Granulomatous Hepatitis, Increased Platelet Aggregation, and Hypercholesterolemia JERRY L. YON, M.D., SINN ANURAS, M.D., F.A.C.P., KENNETH WU, M.D., F.A.C.P., and E. LEE FORKER, M.D., Iowa City, Iowa
Two young patients presented with an unusual liver disease, granulomatous hepatitis with postnecrotic cirrhosis, and both underwent a splenorenal shunt procedure. Each developed an arterial embolic episode probably related to increased platelet aggregation. This represents the first report of a liver disease associated with increased platelet aggregation that was clinically significant, a myocardial infarction in one and a posterior cerebral infarction in the other. Also, unexpectedly, both patients became hypercholesterolemic after the splenorenal shunt was established.
GRANULOMATOUS
LIVER DISEASE
has only
infrequently
been associated with the development of cirrhosis. However, for the past several years, two young women with granulomatous hepatitis with postnecrotic cirrhosis have been seen at the University of Iowa Hospitals. When first evaluated at this institution, both patients had portal hypertension, and both underwent a splenorenal shunt procedure. Several years after the shunt, the patients returned because of a major embolic episode: a myocardial infarction in one and a posterior cerebral infarction in the other. In each instance, spontaneous platelet aggregation and increased platelet aggregates could be seen. In addition, both developed hypercholesterolemia a short time before the embolic event. Neither patient was known to be hypercholesterolemic before or immediately after the splenorenal shunt procedure, nor was there any suggestion of familial hyperlipidemia. Case Reports PATIENT 1
A 17-year-old girl was admitted to the University of Iowa Hospitals in March 1970 because of recurrent jaundice and three episodes of hematemesis in the past year. She had no history of exposure to infections or hepatotoxic drug. Physical examination revealed vascular angiomata on her chest and arms, a spleen palpable 7 cm below the left costal margin, and a liver palpable 5 cm below the right costal margin. Pertinent laboratory results included a serum alkaline phosphatase level of 10.1 BLU/dl normal range, 1.0 to 2.5 BLU/dl); serum glutamic oxalacetic transaminase (SGOT), 460 1U litre; serum albumin, 2.2 g dl; serum globulin, 4.0 g/dl; total serum bilirubin, 1.7 mg/dl; and prothrombin time, • From the Division of Gastroenterology, Medicine, Iowa City, Iowa.
Department
of Interna]
148
Downloaded from https://annals.org by Tulane University user on 01/13/2019
13 sec, with a control of 11 sec. Her hemoglobin level was 10.2 g/dl, and her leukocyte count was normal. Because of her history of hematemesis and a splenic pulp pressure of 33 cm of water, she underwent a splenorenal shunt procedure in April 1970. An operative liver biopsy showed postnecrotic cirrhosis. The patient became and remained asymptomatic. However, she had been treated with prednisone, 7.5 to 12.5 mg, and azathioprine, 25 to 50 mg/day since June 1971, because of persistently elevated alkaline phosphatase (6.7 to 14.7 BLU/ dl) and SGOT (160 to 384 IU/litres) values. In early May 1974, the patient had severe left-sided chest pain that radiated to her left arm. Electrocardiograms taken at a local hospital revealed ST elevation in leads II, III, and aVF on 2 consecutive days; she was admitted for 3 weeks with inferior wall myocardial infarction. Subsequently, the patient developed pedal edema and episodes of angina pectoris. At admission to University of Iowa Hospitals in July 1974, her electrocardiogram showed deep Q waves in leads II, III, and aVF. Cardiac catheterization and coronary angiograms were normal except for the visualization of a small, discrete aneurysm of the inferior wall of the left ventricle. At admission her albumin level was 3.5 g/dl; serum globulin, 3.3 g/dl; alkaline phosphatase, 290 BLU/dl; total bilirubin, 1.6 mg/dl; and SGOT, 105 IU/litre. Her liver biopsy specimen from April 1970 was reviewed, and this time the biopsy showed granulomatous hepatitis with postnecrotic cirrhosis (Figure 1). A percutaneous needle biopsy was then attempted twice, but only one small fragment of liver tissue, which was negative for mycobacteria and fungus, was obtained for culture. Chest X ray was normal. Skin tests with mumps, histoplasmosis, and tuberculosis antigens were negative. Antimitochondrial and antismooth muscle antibodies were negative. Antinuclear antibody was positive at 1:80. Her serum alpha-1-antitrypsin and ceruloplasmin levels were normal, and hepatitis B antigen was negative. Prednisone and azathioprine were withdrawn because there was no significant change in the liver function tests during treatment interval. A serum cholesterol level of 345 mg/dl and a triglyceride level of 59 mg/dl prompted a lipoprotein electrophoresis, which showed a type I la pattern. A low cholesterol diet resulted in serum cholesterol levels of 222 and 240 mg/dl. PATIENT 2
A 15-year-old girl developed a febrile illness characterized by meningism and confusion for 24 hours, and icterus lasting 1 week. Seven weeks later, in June 1968, she developed icterus, pancytopenia, and splenomegaly; she was referred to the University of Iowa Hospitals. She had not been exposed to hepatotoxic drug or infection. At examination she had a spleen palpable at the level of the left iliac crest, but no liver was palpable. Pertinent laboratory data included a hemoglobin level of 10.7 g/dl, leukocyte count of 2400/mm3, and platelet count of 43 OOO/mm3. Liver function tests showed a serum albumin level of 2.4 g/dl; gammaglobulin, 1.3 g/dl; total bilirubin, 2.8 mg/dl; alkaline phosphatase, 10.2 BLU/dl; Annals of Internal Medicine 84:148-150, 1976
Figure 1 . Liver biopsy from Patient 1 shows a lymphoid granuloma and giant cells (arrows) in the portal triad. (Hematoxylin and eosin; magnification, x 200.)
SGOT, 90 IU/litres; and prothrombin time, 16 sec, with a control of 12 sec. A bone marrow aspirate was hypercellular with decreased platelets and increased megakaryocytes. Fungal cultures of the bone marrow were negative. A lupus erythematosus clot was negative. In July 1968 a splenectomy and splenorenal shunt procedure were done for hypersplenism. An operative liver biopsy showed postnecrotic cirrhosis. She was well until July 1970, when she developed gross edema of lower extremities, a weight gain of 8.2 kg, dyspnea on exertion, and icterus. She was treated with a 50-g protein, 1-g sodium diet. In September 1970 pedal edema recurred. Examination revealed scleral icterus and spider angiomas of the chest and shoulders. Since the splenorenal shunt procedure, her alkaline phosphatase level had varied from 0.9 to 16.8 BLU/dl, and her SGOT level had ranged from 50 to 372 IU/litre. She was begun on prednisone therapy, 20 mg daily, and intermittent doses of both spironolactone and hydrochlorothiazide. In February 1971 prednisone therapy was decreased to 10 mg daily, and she was maintained on this dose until October 1974. In October 1974 she experienced sudden blurred vision associated with headache, dizziness, and mild neck stiffness. A neurologic examination, lumbar puncture, brain scan, electroencephalogram, and computerized axial tomography were all consistent with a left-posterior cerebral infarction. Her liver biopsy from July 1968 was reviewed and showed granulomatous hepatitis with postnecrotic cirrhosis (Figure 2). Chest X ray was normal. Skin tests with tuberculosis, mumps, Candida, and trichophyton antigens were all negative. Blood, spinal fluid, and bone marrow bacterial and fungal cultures were negative. Serum complement fixation tests for histoplasmosis, blastomycosis, and coccidioidomycosis were negative. The antinuclear antibody was positive to 1:160. Antimitochondrial and antismooth muscle antibodies were not detected. An attempt at a percutaneous needle liver biopsy in November 1974 was unsuccessful. Prednisone was withdrawn because there was no significant change in the liver function tests during treatment interval. Her serum cholesterol level was 441 mg/dl, and triglyceride level was 90 mg/dl. Serum lipoprotein electrophoresis was consistent with a type Ila pattern. A low cholesterol diet reduced the serum cholesterol level to 243 mg/dl.
adjusted with patient's autologous platelet-poor plasma to 300 000/mm3 when necessary. A 0.5 ml platelet-rich plasma sample was then placed in a cuvette and stirred with a siliconized stirring bar at 37 °C at 900 rpm for 10 minutes. In each determination, the extent of light transmission in the aggregometer was standardized so that the platelet-poor plasma blank would indicate 100% light transmission and the plateletrich sample, 0% light transmission. At the end of 10 minutes the extent of the aggregation of the tested sample, as measured by the height of the curve on the chart, was determined, and the result was expressed as percent of increase in light transmission. The normal range of this test (mean ± 3 SD), derived from a study of 150 normal subjects in our laboratory, was 0% to 7%. Platelet aggregates were determined with a ratio method described previously (3). Using this method, the presence of increased aggregates was indicated by a drop in the ratio, the normal range of which was 0.80 to 1.0. At the time of initial studies, patients took neither aspirin nor other medications that might interfere with platelet aggregation. Results
In Patient 1, the special platelet studies, done approximately 4 weeks after the episode of acute myocardial infarction, showed positive spontaneous platelet aggregation (15%) and increased platelet aggregates, with a platelet aggregate ratio of 0.64 that remained abnormal 3 weeks later. She was then placed on sulfinpyrazone, 200 mg three times daily. Four months later, spontaneous aggregation became negative (3%) and the aggregate ratio went up to 0.74, and she has not had recurrence of angina pectoris or myocardial infarction. In Patient 2, the platelet studies, done 10 days after the cerebral infarction, showed a positive spontaneous platelet aggregation (21%) and increased platelet aggregates, with a ratio of 0.65. Because of the recurrence of transient ischemic attacks, averaging about one episode per day, she was placed on sulfinpyrazone, 200 mg three times daily. Studies repeated 3 weeks later showed that spontaneous aggregation had disappeared, and the platelet aggregate ratio had returned to normal (0.91). During the 3 weeks, only one episode of transient ischemic attacks was experienced. Sulfinpyrazone was withdrawn, and the platelet aggregate ratio dropped to 0.56, with frequent transient ischemic attacks. She was again placed on sulfinpyrazone, 200 mg four times daily, and has had no
Special Studies
Spontaneous platelet aggregation (1) was determined using a platelet aggregometer (Payton Associates, Buffalo, New York) after the principle of Born (2). Nine millilitres of freeflowing venous blood were drawn into a siliconized glass tube containing 1 ml of 3.8% sodium citrate and centrifuged at 220 g for 8 minutes at room temperature to prepare platelet-rich plasma. The platelet concentration of platelet-rich plasma was
Figure 2. Liver biopsy from Patient 2 shows two lymphoid granulomas in the portal tracts. The bile ducts (arrows) are normal in configuration. (Hematoxylin and eosin; magnification, x 82.) Yon et a/. • Granulomatous Hepatitis
Downloaded from https://annals.org by Tulane University user on 01/13/2019
149
transient ischemic attacks. The platelet aggregate ratio has returned to normal. Discussion
The underlying cause of postnecrotic cirrhosis in these two patients is puzzling. Clinically, their disease behaved similarly to chronic active hepatitis, but the liver biopsies showed postnecrotic cirrhosis with granuloma and giant cells. Lymphoid follicles surrounding abnormal bile ducts have been described in chronic aggressive hepatitis and in cirrhosis ( 4 ) , but, unlike primary biliary cirrhosis, true granuloma has never been found ( 5 ) . In both liver biopsy specimens, the granulomas containing giant cells appeared in portal triads that had normal bile ducts, suggesting that they may not be the type of lymphoid follicles seen in chronic hepatitis or cirrhosis by Poulsen and Christoffersen ( 4 ) . Granulomatous hepatitis rarely causes cirrhosis (6-8), but Maddrey and colleagues (9) reported seven cases of cirrhosis and portal hypertension in 20 patients with sarcoidosis who had abnormal liver function tests. In our patients, it is unlikely that a chronic infection caused the liver problem, since an exacerbation with steroid therapy would be expected but did not occur. There was no evidence of sacoidosis and no history suggestive of drug-induced liver disease. Primary biliary cirrhosis seems unlikely because there was no history of pruritus, xanthomas, or progressive icterus; antimitochondrial antibodies were never found; and liver biopsies did not show either a decrease in numbers or abnormal appearance of bile ducts. Although chronic active hepatitis cannot be excluded with certainty, it seems most likely that granulomatous hepatitis (of unknown cause) may be the cause of postnecrotic cirrhosis in these patients. The occurrence of coronary and cerebral arterial thrombosis complications in these two patients is unusual in several respects. Both patients were exceptionally young for the thrombotic disorders, and the coronary arteriography done in one patient shortly after a myocardial infarction showed no evidence of arteriosclerotic arterial diseases. The peripheral arteries in both patients were patent. And yet, platelets were found to be hypersensitive, and platelet aggregates were increased in both patients. After the patients were placed on sulfinpyrazone, both spontaneous aggregation and the platelet aggregate ratio normalized. In addition, the occurrence of transient ischemic attacks in Patient 2 decreased tremendously; withdrawal of the drug was followed by the recurrence of transient ischemic attacks and increased platelet aggregates. These findings suggest that platelet spontaneous aggregation may play a crucial role in the pathogenesis of arterial insufficiency and organ infarction in these patients. A patent coronary arteriogram in Patient 1 further suggests that platelet aggregates may be responsible for the transient vascular occlusion. Although the exact mechanisms for the platelet spontaneous aggregation in our patients are not clear, two factors should be considered. Type II hyperlipidcmia has been associated with increased adenosine diphosphate-induced platelet aggregation ( 1 0 ) , and both
150
patients have type Ha hyperlipidemia. Immune complexes have also been shown to induce platelet aggregation ( 1 1 , 12), and, although direct evidence for immune complexes was lacking, the fact that both patients had positive antinuclear antibodies suggests that immune complexes may have been present in both patients. Two aspects of the hypercholesterolemia seen in these patients deserve comment. Poley and associates (13) have noted an increased cholesterol level with extrahepatic obstruction and diseases of the liver, producing cholestasis. However, neither patient was ever more than moderately icteric, and, at the time hypercholesterolemia developed, they were only minimally hyperbilirubinemic. Neither patient had extrahepatic obstruction. Furthermore, both Patients 1 and 2 developed elevated cholesterol levels 4 and 6 years, respectively, after the splenorenal shunt procedure. Although the portacaval shunt procedure has been suggested as treatment for hypercholesterolemia ( 1 4 ) , clearly our patients were not protected by their shunts from developing an elevated serum cholesterol level. ACKNOWLEDGMENTS: The authors thank Dr. Hyman J. Zimmerman for reviewing the liver biopsies. Grant support: in part by Gastroenterology Training Grant AM 05390 from the National Institutes of Health. Received 22 September 1975; revision accepted 7 November 1975. • Requests for reprints should be addressed to Sinn Anuras, M.D., Division of Gastroenterology, Department of Internal Medicine, University Hospitals, Iowa City, IA 52242. References 1. Wu KK, HOAK JC: Spontaneous platelet aggregation in arterial insufficiency: mechanisms and implications (abstract). Blood 44:934, 1974 2. BORN GVR: Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature (Lond) 194:927-929, 1962 3. Wu KK, HOAK JC: A new method for the quantitative detection of platelet aggregates in patients with arterial insufficiency. Lancet 2:924-926, 1974 4. POULSEN H, CHRISTOFFERSEN P: Abnormal bile duct epithelium in chronic aggressive hepatitis and cirrhosis. A review of morphology and clinical, biochemical, and immunologic features. Human Pathol 3:217-225, 1972 5. CHRISTOFFERSEN P, POULSEN H, SCHEUER PG: Abnormal bile
duct epithelium in chronic aggressive hepatitis and primary biliary cirrhosis. Human Pathol 3:227-235, 1972 6. GUCKIAN JC, PERRY JE: Granulomatous hepatitis. An analysis of 63 cases and review of the literature. Ann Intern Med 65: 1081-1100, 1966 7. MCCULLOUGH NB, EISELE CW: Brucella hepatitis leading to cirrhosis of the liver. Arch Intern Med 88:793-802, 1951 8. SHAPIRO E, WEIMER H: The diagnosis of tertiary syphilis of the liver: 25 years after McCrae. Am J Med Sci 222:494-499, 1951 9. MADDREY WC, JOHNS CJ, BOITNOTT JK, et al: Sarcoidosis and
chronic hepatic disease: a clinical and pathological study of 20 patients. Medicine (Baltimore) 49:375-395, 1970 10. CARVALHO AC, COLMAN RW, LEES RS: Platelet function in
hyperlipoproteinemia. N Engl J Med 290:434-438, 1974 11. PFUEI.LER SL, LUSCHER EF: The effects of immune complexes on blood platelets and their relationship to complement activation, lmmunochemistry 9:1151-1165, 1972 12. PENTTINEN K: Platelet aggregation test in the study of hepatitis. Am J Dis Child 123:418-420, 1972 13. POLEY JR,- ALAUPOVIC P, MCCONATHY WJ, et al: Diagnosis of
extrahepatic biliary obstruction in infants by immunochemical detection of LP-X and modified 131I-Rose Bengal excretion test. J Lab Clin Med 81:325-341, 1973 14. STARZL TE, CHASE HP, PUTNAM CW, et al: Portacaval shunt
February 1976 • Annals of Internal Medicine • Volume 84 • Number 2
Downloaded from https://annals.org by Tulane University user on 01/13/2019
in hyperlipoproteinemia. Lancet 2:940-944, 1973
Two young patients presented with an unusual liver disease, granulomatous hepatitis with postnecrotic cirrhosis, and both underwent a splenorenal shunt procedure. Each developed an arterial embolic episode probably related to increased platelet aggregation. This represents the first report of a liver disease associated with increased platelet aggregation that was clinically significant, a myocardial infarction in one and a posterior cerebral infarction in the other. Also, unexpectedly, both patients became hypercholesterolemic after the splenorenal shunt was established.
GRANULOMATOUS
LIVER DISEASE
has only
infrequently
been associated with the development of cirrhosis. However, for the past several years, two young women with granulomatous hepatitis with postnecrotic cirrhosis have been seen at the University of Iowa Hospitals. When first evaluated at this institution, both patients had portal hypertension, and both underwent a splenorenal shunt procedure. Several years after the shunt, the patients returned because of a major embolic episode: a myocardial infarction in one and a posterior cerebral infarction in the other. In each instance, spontaneous platelet aggregation and increased platelet aggregates could be seen. In addition, both developed hypercholesterolemia a short time before the embolic event. Neither patient was known to be hypercholesterolemic before or immediately after the splenorenal shunt procedure, nor was there any suggestion of familial hyperlipidemia. Case Reports PATIENT 1
A 17-year-old girl was admitted to the University of Iowa Hospitals in March 1970 because of recurrent jaundice and three episodes of hematemesis in the past year. She had no history of exposure to infections or hepatotoxic drug. Physical examination revealed vascular angiomata on her chest and arms, a spleen palpable 7 cm below the left costal margin, and a liver palpable 5 cm below the right costal margin. Pertinent laboratory results included a serum alkaline phosphatase level of 10.1 BLU/dl normal range, 1.0 to 2.5 BLU/dl); serum glutamic oxalacetic transaminase (SGOT), 460 1U litre; serum albumin, 2.2 g dl; serum globulin, 4.0 g/dl; total serum bilirubin, 1.7 mg/dl; and prothrombin time, • From the Division of Gastroenterology, Medicine, Iowa City, Iowa.
Department
of Interna]
148
Downloaded from https://annals.org by Tulane University user on 01/13/2019
13 sec, with a control of 11 sec. Her hemoglobin level was 10.2 g/dl, and her leukocyte count was normal. Because of her history of hematemesis and a splenic pulp pressure of 33 cm of water, she underwent a splenorenal shunt procedure in April 1970. An operative liver biopsy showed postnecrotic cirrhosis. The patient became and remained asymptomatic. However, she had been treated with prednisone, 7.5 to 12.5 mg, and azathioprine, 25 to 50 mg/day since June 1971, because of persistently elevated alkaline phosphatase (6.7 to 14.7 BLU/ dl) and SGOT (160 to 384 IU/litres) values. In early May 1974, the patient had severe left-sided chest pain that radiated to her left arm. Electrocardiograms taken at a local hospital revealed ST elevation in leads II, III, and aVF on 2 consecutive days; she was admitted for 3 weeks with inferior wall myocardial infarction. Subsequently, the patient developed pedal edema and episodes of angina pectoris. At admission to University of Iowa Hospitals in July 1974, her electrocardiogram showed deep Q waves in leads II, III, and aVF. Cardiac catheterization and coronary angiograms were normal except for the visualization of a small, discrete aneurysm of the inferior wall of the left ventricle. At admission her albumin level was 3.5 g/dl; serum globulin, 3.3 g/dl; alkaline phosphatase, 290 BLU/dl; total bilirubin, 1.6 mg/dl; and SGOT, 105 IU/litre. Her liver biopsy specimen from April 1970 was reviewed, and this time the biopsy showed granulomatous hepatitis with postnecrotic cirrhosis (Figure 1). A percutaneous needle biopsy was then attempted twice, but only one small fragment of liver tissue, which was negative for mycobacteria and fungus, was obtained for culture. Chest X ray was normal. Skin tests with mumps, histoplasmosis, and tuberculosis antigens were negative. Antimitochondrial and antismooth muscle antibodies were negative. Antinuclear antibody was positive at 1:80. Her serum alpha-1-antitrypsin and ceruloplasmin levels were normal, and hepatitis B antigen was negative. Prednisone and azathioprine were withdrawn because there was no significant change in the liver function tests during treatment interval. A serum cholesterol level of 345 mg/dl and a triglyceride level of 59 mg/dl prompted a lipoprotein electrophoresis, which showed a type I la pattern. A low cholesterol diet resulted in serum cholesterol levels of 222 and 240 mg/dl. PATIENT 2
A 15-year-old girl developed a febrile illness characterized by meningism and confusion for 24 hours, and icterus lasting 1 week. Seven weeks later, in June 1968, she developed icterus, pancytopenia, and splenomegaly; she was referred to the University of Iowa Hospitals. She had not been exposed to hepatotoxic drug or infection. At examination she had a spleen palpable at the level of the left iliac crest, but no liver was palpable. Pertinent laboratory data included a hemoglobin level of 10.7 g/dl, leukocyte count of 2400/mm3, and platelet count of 43 OOO/mm3. Liver function tests showed a serum albumin level of 2.4 g/dl; gammaglobulin, 1.3 g/dl; total bilirubin, 2.8 mg/dl; alkaline phosphatase, 10.2 BLU/dl; Annals of Internal Medicine 84:148-150, 1976
Figure 1 . Liver biopsy from Patient 1 shows a lymphoid granuloma and giant cells (arrows) in the portal triad. (Hematoxylin and eosin; magnification, x 200.)
SGOT, 90 IU/litres; and prothrombin time, 16 sec, with a control of 12 sec. A bone marrow aspirate was hypercellular with decreased platelets and increased megakaryocytes. Fungal cultures of the bone marrow were negative. A lupus erythematosus clot was negative. In July 1968 a splenectomy and splenorenal shunt procedure were done for hypersplenism. An operative liver biopsy showed postnecrotic cirrhosis. She was well until July 1970, when she developed gross edema of lower extremities, a weight gain of 8.2 kg, dyspnea on exertion, and icterus. She was treated with a 50-g protein, 1-g sodium diet. In September 1970 pedal edema recurred. Examination revealed scleral icterus and spider angiomas of the chest and shoulders. Since the splenorenal shunt procedure, her alkaline phosphatase level had varied from 0.9 to 16.8 BLU/dl, and her SGOT level had ranged from 50 to 372 IU/litre. She was begun on prednisone therapy, 20 mg daily, and intermittent doses of both spironolactone and hydrochlorothiazide. In February 1971 prednisone therapy was decreased to 10 mg daily, and she was maintained on this dose until October 1974. In October 1974 she experienced sudden blurred vision associated with headache, dizziness, and mild neck stiffness. A neurologic examination, lumbar puncture, brain scan, electroencephalogram, and computerized axial tomography were all consistent with a left-posterior cerebral infarction. Her liver biopsy from July 1968 was reviewed and showed granulomatous hepatitis with postnecrotic cirrhosis (Figure 2). Chest X ray was normal. Skin tests with tuberculosis, mumps, Candida, and trichophyton antigens were all negative. Blood, spinal fluid, and bone marrow bacterial and fungal cultures were negative. Serum complement fixation tests for histoplasmosis, blastomycosis, and coccidioidomycosis were negative. The antinuclear antibody was positive to 1:160. Antimitochondrial and antismooth muscle antibodies were not detected. An attempt at a percutaneous needle liver biopsy in November 1974 was unsuccessful. Prednisone was withdrawn because there was no significant change in the liver function tests during treatment interval. Her serum cholesterol level was 441 mg/dl, and triglyceride level was 90 mg/dl. Serum lipoprotein electrophoresis was consistent with a type Ila pattern. A low cholesterol diet reduced the serum cholesterol level to 243 mg/dl.
adjusted with patient's autologous platelet-poor plasma to 300 000/mm3 when necessary. A 0.5 ml platelet-rich plasma sample was then placed in a cuvette and stirred with a siliconized stirring bar at 37 °C at 900 rpm for 10 minutes. In each determination, the extent of light transmission in the aggregometer was standardized so that the platelet-poor plasma blank would indicate 100% light transmission and the plateletrich sample, 0% light transmission. At the end of 10 minutes the extent of the aggregation of the tested sample, as measured by the height of the curve on the chart, was determined, and the result was expressed as percent of increase in light transmission. The normal range of this test (mean ± 3 SD), derived from a study of 150 normal subjects in our laboratory, was 0% to 7%. Platelet aggregates were determined with a ratio method described previously (3). Using this method, the presence of increased aggregates was indicated by a drop in the ratio, the normal range of which was 0.80 to 1.0. At the time of initial studies, patients took neither aspirin nor other medications that might interfere with platelet aggregation. Results
In Patient 1, the special platelet studies, done approximately 4 weeks after the episode of acute myocardial infarction, showed positive spontaneous platelet aggregation (15%) and increased platelet aggregates, with a platelet aggregate ratio of 0.64 that remained abnormal 3 weeks later. She was then placed on sulfinpyrazone, 200 mg three times daily. Four months later, spontaneous aggregation became negative (3%) and the aggregate ratio went up to 0.74, and she has not had recurrence of angina pectoris or myocardial infarction. In Patient 2, the platelet studies, done 10 days after the cerebral infarction, showed a positive spontaneous platelet aggregation (21%) and increased platelet aggregates, with a ratio of 0.65. Because of the recurrence of transient ischemic attacks, averaging about one episode per day, she was placed on sulfinpyrazone, 200 mg three times daily. Studies repeated 3 weeks later showed that spontaneous aggregation had disappeared, and the platelet aggregate ratio had returned to normal (0.91). During the 3 weeks, only one episode of transient ischemic attacks was experienced. Sulfinpyrazone was withdrawn, and the platelet aggregate ratio dropped to 0.56, with frequent transient ischemic attacks. She was again placed on sulfinpyrazone, 200 mg four times daily, and has had no
Special Studies
Spontaneous platelet aggregation (1) was determined using a platelet aggregometer (Payton Associates, Buffalo, New York) after the principle of Born (2). Nine millilitres of freeflowing venous blood were drawn into a siliconized glass tube containing 1 ml of 3.8% sodium citrate and centrifuged at 220 g for 8 minutes at room temperature to prepare platelet-rich plasma. The platelet concentration of platelet-rich plasma was
Figure 2. Liver biopsy from Patient 2 shows two lymphoid granulomas in the portal tracts. The bile ducts (arrows) are normal in configuration. (Hematoxylin and eosin; magnification, x 82.) Yon et a/. • Granulomatous Hepatitis
Downloaded from https://annals.org by Tulane University user on 01/13/2019
149
transient ischemic attacks. The platelet aggregate ratio has returned to normal. Discussion
The underlying cause of postnecrotic cirrhosis in these two patients is puzzling. Clinically, their disease behaved similarly to chronic active hepatitis, but the liver biopsies showed postnecrotic cirrhosis with granuloma and giant cells. Lymphoid follicles surrounding abnormal bile ducts have been described in chronic aggressive hepatitis and in cirrhosis ( 4 ) , but, unlike primary biliary cirrhosis, true granuloma has never been found ( 5 ) . In both liver biopsy specimens, the granulomas containing giant cells appeared in portal triads that had normal bile ducts, suggesting that they may not be the type of lymphoid follicles seen in chronic hepatitis or cirrhosis by Poulsen and Christoffersen ( 4 ) . Granulomatous hepatitis rarely causes cirrhosis (6-8), but Maddrey and colleagues (9) reported seven cases of cirrhosis and portal hypertension in 20 patients with sarcoidosis who had abnormal liver function tests. In our patients, it is unlikely that a chronic infection caused the liver problem, since an exacerbation with steroid therapy would be expected but did not occur. There was no evidence of sacoidosis and no history suggestive of drug-induced liver disease. Primary biliary cirrhosis seems unlikely because there was no history of pruritus, xanthomas, or progressive icterus; antimitochondrial antibodies were never found; and liver biopsies did not show either a decrease in numbers or abnormal appearance of bile ducts. Although chronic active hepatitis cannot be excluded with certainty, it seems most likely that granulomatous hepatitis (of unknown cause) may be the cause of postnecrotic cirrhosis in these patients. The occurrence of coronary and cerebral arterial thrombosis complications in these two patients is unusual in several respects. Both patients were exceptionally young for the thrombotic disorders, and the coronary arteriography done in one patient shortly after a myocardial infarction showed no evidence of arteriosclerotic arterial diseases. The peripheral arteries in both patients were patent. And yet, platelets were found to be hypersensitive, and platelet aggregates were increased in both patients. After the patients were placed on sulfinpyrazone, both spontaneous aggregation and the platelet aggregate ratio normalized. In addition, the occurrence of transient ischemic attacks in Patient 2 decreased tremendously; withdrawal of the drug was followed by the recurrence of transient ischemic attacks and increased platelet aggregates. These findings suggest that platelet spontaneous aggregation may play a crucial role in the pathogenesis of arterial insufficiency and organ infarction in these patients. A patent coronary arteriogram in Patient 1 further suggests that platelet aggregates may be responsible for the transient vascular occlusion. Although the exact mechanisms for the platelet spontaneous aggregation in our patients are not clear, two factors should be considered. Type II hyperlipidcmia has been associated with increased adenosine diphosphate-induced platelet aggregation ( 1 0 ) , and both
150
patients have type Ha hyperlipidemia. Immune complexes have also been shown to induce platelet aggregation ( 1 1 , 12), and, although direct evidence for immune complexes was lacking, the fact that both patients had positive antinuclear antibodies suggests that immune complexes may have been present in both patients. Two aspects of the hypercholesterolemia seen in these patients deserve comment. Poley and associates (13) have noted an increased cholesterol level with extrahepatic obstruction and diseases of the liver, producing cholestasis. However, neither patient was ever more than moderately icteric, and, at the time hypercholesterolemia developed, they were only minimally hyperbilirubinemic. Neither patient had extrahepatic obstruction. Furthermore, both Patients 1 and 2 developed elevated cholesterol levels 4 and 6 years, respectively, after the splenorenal shunt procedure. Although the portacaval shunt procedure has been suggested as treatment for hypercholesterolemia ( 1 4 ) , clearly our patients were not protected by their shunts from developing an elevated serum cholesterol level. ACKNOWLEDGMENTS: The authors thank Dr. Hyman J. Zimmerman for reviewing the liver biopsies. Grant support: in part by Gastroenterology Training Grant AM 05390 from the National Institutes of Health. Received 22 September 1975; revision accepted 7 November 1975. • Requests for reprints should be addressed to Sinn Anuras, M.D., Division of Gastroenterology, Department of Internal Medicine, University Hospitals, Iowa City, IA 52242. References 1. Wu KK, HOAK JC: Spontaneous platelet aggregation in arterial insufficiency: mechanisms and implications (abstract). Blood 44:934, 1974 2. BORN GVR: Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature (Lond) 194:927-929, 1962 3. Wu KK, HOAK JC: A new method for the quantitative detection of platelet aggregates in patients with arterial insufficiency. Lancet 2:924-926, 1974 4. POULSEN H, CHRISTOFFERSEN P: Abnormal bile duct epithelium in chronic aggressive hepatitis and cirrhosis. A review of morphology and clinical, biochemical, and immunologic features. Human Pathol 3:217-225, 1972 5. CHRISTOFFERSEN P, POULSEN H, SCHEUER PG: Abnormal bile
duct epithelium in chronic aggressive hepatitis and primary biliary cirrhosis. Human Pathol 3:227-235, 1972 6. GUCKIAN JC, PERRY JE: Granulomatous hepatitis. An analysis of 63 cases and review of the literature. Ann Intern Med 65: 1081-1100, 1966 7. MCCULLOUGH NB, EISELE CW: Brucella hepatitis leading to cirrhosis of the liver. Arch Intern Med 88:793-802, 1951 8. SHAPIRO E, WEIMER H: The diagnosis of tertiary syphilis of the liver: 25 years after McCrae. Am J Med Sci 222:494-499, 1951 9. MADDREY WC, JOHNS CJ, BOITNOTT JK, et al: Sarcoidosis and
chronic hepatic disease: a clinical and pathological study of 20 patients. Medicine (Baltimore) 49:375-395, 1970 10. CARVALHO AC, COLMAN RW, LEES RS: Platelet function in
hyperlipoproteinemia. N Engl J Med 290:434-438, 1974 11. PFUEI.LER SL, LUSCHER EF: The effects of immune complexes on blood platelets and their relationship to complement activation, lmmunochemistry 9:1151-1165, 1972 12. PENTTINEN K: Platelet aggregation test in the study of hepatitis. Am J Dis Child 123:418-420, 1972 13. POLEY JR,- ALAUPOVIC P, MCCONATHY WJ, et al: Diagnosis of
extrahepatic biliary obstruction in infants by immunochemical detection of LP-X and modified 131I-Rose Bengal excretion test. J Lab Clin Med 81:325-341, 1973 14. STARZL TE, CHASE HP, PUTNAM CW, et al: Portacaval shunt
February 1976 • Annals of Internal Medicine • Volume 84 • Number 2
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