LIVER PHYSIOLOGY AND DISEASE

GASTROENTEROLOGY C opy ri~ht 1972 by The Williams & Wilkins Co. Vol. 62. No.3 Printed in U.S.A. LIVER PHYSIOLOGY AND DISEASE SPLENOMEGALY IN UNCOMPLICATED BILIARY TRACT AND PANCREATIC DISEASE PETER B. GREGORY, M.D., AND GERALD KLATSKIN, M.D. Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut The spleen was in 2 (15%) of 134 patients with surgically documented biliary tract or pancreatic disease, shown by clinical investigation, laparotomy, and liver biopsy to be uncomplicated by cirrhosis, portal vein obstruction, hepatic metastases, or other coincidental disease known to be associated with splenomegaly. That the spleen was not only, but also enlarged in most of these patients was confirmed by direct inspection at laparotomy or by roentgenog raphy in 7 of 8 so examined, and supported by the observation that portal pressure was increased in 2 of the 3 investigated, and that, in all 14 patients reexamined following surgical correction of their underlying biliary tract disease, the spleen was no longer. The clinical, laboratory, and liver biopsy findings in patients with and without splenomegaly did not differ significantly except that the duration of symptoms referable to the biliary tract and pancreas tended to be longer, and the degree of portal fibrosis and inflammation, ductular proliferation, bile stasis, and fatty infiltration tended to be less severe in those with splenomegaly. The data presented do not adequately account for the occurrence of splenomegaly, but suggest that it may be attributable to an increase in resistance to blood flow somewhere in the portal venous system. Splenomegaly is an unexpected and hitherto unreported finding in biliary tract or pancreatic disease uncomplicated by cirrhosis, portal obstruction, hepatic Received September 3, 1971. Accepted October 14, 1971. Address requests for reprints to: Dr. G. Klatskin, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 651. This work was supported by Research Grant AM 5966 and Training Grant 518 from the Institute of Arthritis and Metabolic Diseases, National Institutes of Health, United States Public Health Service, and the Harold C. Strong Liver Research Fund. Dr. P. B. Gregory, who was a Trainee of the Liver Study Unit, is currently in the Department of Medicine, Stanford University School of Medicine. metastases, or other coincidental disorders known to be associated with splenic enlargement. The following report of 2 such cases is worthy of note, since failure to recognize the association between splenomegaly and uncomplicated biliary tract or pancreatic disease may lead to errors in diagnosis. Materials and Methods The 2 cases of splenomegaly to be described were encountered in a group of 134 patients with biliary tract or pancreatic disease who met the following criteria: (1) biliary tract or pancreatic disease documented by surgical exploration, (2) availability of liver biopsy material, and (3) absence of cirrhosis, extrahepatic portal venous obstruction, hepatic 436

March 1972 LIVER PHYSIOLOGY AND DISEASE 437 metastases, or other coincidental disorders known to be associated with splenic enlargement, established by clinical investigation, surgical exploration, and liver biopsy. All patients were investigated by members of the Liver Study Unit staff between 1951 and 1969. Patients were examined in both the recumbent and right lateral decubitus positions to determine whether or not the spleen was, and, in each case, the findings were confirmed by at least two experienced observers. The liver was classified as enlarged if its inferior margin was 2 or more fingerbreadths below the right costal margin in the midclavicular line when the upper level of hepatic dullness was in the fifth intercostal space, and 3 or more fingerbreadths below the costal margin when the upper level of dullness was in the sixth interspace. Only moderate or marked degrees of induration and tenderness were considered significant. The clinical and laboratory features of the 2 patients with a spleen were compared with those in the 114 with similar disorders of the biliary tract and pancreas in whom the spleen was not. Liver biopsy was carried out by needle aspiration in 74, by surgical wedge excision in 41, and by both methods in 19 patients. Needle biopsy specimens were fixed in Carnoy's solution, surgical specimens in formalin. Sections stained with hematoxylin-eosin, Masson's stain for collagen, and Wilder's silver stain for reticulin were examined by one of us (G. K.) to assess the severity of portal inflammation and fibrosis, ductular proliferation, and the degree of intralobular bile stasis, inflammation, degeneration and necrosis, and fatty infiltration. The extent of portal fibrosis was graded as follows: 1+, mild fibrosis and expansion of the triads; 2+, moderate fibrosis and expansion of the triads with only occasional stellate extensions into the parenchyma; and 3+, moderate fibrosis and expansion of the triads with more frequent stellate extensions into the parenchyma and occasional bridging of adjacent triads. Patients with more extensive fibrosis distorting the normal lobular architecture and outlining nodules of parenchyma, graded 4+ and classified as secondary biliary cirrhosis, were excluded from consideration. All other histological abnormalities were graded as mild, moderate, or marked. Results The spleen was on physical examination, and thought to be enlarged clinically, in 2 (15%) of the 134 patients with surgically documented uncomplicated biliary tract or pancreatic disease. On inspiration, the edge of the spleen descended 1 fingerbreadth below the left costal margin in 11, 2 fingerbreadths in 7, and 3 fingerbreadths in 2. That the spleen was not only, but also enlarged was confirmed in 7 of these cases-by direct inspection at laparotomy in 3, by both direct inspection and roentgenography in 2, and by roentgenography alone in 2. These included 2 patients each with choledocholithiasis, cholelithiasis, and carcinoma of the head of the pancreas, and 1 with stricture.of the common bile duct. In the only other case in which the spleen was examined at laparotomy, a patient with choledocholithiasis, apparent enlargement of the spleen by palpation was not confirmed by direct inspection. Portal venous pressure was measured in 3 of the patients with a spleen and was found to be mildly elevated in 2-25 mm of saline on percutaneous cannulation of the splenic pulp in a patient with stricture of the common bile duct, and 28 mm of saline on cannulation of a portal vein radicle at laparotomy in a patient with choledocholithiasis. In both cases, splenic enlargement was confirmed by direct inspection at laparotomy. In the remammg case, a patient with cholelithiasis, the pressure in a portal vein radicle measured during surgery was only 18 mm of saline, but the size of the spleen was not investigated by direct inspection or roentgenography. Splenoportography in 1 of the 2 patients with portal hypertension revealed that both the extrahepatic and intrahepatic portal vessels were normal. X-ray examination of the esophagus in 16 of the 2 patients with a spleen, including all 7 with confirmed splenomegaly and the 2 with documented portal hypertension, revealed no evidence of varices in any. Fourteen of the 2 patients with a spleen were reexamined 3 months to 13 years (average 5 years) following surgical correction of their biliary tract disease. In none of these was the spleen still. Two of the remaining pa-

438 LIVER PHYSIOLOGY AND DISEASE Vol. 62, No.3 tients, both with carcinoma of the pancreas, died during their initial hospitalization, and 4 were lost to follow-up. Unfortunately, postmortem examination was TABLE 1. Comparison of clinical features in patients with and without a spleena Age 17-35 years........ 36-6 years. 61-14 years Sex Male Female Diagnosis Choledocholithiasis. Cholelithiasis with cholecystitis......... Cholecystitis, acute and chronic. Stricture, common bile duct Carcinoma, head of pan- Spleen (2 patients) Spleen not (114 patients) 8 (7%) 5 (44%) 56 (49%) 61 (54%) 53 (44%) 32 (28%) 5 (25%) 26 (23%)C 5 (4%)d 7 (6%)d creas 3 (26%)' Carcinoma, ampulla of Vater Pancreatitis, acute and chronic Duration of symptoms a < 1 month 1-11 months 1-5 years >5 years Duration of jaundice < 4 weeks....... 4-8 weeks > 8 weeks No jaundice.......... Physical findings Hepatomegaly Hepatic induration Hepatic tenderness Jaundice Fever 9 (45%) 7 (35%) 18 (9%) 13 (65%) 11 (55%) 11 (1%) 51 (45%) 3 (26%) 14 (12%) 57 (5%) 5 (4%) 11 (1%) 41 (36%) 76 (67%) 39 (34%) 39 (34%) 73 (64%) 44 (39%) a The duration of symptoms was significantly longer in patients with than in those without a spleen (x' = 21.1, P <.1), but none of the other differences between the two groups was statistically significant. Complicated by pancreatitis and cholelithiasis in 1 case each. C Complicated by pancreatitis in 2 cases. d Complicated by pancreatitis in 1 case. e Complicated by cholelithiasis and local metastases in 2 cases each. TABLE 2. Comparison of laboratory findings in patients with and without a spleena Spleen Spleen not (2 cases) (114 cases) Serum bilirubin (mg/ 1 m!) < 2 4 (35%) 2-1 5 (25%) 39 (34%) 11-2 5 (25%) 27 (24%) > 2 8 (7%) Serum glutamic oxalo- 22 (19%) acetic transaminase > 1 Karmen units Serum albumin < 3. g/ 7/19 (37%) 29/92 (32%) 1 ml Serum globulin > 3.5 g/ 1/19 (53%) 38/92 (41%) 1 ml Serum cholesterol (mg/ 1 ml) > 25 7/15(47%) 21 / 58 (36%) < 15 2/15 (13%) 5/58 (9%) a of the differences between patients with and without a spleen was statistically significant. not carried out in either of the 2 fatal cases. In the 2 patients without splenomegaly who died postoperatively, 1 with carcinoma of the pancreas, the other with choledocholithiasis, postmortem examination confirmed that the spleen was of normal size. The spleen was in a variety of disorders affecting the biliary tract and pancreas, including choledocholithiasis in 6, cholelithiasis with acute or chronic cholecystitis in 5, carcinoma of the head of the pancreas in 4, stricture of the common bile duct in 2, and acute cholecystitis without stones, chronic pancreatitis, and carcinoma of the ampulla of Vater in 1 case each. As shown in table 1, the age, sex, and nature of the biliary tract and pancreatic disease in the 2 patients with a spleen did not differ significantly from that in the 114 in whom the spleen was not, so that meaningful comparisons between the two groups were possible. The duration of symptoms referable to disease in the biliary tract or pancreas was significantly longer in patients with than in those without a spleen,

March 1972 LIVER PHYSIOLOGY AND DISEASE 439 almost half the former having had such symptoms for over 5 years (table 1). However, it should be noted that the duration was less than a month in 3% of those with TABLE 3. Comparison of histological findings in liver biopsy sections in patients with and without a spleen Type of biopsy Needle Surgical Both Portal fibrosis a 1+ 2+ 3+ Portal inflammation" Ductular proliferation C Bile stasis d Intralobular inflammation, degeneration, necrosis Fatty infiltration e Spleen (2 cases) 12 (6%) 7 (35%) 9 (45%) 5 (25%) 6 ( 3%) 11 (55%) Spleen not (114 cases) 62 (54%) 35 (31 %) 17 (15%) 2 (18%) 31 (27%) 44 (38%) 4 (4%) 41 (36%) 48 (42%) 21 (18%) 22 (19%) 58 (51%) 31 (27%) 38 (31%) 2 (18%) 28 (25%) 28 (25%) 35 (31%) 57 (5%) 78 (68%) 25 (22%) 8 (7%) a Portal fibrosis significantly greater in patients without a spleen (x 2 = 9.3, P <.5). " Portal inflammation significantly greater in patients without a spleen (x 2 = 8., P <.5). C Ductular proliferation significantly greater in patients without a spleen (x 2 = 8.8, P <.5). d Bile stasis significantly greater in patients without a spleen (x 2 = 8.4, P <.5). e Fatty infiltration significantly greater in patients without a spleen (x 2 = 1.2, P < O.OI). a spleen, and over a year in 38% of those without a spleen. As is evident from a comparison of the clinical and laboratory features in the two groups (tables 1 and 2, respectively), the occurrence of a spleen was not correlated with the duration of jaundice, enlargement, induration, or tenderness of the liver, the presence of fever, or the serum levels of bilirubin, glutamic oxaloacetic transaminase, albumin, globulin, or cholesterol. Surprisingly, comparison of the liver biopsy findings in the two groups revealed that the severity of portal fibrosis and inflammation, ductular proliferation, and intralobular bile stasis and fatty infiltration were less rather than more severe in the patients with a spleen (table 3). The degree of intralobular inflammation, degeneration, and necrosis did not differ in the two groups. Discussion The data presented do not adequately account for the apparent enlargement of the spleen found on physical examination in 2 of our 134 patients with uncomplicated biliary tract or pancreatic disease. Since it has been found that the spleen can be palpated in almost 3% of presumably healthy college students, 1 the possibility must be considered that the spleens in our series were normal. However, this appears unlikely since enlargement of the spleen was confirmed by direct inspection at laparotomy or by roentgenography in 7 of the 8 patients so investigated, portal hypertension was documented in 2 of the 3 tested, and, in all 14 reexamined following surgical correction of their underlying biliary tract disease, the spleen was no longer. The alternative possibilities, that splenomegaly was attributable to reactive hyperplasia secondary to chronic inflammatory disease in the biliary tract or pancreas, or to compression of the splenic vein by an enlarged or contracted pancreas, would not account for portal hypertension. However, the presence of portal hypertension was not established in all cases and a number of patients had documented pancreatic disease, so that, conceivably,

44 LIVER PHYSIOLOGY AND DISEASE Vol. 62, No. 3 either of these mechanisms may have been operative in at least some of our cases. Although incomplete in many respects, our observations are most consistent with the hypothesis that in most cases, splenomegaly was due to congestion secondary to portal hypertension. Since the spleen was only moderately enlarged in this group, it is unlikely that such hypertension was the result of enhanced portal blood flow, such as occurs in massive tropical splenomegaly.2 A more reasonable explanation is an increase in resistance to blood flow somewhere in the course of the portal vein or its outflow tract. Considering that portal inflammation and fibrosis were less rather than more severe in patients with splenomegaly than in those with a normal-sized spleen, it appears unlikely that resistance to portal blood was increased at the level of the portal triads. Similarly, the fact that in patients with splenomegaly, ductular proliferation, bile stasis, and fatty infiltration were less prominent, and intralobular inflammation, and degeneration and the size and consistency of the liver were no greater than in those without splenomegaly, suggests that resistance to portal flow was not increased at the level of the sinusoids or hepatic veins. The possibility cannot be excluded that the flow of portal blood was impeded in large intrahepatic portal radicles because of previous liver inflammation and fibrosis or the development of vascular lesions similar to those described in hepatoportal sclerosis 3 and idiopathic portal hypertension,' since such lesions might escape detection by liver biopsy. Similarly, it is conceivable that there were constricting adhesions around the extrahepatic portal vein that were overlooked or not recorded by the surgeon. However, in the 1 patient with splenomegaly subjected to splenoportography, both the intrahepatic and extrahepatic portal vessels appeared normal. Obviously, more detailed studies are needed to confirm the role of portal hypertension and to elucidate its pathogenesis in cases of splenomegaly associated with apparently uncomplicated biliary tract or pancreatic disease. Such studies should include documentation of splenic enlargement by roentgenography, scintiscanning and direct inspection at laparotomy, measurement of both splenic pulp and wedged hepatic vein pressure, splenoportography to visualize both the extrahepatic and intrahepatic portal venous system, and, in fatal cases, careful inspection of these vessels. REFERENCES 1. McIntyre RO, Ebaugh FG Jr: Palpable spleens in college freshmen. Ann Intern Med 66 :31-36, 1967 2. Williams R, Parsonson A, Somers K, et al: Portal hypertension in idiopathic tropical splenomegaly. Lancet 1:329-333, 1966 3. Mikkelsen WP, Edmondson HA, Peters RL, et al: Extra- and intrahepatic portal hypertension without cirrhosis (hepatoportal sclerosis). Ann Surg 162:62-618, 1965 4. Boyer JL, Sen Gupta KP, Biswas SK, et al: Idiopathic portal hypertension. Comparison with the portal hypertension of cirrhosis and extrahepatic portal vein obstruction. Ann Intern Med 66:41-68, 1967