We report an autopsy case of pulmonary pexogenic arteriopathy associated with portal hypertension due to alcoholic liver cirrhosis, termed portopulmonary hypertension (PPHT). A 49-year-old man who has had alcoholic liver cirrhosis for 10 years complained of severe dyspnea (Fletcher-Hugh-Jones V). Chest CT revealed marked
enlargement of bilateral hilar pulmonary arteries and cardiomegaly associated with right ventricular hypertrophy. The patient died from hepatic. encephalopathy and respiratory failure. Autopsy c1early revealed the wall thickness of pulmonary small vessels diffusely in peripheral fields on cut surfaces and marked dilatation of the main pulmonary artery, together with liver cirrhosis. Microscopically, the pulmonary small arteries demonstrated grade 5 pulmonary plexogenic arteriopathy inc1uding plexiform lesions and a micronodule resembling an arachnoid granulation or meningioma throughout the lungs. This case suggested that a typical plexogenic arteriopathy morphologically and definitely
contributed to confirm PPHT, although the patient was c1inically suspected of hepatopulmonary syndrome (HPS)

Enomoto, Yasunori

Hamada, Kaoru

Kimura, Hiroshi

Maruyama, Hiroshi

Nakamura, Takahito

Toyoda-Hirana, Yuki

English

Global Institutional repository of Nara Medical University

Case Report AN  AUTOPSY CASE OF PORTOPULMONARY HYPERTENSION ASSOCIATED WITH ALCOHOLIC LIVER CIRRHOSIS HIROSHI MARUYAMN)， YUIHTOYODA-HlRANN) and TAKAHITO NAKAMURA2) Depα吋meη:tsOfl)p，α:thology and 2) RespiratoηM油相e，Hosh4若田kaKosei間的inHosがtalY ASUNORI ENOMOT03)， KAORU HAMADA 4) and HIROSHI KIMURA 4) Depιγtm出丸:tsof3)Diag:叩 sticPalhology a，況がRespiγα10ηM叫 cine，Nar，αMe批日:1Universii旬Received ]uly20， 2011 (81) Absfract: We report an autopsy田町 ofpulmonary plexogenic arteriopathy associated with portal hypertension due to alcoholic liver cirrhosis， termed portopulmonary hypertension (PPHT). A 49-year-old man who has had alcoholic liver cirrhosis for 10 years complained of severe dyspnea (Fletcher】Hugh-JonesV). Chest CT revealed marked enlargement of bilateral hilar pulmonary arteries and cardiomegaly associated with right ventricular hypertrophy. The patient died from hepatic. encephalopathy and respiratory failure. Autopsy c1early revealed the wall thickness of pulmonary small vessels diffusely in periph巴ralfields on cut surfaces and marked dilatation of the main pulmonary artery， together with liver cirrhosis. Microscopically， the pulmonary small arteries demonstrated grade 5 pulmonary plexogenic arteriopathy inc1uding plexiform lesions and a micronodul巴 resemblingan arachnoid granulation or meningioma throughout the lungs. This case suggested that a typical plexogenic arteriopathy morphologically and definitely contributed to confirm PPHT， although the patient was c1inically suspected of hepatopulmonary syndrome (HPS). Key words portopulmonary hypertension， alcoholic liver cirrhosis， plexiform lesion， associated pulmonary arterial hypertension， hepatopulmonary syndrome INTRODUCTlON The plexiform lesion is the cardinal histological finding of plexogenic pulmonary arteriopathy. The lesion is observed in primary plexogenic pulmonary arteriopathy， pulmonary hypertension (PH) secondary to congenital cardiac malformations associated with shunting， and the drug aminorex fumarate. Furthermore， itis rarely found with liver cirrhosis or portal vein thrombosis. It is well-known that a moderate degree of PH is common in patieロtswith portal hypertension due to liver cirrhosis， corresponding to morphological change of c1assic plexogenic pulmonary arteriopathyl). The portopulmonary hypertension (PPHT) is defined as a pulmonary arterial hypertension associated with portal hypertension in the presence or absence of liver disease21 • It was initially reported by Mantz and Craige31 in 1951 that the coexistence of PH as a consequence of hepatic dysfunction (82) H. Maruyama， et al. caused by portal axis thrombosis was found via a postcaval shunt， resulting in cor pulmonale. The prevalence is relatively low in PPHT， and its frequency observed to a greater extent in alcoholic liver cirrhosis. Especially， the incidence of pulmonary arterial hypertension in cases of biopsy-proven liver cirrhosis was between 0.61・2.0%2).We report here on an autopsy case of plexogenic pulmonary arteriopathy associated with alcoholic liver cirrhosis， termed PPHT. Concerning CT findings， the differentiation between PPHT and hepatopulmonary syndrome (HPS) isbriefly discussed CASE REPORT A 49-year-old man complained of severe dyspnea (Fletcher-Hugh-]ones V) and was admitted to our hospital because of the marked enlargement of bilateral hilar shadows on chest X-ray (Fig. 1). He had a history of heavy alcohol intake (mainly， 5 x 180ml/day x 25 years of ]apanese Sake) and was diagnosed with alcoholic liver cirrhosis since 10 years before. Brinkman index was approximately 400. In the past before admission， he underwent a sclerotherapy for esophageal varix. At the time of admission， blood pressure was elevated to 190/110 mmHg， with pulse rate of 86/min.， respiration rate of 18 times/min， and oxygen saturation (Sp02) of 92%. Electrocardiography revealed mild right ventricular hypertrophy and right bundle branch block. Echocardiography did not show any cardiac valvular abnormality， or clear right ventricular dilatation. His consciousness was somnolent， suggesting hepatic encephalopathy of grade I， reflected by high serum ammonia value of 160μg/dl . The skin appeared icteric. Clubbed finger and flapping tremor were also Fig. 1. Chest x-ray showed the enlargement of bilateral hilar shadows and elevation of cardio-thorax ratio (CTR) Fig. 2. Thoracic CT revealed marked enlargement of bilateral hilar pulmonary arteries and venous dilatated appearance in the peripheral lung fields Pulmonary hypertension in liver cirrhosis Table 1. Laboratory data on admission Blood : RBC 449 X 1041μL， HB 16.4 g/dL， HcT 46.8 %， WBC 71001μL， PLT 4.9x 1041μL Hemostasis : PT 30.8 sec‘ PT 24.亘弘 rT-INR2.42司 APTT 81.5 sec‘ Fibrinogen 82 mg/d，L FDP 6.2μ g/mL Biochemistry/lmmuno1ogy : T'Bi1irubin 12.5 mg/dL. D-BIL 5.6 mg/dL. TP 5.2 g/dL. A1b 2.6 g/dL. AST 105 IU/L. ALT 57 IU/L. ALP 1243 U/L.γ 幽 GTP 68 U/L. LDH 589 IU/L. Glucose 131 mg/dL. NH3 160μg/d，L BUN 15.7 mg/dL， Creatinine 0.56 mg/dL， Na 140 mEq/L， K 3.0 mEqlL." C1 106 mEq/L， sNP 96.1pg/m，L CRP 0.18 mg/dL， HBs-Ag: (一)、 HCV-Ab: (-)， Anti-mitochondria Ab : (-) Tumor marker : CEA6.0 ng/m，L，.QA19-9 112.43 U/mL."AFP 14 ng/mL， PIVKA-lI 829 mAU/mL， SCCO.5 ng/mL， NSE7.6 ng/mL， sIL-2R 345U瓜![lUnderline: abnormal values (83) recognized. Laboratory findings are shown in Tab1e 1， and brief1y summarized as thrombo-cytopenia， decrease in prothrombin time and tota1 protein， increase in tota1 bi1irubin (12.5mg/d1)， and HB目Ag，HCV and anti-mitochondria antibody were negative. Tumor markers were e1evated as CA19-9 va1ue: 112.4 U Im1， PIVKA -I: 829 and CEA目 6.0(<5.0). Thoracic CT revea1ed marked en1argement of bi1atera1 hi1ar pu1monary arteries and right ventricles， and moreover marked periphera1 pu1monary veins (Fig. 2). Abdomina1 CT showed liver cirrhosis without space occupying 1esion， nor obstruction of porta1 vein， accompanied with sp1enomega1y and esophagea1 varices. The clinica1 diagnosis denied 1ung cancer on CT findings with negative sputum cyto1ogy， and he was suspected of pu1monary hypertension associated with 1iver cirrhosis. B100d gas samp1e was not taken， and right heart catheterization was a1so not performed because of a refusa1 by the fami1y. The patient died from hepatic encepha10pathy four weeks after admission and was autopsied two hours 1ater. PATHOLOGIC FINDINGS AT AUTOPSY Gross1y， the 1iver was very small， 630g in weight， and diffuse1y micorgranu1ar in approximate1y 3 mm in diameter (Fig. 3). The cut surface did not show any 1iver tumors. There were yellowish ascites (600m1)， jaundice， sp1enomega1y (270g) and esophagea1 varices with mi1d erosion of gastric cardiac portion. The h巴artweighed 590g， with 100 ml of pericardia1 yellowish effusion. There was marked 1eft and right ventricu1ar hypertrophy， with the wall thickness of 17 mm (<10 mm in normal) and 8 mm (<5 mm in normal)， respective1y. Especially， the girth of PA va1ve in 8cm was 1arger than that of aortic va1ve in 7cm. The right 1ung weighed 430g and the 1eft 420g， a1most without congestion and (84) H. Maruyama， et al. Fig. 3. Gross appearance of the liver weighing 630g showed diffuse micorgranules in approximately 3 mm in diameter Fig. 4. At autopsy， after formalin-fixation， the cut surface of the lung showed the wall thickening of small pulmonary arterial vessels hemorrhage. There was pleural effusion (rt: 250ml， lt:40白nl).The cut surface of lung clearly revealed wall thickness of small blood vessels in the periphery， in addition to enlargement of the central pulmonary artery (Fig. 4). The hilar lymph nodes were slightly swollen with softness. Microscopically， the liver revealed micronodular cirrhosis with only a litle fatty change and Mallory body (Fig. 5). Because HBs-Ag and HCV were negative in serum， alcoholic liver cirrhosis was considered. The splenomegaly was observed as congestion associated with cirrhosis. The cardiac muscles of left and right ventricles were histologically hypertrophic， probably due to systemic and PH. In the histologic sections of the lung， the small pulmonary arteries from 200 to 500μm mostly demonstrated al types of hypertensive changes， ranging from muscular medial hypertrophy (Grade 1 in Heath-Edwards' classification of plexogenic pulmonary arteriopathy) to intimal fibrosis (Fig. 6)， plexiform lesions (approximately 300μm in diameter) with peripheral dilatation lesions (Grade 4) (Fig. 7) and a micronodule Pulmonary hypertension in liver cirrhosis (85) Fig. 5. Microscopicaly， the liver showed pseudolobules， suggesting the alcoholic liver cirrhosis (Masson trichrome stain， x20). Fig. 6. Microscopicaly， the small pulmonary arteries of approximately 200-300μm demonstrated intimal fibrosis (Grade 2-3 in Heath-Edwards' classification) (EVG， x40)， suggesting hypertensive change Fig. 7. A small vessel (approximately 300μm in diameter) inthe lung microscopically formed the plexiform lesion (Grade 4) with peripheral capillary dilatation (HE， x40) Fig. 8. Another smal vessel in the lung microscopically demonstrated a micronodule resembling an arachnoid granulation or meningioma (Grade 5) ( HE， xlOO)ーresembling an arachnoid granulation or meningioma (Grade 5) (Fig. 8). But necrotizing arteries of pulmonary arteries (Grade 6) were not observed at histologic sections examined In central area， the pulmonary artery demonstrated intimal and medial wal thickness. The lymph nodes of pulmonary hilum showed nonspecific findings such as sinus histiocytosis and silicoanthracosis， without tumor DISCUSSION The present case was morphologicaly confirmed to show PPHT associated with non-compensatory phase of alcoholic liver cirrhosis， although valuable clinical examinations concerning on pulmonary hypertension were insufficient， such as a direct pulmonary arterial pressure and arterial blood oxygen pressure. That is， plexiform pulmonary arteriopathy was considered as the halmark of primary pulmonary hypertension4l (recently re-termed (86) H. Maruyama， et al. pulmonary arterial hypertension5)). Since the first report by Mantz and Craige3) (aportal thrombosis case) in 1951， and subsequently PH complicated by liver cirrhosis was first described by NaeyeB) in 1960. PPHT is described in low incidence of 0.61-2%2). In Japan， Ito et aF) (1987) reported two autopsy cases of PH in hepatitis B virus-associated liver cirrhosis. According to Nakatani et a18)， PPHT of approximately 60 cases have been reported in English literature， while 32四 sesin Japan have been reported up to 1985， respectively. Recently， the occurrence of PPHT in patients undergoing evaluation for liver transplant has increased as high as 8目5%9). It has b巴enreported by Matsubara et aPO) that patients with severe hepatic injury (94 adult cases) are in a state of subclinical PH and that symptoms of severe PH may develop progressively or abruptly in some of them. They suggested that the wall thickening and the ratio of wall thickness to the anatomical radius of small pulmonary art巴neswer巴significantly larger in the cirrhotic group than in the control group. Edwards et alll) described that PH associated with portal hypertension commonly had a plexogenic appearance (10 of 12 patients) on histologic sections， and that thrombus might also contribute to vascular obstruction. It has been recently described by Dana Point classification (2008) that Plexiform pulmonary arteriopathy (P AH) including PPHT has been reclassified as an associated type of pulmonary arter包1hypertension (APAH)， together with various etiologic disorders， collagen悶vasculardisease， HIV infection， portal hypertension， congenital heart disease， schistosomiasis， chronic hemolytic anemia， and drug/toxin such as aminorex fumarate. In our case， although portal thrombosis was neither recognized with CT imaging or gross findings at autopsy， portal hypertension induced by non-compensatory liver cirrhosis with complication of both splenomegaly and esophageal varices was assumed. It has been indicated that portal hypertension and portosystemic shunting， rather than the hepatic disorder itself including cirrhosis， are most likely to be the determinant risk factor for developing PH. On the other hand， another pulmonary vascular complication in liver dysfunction， hepatopulmonary syndrome (HPS) 12)， is recently important for respiratory clinicians to differentiate from PPHT. HPS is defined by liver disease， intrapulmonary vasodilation and impaired arterial oxygenation. HPS is usually present with dyspnea without any abnormal shadows on chest x-ray， but occasionally with an increase in interstitial markings in the lower lung fields on CT imaging. Infrequently， HPS is not easily distinguished from portopulmonary hypertension because of similar clinical features， such as dyspnea， anemia， ascites， hepatic hydrothorax， and muscle wasting. In our case， oxygen satur・ation(Sp02) was lower at 92%， and there was some difficulty before the death in differentiating betw巴enPPHT and HPS showing the imaging of pulmonary vasodilation in peripheral zone of lung on CT13). However， chest x】rayof the present patient showed marked enlargement of bilateral hilar shadows and elevation of cardio-thorax ratio (CTR)， suggesting some features of PPHT. Microscopically， PPHT shows pulmonary vasoconstriction， intima proliferation， media】hypertrophy and plexiform lesions， but HPS shows capillary and pre-/post-capillary pulmonary vasodilation with lower pulmonary vascular resistance， and right to left shunt formation， in spite of fewer autopsy cases. In western countries， orthotopic liver transplantation is recently recommended in these two pulmonary vascular complications of end-stage liver disease14). It has already been described in 1999 that a case of PPHT following Pulmonary hypertension in liver cirrhosis (87) HPS in a patient with liver cirrhosis showed 25】62mmHg of mean pulmonary art巴rypressure on right-sided catheterization after more than 2-year clinical course， being still alive15). In conclusion， the present case suggests PPHT based on plexogenic pulmonary arteriopathy at autopsy associated with non-compensatory alcoholic liver cirrhosis， in spit巴of clinically differentiating from HPS. The pulmonary complications of end-stage liver dis巴aseinclude PPHT and HPS， and the etiologic pathogenesis of these conditions will need more elucidation in the near future. ACKNOWLEDGMENTS We thank Dr. Hatsue Ueda， Dept. of Pathology， National Cerebral and Cardiovascular Center， Suita， Japan， for advice on the pathologic findings. REFERENCES 1) Heath， D. : Pulmonary vasculature. Chap.21， In Spencer' pathology of the lung， Haleston PS， Eds. fifth edi】tion， McGraw-Hi1， Inc.， New York， pp.649-671， 1996 2) Delcroix， M.: Portopulmonary hypertension. Chap. 8， In Eur Respir Mon， ERS Journals Ltd， London， 34・129-138， 2006 3) Mantz， F.A. and Craige， E. : Portal axis thrombosis with spontaneous portcaval shunt and resulting cor pulmonale目 Arch.Patho1. 52 : 91-97， 1951 4) Ruttner， J.R.， Bartschi， J-P.， Niedermann， R. and Schneider， J.: Plexogenic pulmonary arteriopathy and liver cirrhosis. Thorax 35 : 133-136， 1980 5) American College of Chest Physicians: Diagnosis and managem巴ntof pulmonary arterial hypertension: ACCP evidence-based clinical practice guideline. Chest 126(Suppl)， 2004目6) Naeye， R.L. : Primary pulmonary hypertension with coexisting portal hypertension: A r巴trospectivestudy of six cas巴s.Circulation 22 : 376-384， 1960. 7) Ito， M.， Honda M.， Shauna， S.et al.: Pulmonary hyp巴rtensionin hepatitis B virus carriers目 Acta.Pathol Jpn. 37 : 1935-1943， 1987. 8) Nakatani， Y.， Ogawa， N.， Sasaki， Y. et al. : Pulmonary hypertension associated with portal hypert巴nsionin childhood. Acta. Patho1. Jpn. 38・897-907，1988. 9) Saleemi， S.: Portopulmonary hypertension. Ann. of Thorac. Med. 5 : 5-8， 2010 10) Matsubara， 0.， Nakamura， T.， Uehara， T. and Kasuga， T. : Histometrical investigation of the pulmonary art巴ry111 S巴V巴r巴 h巴paticdisease. J. Patho1. 143 : 31-37， 1984 1) Edwards， B.S.， Weir， E.K.， Edwards， W.D.， Ludwig， J.， Dykoski， R.K. and Edwards， A. : Coexistent pul同monary and portal hypertension: Morphologic and Clinical features. J. Am. Coll. Cardio1. 10 1233-1238， 1987. 12) Schenk， P.， : The hepatopulmonary syndrom巴 Chap.7，In Eur Respir Mon， ERS Journals Ltd， London， 34 : pp. 112-128， 2006 13) Umeda， N. and Kamath， P.S.: Hepatopulmonary syndrome and portopulmonary hypertension. H巴patologyRes. 39 : 1020-1022， 2009 14) Hala叫1:， M.， Ewert， R.， Seyfarth， H.J. and Hoeffken， G. : Portopulmonary hypert巴nsion.J. Gastroentero1. 41 : 837-847， 2006. 15) Mal， H.， Brugiere， O. and Durand， F. et al.: Pulmonary hyp巴rt巴nsionfollowing h巴patopulmonarysyn drome in a patient with cirrhosis. J. Hepatology 31 : 360-364， 1999. 

AN AUTOPSY CASE OF PORTOPULMONARY HYPERTENSION ASSOCIATED WITH ALCOHOLIC LIVER CIRRHOSIS

http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/1877/1/81-87p..pdf

AN AUTOPSY CASE OF PORTOPULMONARY HYPERTENSION ASSOCIATED WITH ALCOHOLIC LIVER CIRRHOSIS

Abstract

Similar works

Full text

Available Versions

Global Institutional repository of Nara Medical University