Oral contraceptives, smoking and nodular hyperplasia of the liver JOHN LOUGH, MD; ROBERT KINCH, MB; STEPHEN SPELLMAN, MD; ELDON SHAFFER, MD

Liver cell adenomas and focal nodular hyperplasia, which appear to be distinctive lesions,1 have been reported with increasing frequency in younger women and may be associated with the prolonged use of oral contraceptive medication. Either type of lesion may present clinically as a palpable abdominal mass, right upper quadrant pain sometimes coinciding with the onset of menstruation, or acute intra-abdominal hemorrhage, or it may be an incidental finding at laparotomy. The adenomas have been described as circumscribed nodules of liver cells with nuclear variation no greater than that of normal cells and lacking bile ducts or ductules. In focal nodular hyperplasia parenchymal nodules and bile ducts are found about a central vascular scar."2 The cause of these lesions is uncertain; the adenomas are thought to be the result of hormonal stimulation of liver cell proliferation. Focal nodular hyperplasia may have a somewhat different pathogenesis, one that could explain the observed myointimal hyperplasia in the blood vessels' associated with necrosis, hemorrhage and nodular regeneration. The vascular changes and the association with cigarette smoking are emphasized in the following description of four recent cases of focal nodular hyperplasia.

Case reports Case 1 A 44-year-old nulliparous woman was admitted to hospital for elective cholecystectomy. An oral cholecystogram showed multiple radiolucent gallstones. Her last menstrual period had begun 9 days before admission. For 6 years before admission she had taken a norethindronemestranol preparation. She smoked cigarettes irregularly. At laparotomy the gallbladder was found to contain gallstones. A cystic lesion 3 X 4 cm incidentally found in the right lobe of the liver was excised totally. Case 2 A 21-year-old woman, gravida 2, para 1, abortus 1, had suffered from recurrent episodes of right upper quadrant postprandial pain for 3 years. She had taken From the departments of pathology, gynecology and medicine, Montreal General Hospital and McGill University Reprint requests to: Dr. John Laugh, Department of pathology, Montreal General Hospital, 1650 Cedar Ave., Montreal, PQ H3G lA4

oral contraceptives (type unknown) for 4 years, stopping 3 months before admission. Her last menstrual period had begun 3 weeks before admission. She had smoked at least a package of cigarettes a day for 5 years. At laparotomy a 6 X 4 cm whitish vascular nodule was found on the anterior surface of the right hepatic lobe and was excised completely. Case 3 A 40-year-old woman, gravida 5, para 4, abortus 1, had a 3-year history of recurrent right upper quadrant discomfort. She had taken an oral contraceptive preparation (norethindrone, 2 mg; mestranol, 0.1 mg) for 4 years and had smoked 1½ packages of cigarettes a day for many years. After a hysterectomy sequential therapy with norethindrone-mestranol and mestranol was taken for 3 more years. At laparotomy the gallbladder was found to contain calculi. A nodular lesion 3 cm in diameter was discovered on the anterior margin of the left lobe of the liver and was excised completely. Case 4 A 45-year-old woman, gravida 4, para 4, had a 3-year history of recurrent epigastric pain associated with nausea and belching. She had taken norgestrel and ethinyl estradiol for 6 years before admission and had smoked 15 to 20 cigarettes a day. At laparotomy the gallbladder was found to contain many small calculi. A well circumscribed nodular tumour 5 cm in diameter was found in the free edge of the liver at the junction of the right and left lobes. It was excised completely. Pathologic findings The liver lesions were similar in each case: bosselated nodules 3 to 6 cm in diameter bulging the capsule of the liver. The sectioned surface was yellowish and multinodular, with a central fibrous scar radiating into the parenchyma and resembling that of focal postnecrotic cirrhosis. One lesion was cystic and one had a central area of hemorrhage and necrosis. Microscopically the regenerative nodules were circumscribed without encapsulation but they were compressing adjacent liver parenchyma (Fig. 1). The normal liver lobular architecture was replaced by nodules of regenerating parenchyma, with the hepatocytes in a pseudoacinar pattern (Figs. 2 and 3). Ductular proliferation along the margins in the vascular stroma was often associated with a lymphocytic infiltrate. Liver parenchymal proliferation was most pronounced in the cystic hemorrhagic area associated with liver cell necrosis (Fig. 4). Thick-walled blood vessels were prominent in each specimen; many had smooth muscle in the wall and could

be recognized as arteries, but veins appeared to be affected as well (Fig. 2). Intimal proliferation with narrowing of the lumen was very noticeable. Fibrin thrombosis was seen occasionally (Fig. 3) and there was no evidence of vasculitis. Similar vascular lesions were found occasionally in normal parenchyma outside the regenerative nodules (Figs. 1 and 5) but most of the vessels in the adjacent parenchyma were morphologically normal. Discuasion

Vascular lesions characterized by myointimal hyperplasia and luminal narrowing or occlusion have been described previously in association with focal nodular hyperplasia."2 Similar vascular changes have been observed in the pulmonary, coronary, renal, mesenteric, uterine and adrenal arteries and in the mesenteric and hepatic veins of pregnant women, women in the postpartum period and women taking oral contraceptives.3'4 There are also several case reports of hepatic vein thrombosis and the Budd-Chiari syndrome associated with use of oral contraceptives.5 It is likely, therefore, that occlusive vascular disease does occur in the liver of predisposed women and results in focal subcapsular ischemia, necrosis and infarction. Infarcts of human liver are uncommon and there has been little experimental work on the healing of ischemic liver necrosis after segmental occlusion of a lobular hepatic artery. The vascular lesions of periarteritis nodosa

FIG. 1-Case 3: myointimal hyperplasia occluding artery in normal liver adjacent to regenerative area in upper right (hematoxylin-eosan [H-El; X400).

CMA JOURNAL/FEBRUARY 18, 1978/VOL. 118 403

that the four women in this series were smokers suggests that oral contraceptives and cigarettes may have a synergistic effect on coagulation in susceptible women. 4ft '#4.. The natural history of focal nodular hyperplasia can best be explained as a progressive occlusion of hepatic lobular arteries as a result of either recurrent thrombosis or stimulation of intimal proliferation by contraceptive steroids. Ischemia, infarction and hemorrhage may then occur, followed by rapid development of collateral vessels and nodular regeneration about a central scar. The process is therefore not primarily neoplastic but one of focal postnecrotic cirrhosis; subsequent malignant transformation may occur occasionally as it does in cirrhosis. It can be anticipated, however, that when the conFIG. 4-Case 4: acute ischemic necrosis traceptive steroids are withdrawn the of liver with inflammation and early re- lesions will regress.17 Women who generation; devitalized cells have pyknotic smoke would be well advised to stop. nuclei and pale cytoplasm, whereas new cells have large dense nudei and dark cytoplasm (H-E; X1000). References 'V

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FIG. 2-Case 2: asymmetric luminal narrowing of blood vessel by subintimal byperplasia within regenerative nodule, perhaps the result of recanalization (H-E; X400)



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FIG 3-Case 4: fibrin thrombus in vein; liver parenchymal cells have pseudoacinar pattern typical of regeneration (H-E; X1200, reduced by 39%).

FIG. 5-Case4: large blood vessel in normal liver ontside regenerative nodule; lumen obliterated by myointimal hyperplasia (H-E; X 1000, reduced by 39%).

resemble the myointimal proliferation seen in focal nodular hyperplasia, and periarteritis occasionally causes hepatic infarction, with intra-abdominal hemorrhage formation of regenerating adenomatoid nodules and cirrhosis of the liver which suggests that focal infarction heals by nodular regeneration. Brauer' has stated that dearterialization of a portion of the liver is difficult to maintain because of the prompt opening of collateral arterial channels, which localizes necrosis to the area supplied by the occluded branch of the hepatic artery' This observation is consistent with the findings on hepatic angiograms characteristic circumscribed parallel peripheral vessels about areas of focal nodular hyperplasia resembling the findings in regenerative nodular cirrhosis .' Indeed, Benz and Baggenstoss originally suggested that lesions of this sort should be considered to be a form of focal cirrhosis.. The myoin-

timal proliferation of focal nodular hyperplasia has been considered to be part of the reparative process but it is also present in normal liver outside the regenerative nodules (Figs. 1 and 5). Similar intimal vascular changes have been produced in guinea pigs by administration of estrogens11 and in female rats by administration of synthetic sex steroids.12 These changes are thought to be the result of stimulation of intimal proliferation by exogenous or endogenous female reproductive steroids.' Oral contraceptives are said to cause hypercoagulabiity and possibly predispose to thrombosis in some women.14 Occasional platelet fibrin thrombi are observed in areas of focal nodular hyperplasia, and repeated thromboembolic injury to endothelium does result in myointimal proliferation and vascular compromise.15 Cigarette smoking enhances platelet aggregation;1 the fact


1. FEcHNER RB: Benign hepatic lesions and orally administered contraceptives - report of 7 cases and a critical analysis of literature. Hum Paihol 8: 255. 1977 2. MAYa ET, CHRISTOPHERSON WM, Bmows OH: Focal nodular hyperplasia of the liver. Possible relationship to oral contraceptives. Am I Clin Pathol 61: 735, 1974 3. Iaa. N5, Noasis HJ: Intimal v;scular lesions associated with female reproductive steroids. Arch Paihol 96: 227. 1973 4. Paurr FW, Kuat.it OK: Massive colonic bleeding and oral contraceptive 'pills'. Am J Obstet Gynecol 125: 695, 1976 5. HOTUMPA AM sa, Scssn's' L, HELFMAN EL: Budd-Chiari syndrome in women taking oral contraceptives. Am I Med 50: 137, 1971 6. CARROLL R: Infarction of the human liver. I Clin Pathol 16: 133, 1963 7. Mowaev FH. LUNDDERG EA: Clinical manifestations of essential polyanglitis (periarteritis nodosa), with emphasis on hepatic manifestations. Ann Intern Med 40: 1145, 1954 5. BRAUBR RW: Liver circulation and function. Physiol Rev 43: 115, 1963 9. RAMSIR8M 5: Studies on the hepatic artery's anatomy and on liver necrosis foliowing Its ligation; some aspects on the hepatorenal syndrome. Acta Chir Scand 106: 322, 1953 10. GOLDSTEIN HM, NEIMAN HL, MENA B, et a!: Angiographic findings in benign liver cell tumors. RadIology 110: 339, 1974 11. BENZ El, BAGGENSTOSS AH: Focal cirrhosis of the liver; its relation to the so-called hamartoma (adenoma, benign hepatoma). Cancer 6: 743. 1953 12. BRuzzoNE 5, ELGUETA H, IOLF.sIAs R, et al: Oestrogen-induced fibroids of the thoracic serosa. Br I Cancer 2: 267, 1948 13. GAMMAL ED: Intimal thickening in arteries of rats treated with synthetic sex hormones. Br I Exp Pathol 57: 248, 1976 14. DUODALE M, MAss AT: Hormonal contraception and thromboembolic disease: effects of the oral contraceptives on hemostatic mechanisms. A review of the literature. I Chronic Di, 23: 775. 1971 15. LOtION J, Moomz 5: Platelet embolic injury; the healing process. Exp Mol Pathol 17: 132, 1972 16. LEVINE PH: An acute effect of cigarette smoking on platelet function. A possible link between smoking and arterial thrombosis. Circulation 48: 619, 1973 17. Ross D, PINNA J, MIaZA M, et al: Regression of focal nodular hyperplasia aftcr discontinuation of oral contraceptives. Ann Intern Med 85: 203. 1976

Oral contraceptives, smoking and nodular hyperplasia of the liver.

Case studies of 4 women (aged 21, 40, 44, and 45) who smoked, had used oral contraceptives, and had nodular hyperplasia of the liver are reviewed, wit...
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