Intermittent Idiopathic Portal Hypertension

Intermittent Idiopathic Portal Hypertension

GASTROENTEROLOGY Co p~· r il( ht Vol. 67, No. 1 67: 142-148, 1974 Printed in U.S .A. © 1974 by Th e Willia ms & Wil kins Co. INTERMITTENT IDIOPA...

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GASTROENTEROLOGY

Co p~· r il( ht

Vol. 67, No. 1

67: 142-148, 1974

Printed in U.S .A.

© 1974 by Th e Willia ms & Wil kins Co.

INTERMITTENT IDIOPATIDC PORTAL HYPERTENSION A. Case Report

c.

L.

MENDENHALL, M .D. , PH .D .,

J.

SHERMAN, M.D., AND

A.

CHEDID, M .D.

Division of Gastro enterology , Veterans Administration Hospital, Cincinnati, Ohio

A patient with idiopathic portal hypertension is described in whom exacerbations and remissions were well documented by clinical, laboratory, and manometric techniques. As is typical of idiopathic portal hypertension, the liver histology was initially normal, but gradually deteriorated over an 18-month period of observation. Portal hemodynamic studies revealed a marked increase in portal and sinusoidal pressure, with a moderate presinusoidal component, reduced hepatic blood flow, and a widely dilated patent portal vein with esophageal varices, but with a decreased hepatic venous pattern. The various theories regarding the pathophysiology of this entity are discussed, and their validity is evaluated relative to the finding in this patient . The occurrence of portal hypertension without cirrhosis was first described in 1953 .' Since then, a number of such cases have been reported. 2 - 9 Characteristically, these are patients who are presumably well until one of the complications of portal hypertension, i.e., bleeding from esophageal varices, or ascites, becomes manifest, and who, in the early stages, have normal liver function tests and essentially normal liver biopsy. Unfortunately , the underlying disease is progressive so that, subsequently, liver function is impaired and hepatic encephalopathy develops. Periportal fibrosis becomes extensive, but without nodular regeneration, and ultimately death results from hepatic failure. This case is being presented as another example of this condition , and also because this patient manifests a hithertofore unrecognized feature of this disease , in that Receive d July 27. 1973. Acce pted Dece mber 10, 1973. Address reques ts for reprint s to: Dr. Charles L. M endenha ll. Di\'is ion of Gastroenterology . Veterans Administ ra tion Hos pit a l. 3200 Vine St reet , Cincinnati. Ohio 45220.

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his portal hypertension was intermittent in nature. This is of special significance since it suggests, at least initially, a nonstructural alteration in portal vasculature as being responsible for the early increases in portal pressure. Case Report C. B. , a 46-year-old white male, was admitted to the General Medicine Service with a chief complaint of vomiting blood. The patient stated that after a light evening meal he experienced vague upper abdominal discomfort, became nauseated , and vomited an estimated 200 cc of liquid which initially contained only food particles, but which changed shortly to red blood. His past history included an episode of jaundice which occurred 25 years previously in the military . The jaundice cleared completely without apparent residual. He denied significant alcohol intake. The patient is an adult-onset diabetic of 7-year duration whose diabetes is easily controlled with Orinase. On admission , he appeared well nourished and not acutely ill . The liver was not enlarged, but the spleen was easily palpable 10 em below the left costal margin and was nontender. There was no palmar erythema , spider nevi, or other evidence of chronic liver disease. Admission studies included the following:

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hemoglobin 16.2 g per 100 ml, hematocrit 46%, WBC 2,500 mm 3 with a normal differential, and 64,000 platelets per mm 3 • All additional laboratory studies were normal. These included urinalysis, blood urea nitrogen, electrolytes, cholesterol, amylase, and a battery of liver function tests consisting of total bilirubin, SGOT, alkaline phosphatase, prothrombin time, serum albumin, and total protein. Bromosulfophthalein retention was also measured both at 30 min and 45 min, and was observed to be slightly abnormal , at 11 and 9%, respectively. These changes were attributed to changes in blood volume resulting from his recent hematemesis . Fasting blood sugar was slightly elevated at 131 mg per 100 ml, consistent with the known history of mild diabetes. On his 3rd hospital day, esophagoscopy was performed and demonstrated esophageal varices from the midesophagus to the cardia. No frank blood was seen. On this same day, an upper gastrointestinal series with fluoroscopy revealed findings consistent with esophageal varices. A bone marrow done on the 7th hospital day demonstrated pan-marrow hyperplasia , which was interpreted as being compatible with hypersplenism. On the 13th hospital day, a needle biopsy from the right lobe of the liver was performed and reported as essentially normal. A more detailed description of the liver histology will be presented later . In view of the unexplained nature of his portal hypertension , hepatic vein catheterization was performed without difficulty, and a mean hepatic wedge pressure of 272.0 mm of saline was obtained. To ensure an accurate wedge pressure , the catheter was appropriately positioned, the pressure recorded at the level of the right atrium, and 10 ml of 50% hypaque injected to ensure a true wedge position. The catheter was then withdrawn and repositioned in an identical manner in a different hepatic venous radicle. The value listed here represents the mean of these three measurements. Hepatic blood flow, calculated by Fick principle using indocyanine green , 10 was found to be decreased to 642 ml per min (normal 1000 to 1500 ml per min). This value represents the mean of five estimations taken over a 40-min period. To evaluate presinusoidal portal pressure, splenoportography was performed. A 16-gauge angiocath needle was positioned deep in the splenic pulp, such that a free return of dark venous blood was observed. Resting pressures were recorded at the level of the right atrium before and after a Valsalva maneuver to ensure a free

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venous communication. A mean resting splenic pulp pressure of 328 mm of saline was observed. Visualization of the portal system demonstrated marked dilation of splenic and portal veins without occlusion or narrowing. However, the intrahepatic vascular markings were poorly visualized. His hospital course was uneventful. However, it was observed that with no specific therapy the spleen steadily decreased in size such that by the 28th hospital day, it was not palpable. Concomitantly, his platelet count rose steadily to 148,000 mm 3 • On the 27th hospital day, he was discharged to be reevaluated in 1 month. The patient did well at home for 11 days, at which time he experienced his second episode of abdominal discomfort and nausea followed by hematemesis. The vomitus consisted of 100 cc of bright red blood. On readmission, liver size was still within normal limits; however, the spleen was again readily palpable 10 em below the left costal margin and slightly tender. Platelet count had again decreased to 86,000 mm 3 . Other laboratory studies were again within normal limits . Repeat esophagoscopy revealed moderatesized varices extruding up the lower esophagus. A repeat needle biopsy of the liver was again performed, and was again reported to be within normal limits. The specimen on this occasion was obtained from the left lobe of the liver. A liver-spleen scan confirmed the normal size of the liver, but showed some areas of patchy uptake, which was interpreted as being compatible with either cirrhosis or impaired liver perfusion. Splenomegaly was noted to be present measuring 18 em in the long axis. The upper gastrointestinal series again was interpreted as normal, except for esophageal varices. Because of the intermittent nature of his splenomegaly and the associated hypersplenic thrombocytopenia, it was thought that a vasospastic component existed, which either contributed to or caused his portal hypertension rather than fixed structural changes in small intrahepatic portal vessels. Since Shaldon 11 has previously reported success with the use of guanethidine in 2 similar patients, or~! guanethidine, 10 mg per day, was instituted. Base line splenic pulp pressure just prior to therapy was 238 mm of saline. Repeat splenic pulp pressures obtained on the 3rd and 15th days of therapy revealed a rapid fall in pressure to within normal limits, 122 and 162 mm of saline, respectively. Concomitantly, splenic size decreased, so that by the 19th day of therapy , the spleen was no longer palpable, and the 3 platelet count had risen to 138,000 mm . The

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patient was disc harged and instructed to continue the guanethidine, 10 mg daily, at home. After discharge, he did well for 1 month at which time he developed general malaise and nausea. For 2 days he vomited intermittently but had no hematemesis. At th is point , because of the nausea , the patient stopped taking the guanethidine . On the 3rd day, he again vomited blood. Physical exam revealed a blood pressure of 100/60 and a pulse of 88. The spleen was not palpable at this time. Admission H gb was 14 g per 100 ml , and Hct was 38%. Platelet count was 128,000 mm 3 . Due to an oversight , no guanethidine was given after his hospital admission. By the 6th hospital day (9 days off guanethidine), his spleen was again readily palpable. A splenoportogram done on the 7th hospital day revealed a pulp pressure of 258 mm of saline, and a dilated unobstructed portal vein. Esophageal varices were again demonstrated. At this time, guanethidine was reinstituted on a larger dose of 25 mg per day. After 6 days of t his therapy combined with antacids, esophagogastroscopy was repeated, and it revealed a normal-appearing esophagus without varices or esophagitis. In an effort to get the maximum tolerated effect from the guanethidin e, the dosage was increased to 30 mg daily . The patient tolerated this dosage well, with a resting blood pressure of 110/70. After 6 weeks on this program , the platelet count had again risen to 237,000 mm 3 , and spl enic pulp pressure measured at 108 mm of salin e. The patient was again discharged to be followed in the gastrointestinal clinic. During t he next 2 weeks, the patient was bothered with intermittent left -sided abdominal discomfort. On the 14th day after discharge, the abdominal pain became somewhat worse, and the patient vomited, but t here was no hematemesis . It is thought that he stopped his guanethidine at this point, but this cou ld not be documented. On the 16th day after discharge, the patient passed two melanotic stools and felt weak. Admitting physical exam revealed a spleen again palpable 3 em below the left costal margin , with a liver of normal size. Pertinent laboratory stud ies included Hgb 11.5 g per 100 ml , Hct 37o/c, WBC 2,200 mm 3 , platelet count 102,000 mm ', and normal liver function tests. Endoscopy done on the day of admission rev~aled a recurrence of the bleeding esophageal va n ces. but no esophagitis. The stomach was normal. On the 12th day afte r admis~ion , the patient was taken to surgery. At lapa rotomy, pressure

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in t he gastroepiploic vein was 450 mm of saline. A splenorenal shunt with splenectomy was performed. Although the liver grossly appeared normal , a biopsy was taken. Postoperatively, the patient did well and has been followed for the past year in the gastroin testinal clinic at regular intervals. Because progressive hepatic deterioration 8 • 12 is known to occur in this condition, he was admitted after 1 year for reevaluation. During this interval, he had had no recurrence of his hematemesis, and liver function tests remained normal. The hepatic vein wedge pressure was still elevated at 245 mm of water (18 mm Hg). Attempts at selective catheterization of t he portal vein through the left renal vein were unsuccessful, so that no estimate of t he portal pressure was available. Barium swallow, however, showed no evidence of recurrence of t he esophageal varices. A repeat liver biopsy was also obta ined.

Pathology In an effort to evaluate any progression of the underlying disease process, the hepatic histopathology of t he three presurgical percutaneous liver biopsies, the much larger surgical biopsy, and the follow-up liver biopsy 1 year postsplenorenal shunt, have been reviewed. The following are the results of these comparisons. The t hree presurgical needle biopsies, as well as t he surgical wedge biopsy, all demonstrated normal hepatic parenchymal cells. The portal areas initially appeared completely normal. However, in both the third presurgical specimen and the wedge biopsy, some increased periportal round cell infi ltration was observed. On the surgical specimen, using a Masson's trichrome stain , fine delicate strands of collagenous tissue could be seen to connect some of the portal areas. In none of t he specimens was disruption of normal architecture by nodular regeneration , fatty infiltration, bile duct proliferation, or necrosis observed. The liver biopsy performed 1 year after splenorenal shunt surgery again sh owed relatively normal parenchymal cells without distortion of architecture, fatty infiltration, or necrosis. However, on comparing this with t he previous biopsies , several changes were evident. Now the portal areas were much more conspicuous. This was primarily a result of venous dilation with

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FIG. 1. A, a representative portal tract with portions of the adjacent lobules. Minimal fibrosis with delicate strands of collagen extending into the lobule with minimal mononuclear inflammatory cells. Specimen obtained at the time of the splenorenal shunt ( x 200). B, a representative portal triad from a needle biopsy 18 months later . Increased fibrosis with widening of the triads is present. The mild int1ammatory component is unchanged from previous biopsy. The lobular architecture and hepatocytes are normal in both specimens ( x 200).

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increased prominence and density of the adjacent supporting collagenous tissue, as well as thickening of the arterial muscularis. From these larger, more conspicuous portal areas, small strands of collagenous tissue could be seen streaming out toward adjacent portal areas. Phlebosclerosis was not seen in any of the sections. The final pathological impression was a slowly progressive periportal fibrosis of undetermined etiology consistent with idiopathic portal hypertension (see figure 1). Discussion This patient is of special interest for three reasons. (1) Idiopathic portal hypertension, although uncommon, must be considered in the differential diagnosis of all patients with portal hypertension in whom liver disease is not obvious. This patient helps bring out the salient features of this condition, i.e., a patient previously in good health who is seen for the first time because of a complication of portal hypertens ion, in this case bleeding esophageal varices, who shows no evidence of portal vein obstruction or hepatic cirrhosis, and who subsequently has progressive periportal inflammation and fibrosis without cirrhosis. (2) Because the diagnosis was made early and was extensively studied , this case offers a unique opportunity to observe serial changes in splanchnic hemodynamics, hepatic blood flow , and portal pressure, and to follow the progressive histological alterations over an 18-month period. The obstruction to portal venous outflow in this patient corroborates the observations of others 8 in that his hepatic vein wedge pressure (sinusoidal pressure) was increased, but to a lesser degree than the portal pressure measured through the splenic pulp , the initial gradient between these measurements being 272 versus 328 mm of saline, respectively . These values, as well as the persistent elevation of the sinusoidal pressure even after a splenorenal shunt, implies the presence of a combined presinusoidal and parasinusoidal component to the vascular obstruction. Concomitant with this, a marked impairment to

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hepatic blood flow was also observed. The progressive pathological changes seen in the liver biopsies resemble those reported by others 12 • 13 in that there was a slowly progressive periportal fibrosis and inflammation , but without evidence of nodular regeneration. (3) A previously unreported feature of this disease was observed in this patient, i.e. , the portal hypertension was intermittent in nature . Clinically, this could be evaluated by the presence of a large, readily palpable congested spleen , which repeatedly was observed durin g exacerbation, and which subsequently returned to normal size during remissions. (This occurred three times during his hospitalizations , and was verified by a number of different observers.) Laboratory confirmation was obtained from the occurrence of his hypersplenic thrombocytopenia , which fluctuated concomitantly with the size of the spleen , and ranged from a low of 44,000 mm 3 during exacerbation to a high of 237,000 mm 3 during remission. Special procedures, such as barium swallow and esophagoscopy, revealed the initial presence, subsequent disappearance, and final reappearance of esophageal varices. In addition, direct manometric measurements of the portal pressure through the splenic pulp demonstrated an initial high of 328 mm of saline, falling to normal levels of 122, 162, and 108 mm of saline, and subsequently risin g again to a high of 450 mm of saline at the time of surgery. These studies all lend irrefutable evidence to the intermittent nature of this patient's portal hypertension. The fact that guanethidine was adminis· tered just prior to two of his remissions is not meant to imply proof of a cause and effect relationship, only a listin g of the events as they occurred. Our own impression, however, was that the remissions were markedly accelerated by, if not the result of, this therapy. Unfortunately, none of the remissions were of long duration , and ultimately surgery was necessary. Of particular concern is the fact that exacerbations and remissions have not been previously reported. One possibility is

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that this patient represents a new entity distinct from idiopathic portal hypertension. This is unlikely since his overall clinical course and histological picture is identical to previously reported cases. The more likely explanation is that .this patient presented with a ·unique manifestation of his disease, i.e. , a very large spleen and thrombocytopenia. These were readily observed to change, alerting us to the fluctuating nature of their occurrence, and thus prompting us to perform serially more definitive manometric studies. In the early . reports of this ,entity, 6 the authors theorized that its pathogenesis resulted from intrasplenic and splanchnic capillary shunting, which secondarily produced a rharked increase •in flow through the liver and splanchnic venous system sufficient to produce the observed portal hypertension . Unfortunately, they did not substantiate thei~ hypothesis by data related to hepatic"and splanchnic blood flow. Indeed, such changes could be 'intermittent in nature and produce portal hypertension, as was seen in this patient ; However, they are not con~ istent with the observed decrease in total hepatic blood flow or the persistence of the elevated sinusoidal pressure, even after a splenorenal shunt. Another more recently proposed mechanism is thatthe portal hypertension results from a progressive intra- and extrahepatic subendothelial portal sclerosis which is documented by histological changes in these veins. 12 • 13 However, the possibility was not ruled out that such changes were secondary to the hypertension , rather than its cause. Indeed, the presence of an intermittent portal hypertension , as demonstrated in this case, is strong evidence against a fixed structural alteration in portal vasculature. The possibility of such a process, which initially produces intermittent functional hypertension, and secondarily results in endothelial sclerosis and fibrosis terminating in a fi~ed structural hypertension, is certainly not unprecedented in other organs. Numerous observations, both in man and experimental animals, ' have shown similar endothelia! sclerosis in heart and lungs as a

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result of continued vasoconstriction and vascular hypertension. 14 - 19 In addition, in experiments in dogs, portal hypertension, induced by anastomosing the hepatic artery with the portal vein, predictably results in endothelial portal fibrosis. 20 Indeed, the available data are far more consistent with a vasospastic process resulting from either a circulating or fixed tissue substance which effects both sinusoidal and portal vasculature so as to produce a combined para- and presinusoidal hypertension with a decreased total hepatic blood flow. The presence of such a pressor substance in idiopathic portal hypertension has previously been suggested by lber, 21 but again without laboratory or clinical documentation. This case lends clinical support to this theory . REFERENCES 1. Garrett N, Gall EA: Esophageal varices without

hepatic cirrhosis. Arch Pathol 55: 196- 202 , 1953 2. Britton RC: Discussion of Hallenbeck GA and Adson M: Esophagogastric varices without hepatic cirrhosis. Arch Surg 83:380- 383, 1961 3. Hallenbeck GA, Adson MA: Esophagogastric varices without hepatic cirrhosis. Arch Surg 83:370380, 1961 4. Miller MC, Brandt JL: Portal hypertension in the absence of both liver disease and vascular obstruction. Am J Dig Dis 7:442- 448, 1962 5. Siderys H, Vellios F: Portal hypertension without cirrhosis or extrahepatic obstruction. Am J Surg 108:785-789 , 1964 6. Tisdale WA , Klatskin G, Glenn WW: Portal hypertens ion and bleeding esophageal va rices . Their occurrence in the absence of both intrahepatic and extrahepatic obstruction of the portal vein. N Eng! J Med 261:209- 218, 1959 7. Ramalingaswami V, Wig KL , Sarna SK: Cirrhosis of the liv er in Northern India: a clinicopathological study. Arch Intern Med 110:350-358, 1962 8. Boyer JL, Sen Gupta KP , Biswas SK, et al: Idiopathic portal hypertens ion: comparison obstruction . Ann Intern Med 66:41 - 68, 1967 9. Reynolds TB, Hidemura R, Michel H , et al: Portal hypertension without cirrhosis in alcoholic liver disease. Ann Intern Med 70:497-506, 1969 10. Leevy CM, Mendenhall CL, Lesko W, et al: Estimation of hepatic blood flow with Indocya nine Green. J Clin Invest 41:1169-1179, 1962 11. Shaldon C: Dynamic aspects of portal hypertension. Ann Roy Call Surg Eng 31: 308-3 29, 1962 12. Mikkelsen WP , Edmondson HA , Peters RL, et al:

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14.

15.

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Extra- and intrahepatic portal hypertension without cir rh osis. Ann Surg 162:602- 618, 1965 Nay ak NC , Ramalingaswami V: Obliterative porta l venopathy of the liver. Arch Pathol 87:359- 369, 1969 Brachfeld J , Reale A, Goldberg H: Pitfalls in diagnosis of pulmonary hyperte nsion. Am Heart J 55:905-918, 1958 Edwards .JE: Functional pathology of the pulmonary vascu lar tree in co ngenital card iac disease. Circulation 15:164- 196, 1957 Van Vliet PO , Burchell HB , Titus JL: Focal myoca rditis assoc iated with ph eochromocytoma. N Eng! J Med 274:1102-1108, 1966

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17 . Raab W: Key position of catec holamines in functional an d d egenerative cardiovasc ular patholog~·. Am J Cardiol 5:57 1- 578. 1960 18. Guernsey JM, Con nolly JE: Deleterious effects of !-norepinephrine on the myocardium: an experi mental st udy. Ci rculation 28:731. 1963 19. Szakacs JE , Ca nnon A: 1-Norepinephrine m~• o­ carditis. Am J Clin Pathol 30 :42.1-4:14. 195S 20. Zuidema GO , Gaisford WD , Neill SA. et a l: Segmental portal arteria li zation of can in e liver. Surgery 53:689- 698, 1963 21. Iber FL: Obliterative portal ve nopat hy oft h e I iver and " Idi opat hi c Portal Hypertens ion ... Ann In tern Med 71:660-661 , 1969