Nodular regenerative hyperplasia of the liver associated with primary pulmonary hypertension

Nodular Regenerative Hyperplasia of the Liver Associated With Primary Pulmonary Hypertension CHIKAO YUTANI, MD,* MASAMI IMAKITA, MD,* HATSUE ISHIBASHI-UEDA, MD,* SHUMPEI OKUBO, MD,t MASAHIRO NAITO, MD,t AND TAKEYOSHI KUNIEDA, MD ~ Nodular regenerative hyperplasia (NRH), a rare hyperplastic condition of the liver, is reported in two patients with primary pulmonary hypertension (PPH). The first patient was a 26year-old man who died of PPH and showed multiple NRH without cirrhosis of the liver. The second patient was a 25-year-old man who had a PPH with pulmonary arterial thrombi and N R H of the liver. N R H has been described in association with immune disease, hematopoietic disorder, and diabetes meUitus, so that N R H with PPH is considered to be very rare. Histologic findings of the lungs show typically plexogenic pulmonary arteriopathy in both cases, and the livers of these patients are composed of multiple nodules that are histologically represented by slightly larger hepatocytes arranged in a cobblestone-like fashion, and are ultramicroscopically characterized by massive proliferation of mitochondria. The pathogenetic association of nodular regenerative hyperplasia with primary pulmonary hypertension will be discussed. HUM PATHOL 19:726--731. 9 1988 by W.B. Saunders Company.

Nodular regenerative hyperplasia (NRH) is a recently recognized pathologic condition in which numerous regenerative nodules develop, without formation of fibrous septa.1 This condition has also been called " n o d u l a r transformation, ''2 "noncirrhotic nodulation, ''3 "hepatocellular adenomatosis, ''4 and " a d e n o m a t o u s hyperplasia. ''5 N R H has been described in association with several clinical conditions such as rheumatoid arthritis, 6'7 CRST syndrome, s m y e l o f i b r o s i s , ~ d i a b e t e s m e l l i t u s , TM m a c r o globulinemia, 11 systemic lupus erythematosus, 12 and polyarteritis nodosa, t3 However, N R H is rarely reported in primary pulmonary hypertension (PPH). 14 To our knowledge, there is only one such case report. In this report, we present two autopsy cases of N R H associated with PPH. CASE REPORTS Case I

In July 1985, a 26-year-old Japanese man was admitted to the National Cardiovascular Center comFrom the *Division of Pathology and the ]'Department of Internal Medicine, National Cardiovascular Center, Fujishirodai, Suita, Osaka, Japan. Revision accepted for publication September 3, 1987. Address correspondence and reprint requests to Dr Yutani: Chief, Division of Pathology, National Cardiovascular Center, 57-1, Fujishirodai, Suita, Osaka 565, Japan. Keywords: primary pulmonary hypertension, nodular regenerative hyperplasia.

plaining of dyspnea on exertion; chest x-rays revealed pulmonary artery dilatation. He had been well until January 1981, when he suddenly suffered from dyspnea, tachycardia, and syncope while playing tennis. At that time, he was admitted to a local hospital, where liver function test results were abnormal. Cardiac catheterization revealed high pulmonary arterial pressure (150/60/110 mmHg), and PPH was diagnosed. In spite of therapy, his dyspnea progressed and he died in November 1985. Autopsy disclosed jaundice, esophageal varices, sclerosis of the portal vein system, and splenomegaly (570 g). The heart weighed 440 g, and revealed right ventricular hypertrophy, with an average wall thickness of 5 mm. The lungs, which weighed 250 g (left lung) and 320 g (right lung), were grossly normal. Atherosclerosis of the p u l m o n a r y artery was observed. The liver weighed 900 g. Variably sized, swollen, soft, pale tan nodules (about 1 mm to 2 cm) were seen on the cut surface of the liver (fig. 1). Extranodular areas were severely congested and depressed. On microscopic examination, p u l m o n a r y arteries showed medial hypertrophy, concentric fibrous intimal thickening, and formation of plexiform lesions (fig. 2). Histologic sections of the liver showed multiple nodules of hyperplastic hepatocytes without marginal bands of fibrous connective tissue. The hepatocytes in nodules were arranged in irregular cords with a thickness of two or more cells and narrow sinusoidal spaces. There were seen little of portal tracts and central veins in nodules; on the other hand, massive hemorrhagic centrilobular necrosis with marked dilatation of sinusoidal spaces in extranodular parenchymas were observed (fig. 1). Electron microscopically, the hepatocytes of the N R H included numerous mitochondria with almost identical sizes. Glycogen granules and endoplasmic reticula were decreased. Bile canaliculi and junctional complex were also reduced in number when compared with normal liver cells. However, the cytoarchitecture was basically indistinguishable from that of normal liver cells. The gross color of white nodular lesions is due probably to abundant mitochondria in the hepatocytes. Case 2

A 25-year-old man was admitted to the National Cardiovascular C e n t e r in S e p t e m b e r 1985 with

9 1988 by W.B. Saunders Company. 0046-8177/88/1906-001455.00/0

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FIGURE I. [A) Irregular nodules of variable size are found throughout the hepatic parenchyma. The nodules are grossly white in color and not bounded by fibrous tissue. (B) Nodules of hyperplastic hepatocytes distort the parenchyma. Sinusoidal dilation and hemorrhagic necrosis are present in the atrophic parenchyma outside nodules. [Hematoxylin-eosin stain, approximate magnification x100] (C) Distortion of the reticulum pattern is produced by plates of hepatocytes more than one ceil in thickness, and sinusoidal dilatation [right upper]. [Modified Gomori's reticulum stain, approximate magnification x 40]

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FIGURE 2. (A) Arterioles in the lungs showing concentric infimal thickening. [Hematoxylin-eosin stain, approximate magnification xl00.] (B) Plexiform lesions are present in the arterioles in the lungs. [Elastica van Gieson stain, approximate magnification x200.]

edema of the face and lower legs and dyspnea on exertion. At the age of 15, he had received a diagnosis of pulmonary hypertension (pulmonary arterial pressure, 84/26/54 mmHg) and heart murmur, but no subjective symptoms were documented. As a result of blood work-up, a diagnosis of PPH was made. Pulmonary thrombi were diagnosed by computed tomography (CT), and warfarin treatment was begun. In August 1986, the patient experienced an abrupt onset of headache and double vision, and subdural hematoma was found on brain CT. Although the hematoma was removed and subdural drainage was performed, epidural hematoma followed. The patient died of DIC immediately after second operation. At autopsy, the heart weighed 550 g, and the

right atrium and ventricle were dilated. The hypertrophied right ventricle measured 7 mm in thickness. Other cardiac measurements were normal. Grossly, saccular dilatation of the trunk and main branch of the right pulmonary artery, which contained organized and fresh mural thrombi, was seen. The weight of the left lung was 450 g, and the right lung weighed 500 g. Atheromata were present in the elastic arteries. Old infarcts with fibrous pleural thickening were seen in the right lower lobe. The liver weighed 1,100 g. T h e surface was smooth, but on the cut surface there were many nodular lesions, measuring up to 2 cm in diameter. The nodules were sharply demarcated and pale colored in comparison with the congested surrounding tissue, and were also not encapsulated. T h e congested 728

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spleen weighed 200 g. No thrombi were found in the pelvic or leg veins. Microscopic examination of the lung revealed severe pulmonary vascular disease, from medial hypertrophy to plexiform lesions. The dilated pulmonary elastic artery showed a thin layer of the media, and organized and fresh fibrin thrombi. There was no evidence of arteritis or aneurysm in the pulmonary arteries. Histologically, the nodules in the liver were not so clearly demarcated from the surrounding liver parenchyma as the gross findings. They were made up o f normal-appearing hepatocytes except for occasional two or three liver cell plates with hyperchromatic nuclei. The histopathology of the remainder of the liver tissue was almost identical with that of case 1. The ultrastructural findings of the nodules in the liver were also similar to those of case 1 (fig. 3). Laboratory data of cases 1 and 2 are listed in tables 1 and 2. DISCUSSION Among p.atients with pulmonary hypertension, a group exists m which no underlying cardiac, emboli,

or pulmonary parenchymal disorders can be identified clinically to account for the hypertensive state; affected patients are considered to have primary or unexplained pulmonary hypertension. 16 However, clinical primary pulmonary hypertension is not a single disease entity but encompasses at least three distinct histopathologic types--namely, thrombo-embolic pulmonary hypertension, primary plexogenic pulmonary arteriopathy, and pulmonary veno-occlusive disease. 17 Plexiform lesions, as found in both of our cases, are the histopathologic hallmark of primary plexogenie pulmonary arteriopathy, but concentric intimal proliferation and fibroelastosis are also highly suggestive of this disorder. When a case has both plexiform and thrombotic lesions such as case 2 presented here, it is classified as plexogenic arteriopathy.16 W. C. Roberts 18 mentioned that the plexiform lesions might act as a dissipator of the extremely high pulmonary arterial pressure and that the plexiform lesions represented irreversible pulmonary hypertension. As yet, the exact cause of plexiform lesions is unknown. However, there are lines of evidence that provide some clues to possible pathogenic factors; for exam-

FIGURE 3. ElectTon mJcrograph in case 2 showing regenerative hyperplasfic hepatocytes with massive proliferation of mitochondria. (Approximate magnification x3,000.)

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TABLE t. Peripheral blood RBC Hb Ht WBC Plt Blood chemistry TP Alb 7-G1 TBil DBil S-GOT S-GPT A1-P ~-GTP LDH

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Case I, Laboratory Data on Admission 550 x 104/p~L 15.5 49.8 14,000/~L 46,000/IxL

PTT PT FDP Fibrinogen

47 sec 35% (- ) 151mg/dL

5.9 g/dL 3.4 g/dL 1.37 g/dL 3.5 mg/dL 0.9 mg/dL 61 U/L 50 U/L 101 U/L 39 U/L 617 U/L

TChol BUN Creatinine Glucose HBs Ag Ab Na K C1 Ca

146 mg/dL 20 mg/dL 1.7 164 (-) (- ) 139 4.8 109 8.7 mg/dL

pie, the association of pulmonary hypertension with advanced liver disease, implicating vasoactive compounds that bypass liver degradation, with collagen vascular diseases and Raynaud's phenomenon. 19 As concerns the mechanism of PPH associated with advanced liver disease--namely, liver cirrhosis or portal hypertension--McDonnell et al 2~ described that this association was not coincidental. Various pathogenic processes such as t h r o m b o e m b o l i s m theory, 21 porta-pulmonary anastomosis theory, 22 hemody~amic disturbance theory, 23 and metabolic theory have also been invoked. 24 The number of reports of coexisting portal and pulmonary hypertension has been increasing. In most cases, portal hypertension was due to severe liver injury. To our knowledge, there was only one reported case with association of pulmonary hypertension and nodular regenerative hyperplasia of the liver. 12 Nodular regenerative hyperplasia (NRH) of the liver is an entity of poorly understood etiology and pathogenesis that frequently Plresents with manifestations of portal hypertension. It is clinically silent, although many patients with NRH have been discovered to have mildly abnormal liver function tests on routine examination, la as was seen in our case. As we have mentioned previously, patients with NRH frequently have portal hyperten-

sion and splenomegaly; in our cases splenomegaly was recorded, with esophageal varices in case 1. T h e following findings were peculiar to our cases, compared with previously reported cases of NRH: (1) association with PPH, with pathologic findings in the liver of hemorrhagic centrilobular necrosis with prominent sinusoidal dilatation due to highly elevated venous pressure; (2) apparent hyperplastic hepatocytes around the portal tracts; that is, residual periportal liver cells reactive to central zone changes; (3) ultrastructural findings of massive proliferation of mitochondria in the hepatocytes of NRH, which were not so variable as seen in liver cell adenoma; 15 (4) size of nodules within 2 cm, and diffuse nodularity, which suggests that these nodules might be diffuse reactive lesion; (5) most of reactive nodules do not include central veins but portal tracts; (6) association with suggestive portal hypertension; namely, splenomegaly with esophageal varices which might implicate the post-sinusoidal block of the blood flow by the nodules and hyperplastic periportal hepatocytes leading to the increase in the pressure of the portal vein. The disturbance of microcirculation and, more importantly, of sinusoidal dilatation with hemorrhagic centrilobular necrosis and portal venous flow within the liver, might be inciting and/or promoting factors for NRH in our cases. However, there have been many other speculations of the origin of NRH described before. Unfortunately, most of the previous studies of NRH were either retrospective on autopsy specimens or sporadic case reports, and no longterm followup study of clinically diagnosed cases has been available. Therefore, further clinical workup will be needed. REFERENCES 1. Omata M: Noncirrhotic portal hypertension. In Peters RL, Craig JR (eds): Liver Pathology. New York, Churchill Livingstone, 1986 2. Lurie B, Novis B, Bank S, et al: CRST syndrome and nodular transformation of the liver. A case report. Gastroenterology 64:457, 1973 3. Smith JC: Noncirrhotic nodulation of the liver. Arch Pathol Lab Med 102:398, 1978 4. Stumpf HH, Liber AF: Hepatocellular adenomatosis: Report of a case with liver function studies. A m J Med 17:887, 1954 5. Gindhart TD, Cimis RJ, Mosenthal WT, et al: Adenomatous hyperplasia of the liver. Arch Pathol Lab Med 103:34, 1979 6. Blendis LM, Parkinson MC, Shilkin KB, et al: Nodular regenerative hyperplasia of the liver in Felty's syndrome. Quart J Med 43:25, 1974 7. Harris M, Rash RM, Dymock IW: Nodular, noncirrhotic liver associated with portal hypertension in a patient with rheumatoid arthritis. J Clin Pathol 27:963, 1974 8. Stromeyer FW, Ishak KG: Nodular transformation (nodular "regeneration" hyperplasia) of the liver: A clinicopathologic study of 30 cases. HUM PATHOL 12:60, 1981 9. Shorey J, Weinberg MN, Frankel EP, et al: Nodular regenerative hyperplasia of the liver in a case of myelofibrosis with extramedullary hematopoiesis and secondary portal venous hypertension. Am J Clin Pathol 72:122, 1979 10. Thung SN, Gerber MA, Bodengeimer HC, Jr: Nodular regenerative hyperplasia of the liver in a patient with diabetes mellitus. Cancer 49:543, 1982 11. Wanless IR, Solt LC, Kortan P, et al: Nodular regenerative

TABLE 2. Case 2, Laboratory Data on Admission RBC Hb Hct Pit WBC PT APTT Fibrinogen FDP ATIII ESR

4.90 • 106 14.6 g/dL 43.2% 91 x 103 7100 80% 39 sec 195 mg/dL 14 ixg/dL 13.7 mg/dL 4/5 mm (30 mirdl hr)

TP TB DB GOT GPT ALP -f-GTP LDH CPK BUN Creatinine Na K C1

6.3 g/dL 2.1 mg/dL 1.2 mg/dL 44 U/L 35 U/L 93 U/L 86 U/L 298 U/L 251 U/L 11 mg/dL 1.0 mg/dL 138 mEq/dL 3.8 mEq/dL 109 mEq/dL

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12. 13. 14. 15. 16. 17.

hyperplasia of the liver associated with macroglobulinemia. AmJ Med 70:1203, 1981 Kuramochi S, Tashiro Y, Torikata C, et al: Systemic lupus erythematosus associated with multiple nodular hyperplasia of the liver. Acta Pathol Jpn 32:574, 1982 Nakamura Y, Ohta G, Sasaki K: Nodular regenerative hyperplasia of the liver associated with polyarteritis nodosa. Arch Pathol Lab Med 108:133, 1977 Wagenvoort CA, Wagenvoort N: Pathology of Pulmonary Hypertension. New York, Wiley, 1977 Philips MJ, Langer B, Stone R, et al: Benign liver cell tumors. Classification and ultrastructural pathology. Cancer 32:463, 1973 Bjornsson J, Edwards WD: Primary pulmonary hypertension: A histopathologic study of 80 cases. Mayo Clin Proc 60:16, 1985 Edwards WD, EdwardsJE: Clinical primary pulmonary hypertension: Three pathologic types. Circulation 56:884, 1977

18. Roberts WC: A simple histologic classification of pulmonary arterial hypertension. Am J Cardiol 58:385, 1986 19. Rich S, Brundage BH: Primary pulmonary hypertension. Current update. JAMA 251:2252, 1984 20. McDonnell PJ, Toye PA, Huchins GM: Primary pulmonary hypertension and cirrhosis: Are they related? Am Rev Respir Dis 127:437, 1983 21. Naeye RL: "Primary" pulmonary hypertension with coexisting portal hypertension. A retrospective study of six cases. Circulation 22:376, 1960 22. Calabresi P, Abelmann WH: Portocaval and porto-pulmonary anastomoses in Laennec's cirrhosis and in heart failure. J Clin Invest 36:1257, 1957 23. Heinemann O: Respiration and circulation in patients with portal cirrhosis of the liver. Circulation 22:154, 1960 24. Rfittner JR, BartschiJ-P, Niedermann R, et al: Plexogenic pulmonary arteriopathy and liver cirrhosis. Thorax 35:133, 1980

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