actin and has contractile properties, is thought to play a role in bile secretion, perhaps by squeezing the canaliculus closcd or crcating movement in the microvilli of the membrane. Other agents that might produce cholestasis clinically and biochemically have been shown to damage this microfilamentous contractile network. Severa! other conditions appear to result from dysfunction at the level of the canaliculus, since they are associated with cholestatic jaundice and centrolobular bile plugs on liver biopsy with no other apparent abnormalities. These include the cholestasis of sepsis, benign postoperative cholestasis, the idiopathie cholestasis sometimes scen in Hodgkin's disease, and the occasional cholestasis of sickle cell crises. The cholestasis of sepsis is interesting in that patients with severe in-· fections, with or without bacteremia, have long been known to develop jaundice. Recently it has been demonstrated experimentally that hacterial endotoxins impair bile flow and interfere with the excretion of bilirubin. This cholestasis of sepsis occurs in the absence of shock and vascular collapsc, which in themselves can

Hiopsy SIIL'cimen clemorutrates features of large duel oi1Sintction of relative/y reCl'nt origin. Note the marked, shm71lv dellwn·atecl t•clcma ancl bile cluct l!roliferation in 1111rta/ ZCitll'. Jlospital Practkc August 1978

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produce severe liver necrosis and, therefore, jaundice. Benign postoperative cholestasis, or postoperative jaundice, is a multifactorial entity or group of entities. Sorne patients develop iaundice after general anesthesia and/or uncomplicated procedures; no cause can be identified and their prognosis is usually good. More often, however, the etiology of jaundice in the postoperative patient is complex, involving transfusions, infection, shock, drug hepatitis, underlying liver disease, etc. ln sorne 10% to 15% of those patients with Hodgkin's disease who develop jaundice, no cause can be identified. Often the Hodgkin's disease is localized in these patients, and definitive radiation therapy results in the disappearance of the hepatic abnormality. Cholestasis can sometimes be a presenting fe a ture of localized Hodgkin's disease in lymph nodes remote from the liver, and the liver itself may not be involved. Conditions arising distal to the canaliculus may involve the interlobular bile ducts in the portal zone and may be associated with diffuse obstruction throughout the liver. Destructive and obliterative cholangitis or microscopie cholangiolitis is usually the underlying mechanism, as in primary biliary cirrhosis. The latter is a presumed autoimmune disease largely of middle-aged and elderly women. The condition is thought to result from a primary immune attack on the interlobular bile duct that causes destruction and ultimately virtual obliteration of almost ali interlobular bile ducts - to the extent that eventually they cannot be found on biopsy. Rarely, a similar lesion is seen in sarcoidosis or as a long-term consequence of thorazinc hypersensitivity. Gencrally, the patient presents with pruritus, often with xanthoma; jaundice occurs later. Antimitochondrial autibody is present in over 90% of patients with primary biliary cirrhosis. Since the antibody is also seen in other conditions, it is not diagnostic for primary biliary cirrhosis, nor does it exclude other causes of cholestasis, but it is a good confirmatory finding. In a number of forms of intrahepatic cholestasis, it is unclear whether the dysfunction is located primarily at the lev cl of the canaliculus or the interlobular bile duct. Such types as viral, alcoholic, or benign recurrent cholestasis appear most likely to be canalicular. Others, such as those obscrved with pericholangitis and infiltrative processes, appear to be ductular. Let us now examine thcsc in somewhat more detail. The prolonged cholestasis (it may persist for many months) scen in a very small percentage of viral hepatitis patients ultimately resolves and so carries a good prognosis. The persistence of chclestasis in such individuals should not be confused with chronic active hepatitis. Alcohol is an important cause of cholestasis among patients such as those wc sec at our Veterans Administration hospital. Usually patients with alcoholic cholestasis are binge drinkers, and their recurrent episodes of jaundice and pm ritus are associated with the characteristic markers: high alkaline phosphatase, hypercholestcrolemia, and marked cholestasis on liver biopsy. They usually have fatty infiltration of the liver and may or may not have liver ccli necrosis (alcoholic hepatitis). How alcohol produces impairment in bile secretion is not known. Patients with benign, recurrent (familial) intrahepatic cholestasis - a disease that has been rcported mainly in people under the age of 30 - develop recurrent episodes of jaundice, pruritus, and high alkaline phosphatase, and their liver biopsies show canalicular bile plugs. This illness carries a good prognosis in that there is no progessive liver disease. ln many patients with inflammatory bowel disease a liver biopsy will show inflammation, with chronic inflammatory cells and fibrosis surrounding interlobular bile ducts (pericholangitis). Sorne patients develop jaundice. This appcars to be a benign, nonprogressive form of cholestasis. However, it may be part

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Uospital Practice Auaust un8

of a spectrum of intra- and extrahepatic fibrosing diseases of bile ducts seen in these patients. Infiltrative diseases, such as cancers, can produce localized cholestasis, often leading to raised alkaline phosphatase in the blood and, in the very advanced stage, to actual jaundice. The mechanism probably is purely mechanical. Continuing the clinical-anatomic approach to cholestasis, we come to the macroscopic intrahepatic ducts. Primary cholestatic disease occurs at this leve! of the biliary trec owing to the development of cholangiocarcinoma or sorne times to congenital defects of the biliary trec. One of the latter is Caroli's disease, in which cysts of the macroscopic intrahepatic ducts are seen on the cholangiogram as grapelike clusters. Cystic dilation of the intrahepatic ducts produces stasis, fostering bacterial growth and recurrent episodes of cholangitis and jaundice. These episodes are associated with fever and rigors, but between episodes evidence of cholestasis is minimal. Ultimately biliary cirrhosis may develop. Other congenital defects of the biliary trec may occur singly or in any corn bi nation; the range encompasses congenital hepatic fibrosis and choledochal cysts. In ali these disorders associated with bile stasis, the potential for stone formation exists because of bacterial overgrowth, which is accompànied by bacterial production of bcta-glucuronidase. This enzyme hydrolyzes bilirubin glucuronides, giving rise to insoluble unconjugated bilirubin that precipitates and forms pigment gallstones. Wc have now arrivcd in our anatomie progression at the extrahepatic ducts. At the arca of the bifurcation of the left and right hepatic ducts and the common hcpatic duct, a relatively rare form of biliary tract cancer occurs: cholangiocarcinoma of the bifurcation. This condition may present insidiously as cholestasis, cither persistent or recurrent, which may last for months and even years. Most patients die not of the cancer itsclf but of liver failure, as a consequence of the long-standing hiliary obstruction. Early in the disease sorne patients present with pruritus, without jaundice, and with alkaline phosphatase elevation, particularly when the tumor involves one branch rather than the bifurcation. Only when the patient's tumor actually ohstructs both branches at the bifurcation does jaundice appear. If the tumor obstructs only one duct, the other duct system will be able to compcnsatc by clearing the hlood of retained bilirubin and bile acids, and the only evidence of localized (one lobe) cholestasis may he the elevated alkalinc phosphatase. The most common cause of extrahcpatic obstruction is probably choledocholithiasis, gallstone migration into the common bile duct. Characteristically, patients experience the classic pattern of biliary colic, often with sepsis followed by spontaneous passage of the stone into the intestine, althqugh occasionally the stone hecomes impacted. Other causes of cholcstasis in the main extrahcpatic system include henign stricturcs that in volve the extrahepatic biliary tree either segmentally or diffusely. Segmentai strictures can occur as a consequence of fibrosis and scarring following passage of stones or a cholecystectomy. Sclerosing cholangitis, a fihrosing, constricting process of the extrahepatic hiliary trec, can also he segmentai or diffuse; sorne bclieve it to be part of the overall spectrum of pericholangitis at the microscopie leve!. lnflammatory howel disease is associated with about a fourth of such cases. The major problem with these sclerosing processes is that cholangiocarcinomas produce a desmoplastic response that can make it very difficult to distinguish sclerosing strictures from sclerosing tumors. Sometimcs, it is impossible to differentia te the two, even at operation. Sorne experts be lieve that sclcrosing cholangitis is in fact always tumor, although this has not been proved. Other entities that obstruct the çommon bile duct are located either at the sphincter of Oddi or in the intrapancreatic portion of the common bile duct. As everyone rccognizes, severe, unrelenting cholcstasis, or obstructive jaundice, is

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l.arge canalicular bile r1lug (tor1 arrow) and plug in small bile duct (bottom arrow) indicate marked intrahepatic cholestash. Prognosis is good, since lhere ts n11 progre.\'.~ive ltverdisease. Hospital Pradice August 1978

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Longitudinal right parasagittal t4ltrasonogram reveals dilated intrahepatic durts (arrows), indicative of obstruction. Thin needle cholangiography is indicated. If bile duels were not dilatëd, retrograde endoscopie cholangiography would be choice.

a feature of carcinoma of the head of the pancreas. It is Jess widely appreciated that chronic inflammatory processes with scarring or acute edematous processes of the pancreas can also, either chronically or acutely, produce obstruction of the common bile duct. Here at the Wadsworth VA Hospital we have had extensive experience with this entity in association with chronic alcoholic pancreatitis. Nearly 10% of more than 200 of our patients with chronic alcoholic pancreatitis had chronic common bile duct obstruction on the basis of chronic scarring. Although these patients seem to have a very tight stenosis on cholangiography, with proximal dilation and only a hair-lïke distal common bile duct visible, interestingly the majority are not jaundiced. A high alkaline phosphatase is usually their only clinical biochemical abnormality. Yet they can have the full spectrum of liver histopathologic abnormalities from duct obstruction ali the way to biliary cirrhosis. Because of the makeup of our patient population, we find that chronic alcoholic pancreatitis is the most common cause of secondary biliary cirrhosis at our hospital. Those patients with common bile duct stenosis in association with chronic pancreatitis can become jaundiced transiently. Acute relapses of chronic pancreatitis can temporarily stenose the common bile duct and lead to cholestasis, which resolves when the pancreatic edema resolves. This feature is important in distinguishing this condition from carcinoma of the pancreas, which produces unrclenting progressive jaundice with complete obstruction. Thus, alcoholics can devclop hoth an intrahepatic cholestasis, as previonsly mentioned, and an extrahepatic cholestasis as a consequence of chronic pancreatitis. They may eithcr progrcss to chronic duct obstruction or undcrgo transicnt acutc relapses. Tu mors or aneurysms may bleed into the biliary trec, produce clots, and cause obstructive jaundice, lmt this condition, known as hemobilia, is quite unusual as a cause of cholestasis. Trauma to the liver (including liver biopsy) may a Iso cause he mo bilia. An unusual cause of infection and obstruction of the biliary trec is worm infestation. Although this condition is very uncommon in the United States, the popularity of international travel requires one to consider it in persans who have recently visited the Far East or Africa. About once a year we encounter a patient in whom a worm can be seen extruding from the common bile duct when the ampulla of Vater is viewed through an endoscope. 90

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Carcinoma of the ampulla of Vater (periampullary carcinoma) resembles ather forms of biliary tract cancer from a clinical and biochemical point of view. Since it is in continuity with the lumen of the Cl tract, however, it produces occult gastrointestinal bleeding much more often than do biliary tract cancers. Clinical experier.ce indicates that the prognosis of operable candidates, in tenns of survival after surgical resection, is significantly better than that of patients with pancreatic carcinoma, so that distinguishing between the two is important.

Intrahepatic vs Extrahepatic Di.fferentiation In the past, the approach to differentiating between intra- and extrahepatic cholestasis was a combination of observation over time and, ultimately, if there was no improvement, explora tory laparotomy. Liver biopsy was sometimes helpful but generally avoided in a deeply jaundiced patient because of the possiblity of bile leakage and bile peritonitis. This fear has been somewhat obviated by recent data that indicate a 'relatively law morbidity and virtually no mortality from pc:rcutaneous liver biopsy in individuals with documented obstructive disease. Although liver biopsies often suggest the diagnosis of extrahepatic obstruction, the information they provide is essentially indirect. In the first few weeks of extrahepatic obstruction, biopsy may disclose intrahepatic cholestasis and portal edema; later, bile duct proliferation, microscopie cholangitis, and other_abnormalities may be seen, but many of these histologie abnormalities also may be obscrved in cholestasis of intrahepatic origin. The definitive technique for distinguishing intrahepatic fr~m extrahepatic cholestasis is cholangiography. As a screening procedure, however, we advocate ultrasonography of the liver and the extrahepatic biliary tree, which may demonstrate dilation of intrahepatic ducts. Ultrasonography is much less likely to provide good direct information about the extrahepatic biliary tree, but it does delineate stones in the gallbladder. If the intrahepatic ducts are dilated on echography, a follow-up thin needle cholangiogram is performed. As described in more detail below, the contrast medium is very likely to enter the dilated ducts and define the anatomy. If on echography the intrahepatic ducts are not dilated, retrograde endoscopie cholangiography is indicated. ln the individual with a serum bilirubin of less than 3 mg/100 ml, one may try an intravenous cholangiogram using a soluble contrast agent like iodipamide, which is transported by hepatocytes into bile, thus outlining the extrahepatic biliary tree. When the bilirubin is over 3 mg, however, there is virtually no chance of visualization by intravenous infusion of dye, and the more invasive approaches must be adopted. The Japanese introduced thin needle cholangiography, a procedure that carries a very low morbidity in the setting of obstructive jaundice. lt is virtually 100% successful in cases of obstruction with intrahepatic duct dilation and frequently successful even in nonobstructed cases. The thin, flexible needle is introduced perèutaneously into the liver in the same way as for liver biopsy. The stylet is removed and the needle attached ta a reservoir of contrast agent. Theo, while contrast agent is continuously injected, the needle is slowly withdrawn until a duct is entered, which is followed by opacification of the entire biliary tree. If it is thought that the biliary system is obstructed, bile is first removed so that the dye injection will not overdistend the biliary tree. Success depends in sorne degree upon whether the system is obstructed. Usually up to ~ix or seven passes with the needle are tried, and if an obstruction is not found on any pass, it is virtually certain that the patient does not have dilated intrahepatic ducts. ln endoscopie retrograde cholangiography, success is not determined by the degree of dilation of the bile ducts but by the skill of the endoscopist. At most centers with experience in this procedure, it has become a reasonable alternative

l'ercutaneuus traMher1atic thin needle cholangiugraphy reveals dilation of intrahepatlc, common hepatlc, and common hile ducts as a result of stenosis of intrapancreatlc segment (arrow).

Endo.~t'Clllic

retrograde cholangiogram dilated right and left hepatic ducts resulting from stenusis of the commun duct, indicated hy am1w. disclose.~

Hospital Practice

A~~&ud

1978

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to the thin needle approach. A side-viewing duodenoscope is employed to provide a direct view of the ampulla of Va ter. The approach ena bles one to visualize any apparent malignancy; it also facilitates cannulation of the common bile duct and the pancreatic duct. A pancreatogram permits evaluation of the pancreas for cancer or chronic pancreatitis. ln both the thin needlc and the endoscopie approaches we treat the patient for 24 hours beforc and after the procedure with ampicillin or gentamicin in order to a vert septicemia that might be induced by injecting contrast material into the biHary trec and increasing the local pressure. If cither approach reveals a specifie defect in the anatomy of the biliary trec, a decision regarding surgery must be made. If the anatomy is normal, a liver biopsy is pcrformed in an attempt to define the cause of the intrahepatic cholestasis. Cenerally, biopsy rcsults are not sufficiently specifie for diagnosis, but occasionally evidence of primary biliary cirrhosis or infiltrative processes is obtained. This general approach must be somewhat modified in the alcoholic. We do a liver biopsy first, and if that shows features suggestive of extrahcpatic obstruction, we follow with a cholangiographic study. The critical point in the alcoholic, however, is the seriousness of hepatocellular damage. Even if a cholangiogram is undertaken first and reveals a surgicallesion, a liver biopsy to determine the activity and scvcrity of alcoholic liver disease is essential before a decision can be reached regarding surgery. Whilc surgery can often correct or pallia te the lesion in extrahepatic cholestasis, there is no curative therapy for primary intrahepatic cholestasis. One can only try to manage the medical complications, which are mainly pruritus and malabsorption of fat-soluble vitamins. Symptomatic steatorrhea can be improved hy substitution of medium-chain triglycerides. Supplemental vitamin D by injection or oral use of the newer hydroxylated derivatives when available may be ncccssary to maintain calcium balance and prevent disabling vertebral collapsc and bone fractures. The best treatment for pruritus seems to be the use of the bile acid binding anion exchange resin, cholestyramine. In an individual with partial obstruction at any leve! in the biliary tree, cholestyramine will reduce the si1.e of the circulating bile acid pool by sequestering bile acids in the CI tract and thus increasing their fecal elimination. Long-term medical treatmcnt of cholestasis must aIso consider the nutritional status, particularly in regard to fat and fat-soluble vitamins. One can only hope that further investigation will eventually lead to an adequate control of intrahcpatic cholestasis itself. D

Selected Reading Whcclcr HO: Secretion of hile. Discases of the Liver, 4th cd, Schiff L (Ed). J.R. Lippincott, New York, 1975 Bcrk PD, Javitt NB: llyperhiliruhincmia and cholcstasis. Am J Mcd 64:~ 11, 1978 Phillips MJ ct al: Microfilament dysfunction as a possible cause of intrahepatic cholcstasis. Castroentcrology 6Q:48, 1975 Layden TJ, Boyer JL: Taurolithocholate-induced l"holcstasis and hile canalicular membrane injury. Castroentcrology 73:120, 1977 Morris JS ct al: Pcrcutaneous liver hiopsy in patients with large hile duct obstruction. Gastrocntcrology 68:750, 1975 Littcnhcrg G, Afroudakis A, Kaplowitz N: Common hile duct stenosis in chronic pancrcatitis, a clinical and pathologie spectrum. Medicine (in press) Pcnnington CR, Ross PE, Bou chier lAD: Serum bile acids in the diagnosis of hepatohiliary discase. Cut t8:Q03, 1977 Brcnsilver HL, Kaplan MM: Significancc of elevated liver alkaline phosphatase in serum. Castroenterology 68:1556, 1975

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Hospital Practice Augu•t 197S