Hepatic and portal vein thrombosis in cirrhosis: Possible role in development of parenchymal...

Hepatic and Portal Vein Thrombosis in Cirrhosis: Possible Role in Development of Parenchymal Extinction

and Portal Hypertension

IAN R. WANLESS, 1 FLORENCE WONG, 2 LAWRENCE M. BLENDIS, 2 PAUL GREIG, 3 E. JENNY HEATHCOTE, 2 AND GARY LEVY 2

Obliterative l e s ions in portal ve ins (PVs) and hepat ic ve ins (HVs) of all s izes are k n o w n to occur in c irrhot ic livers. PV les ions h a v e general ly been attr ibuted to thrombosis , but the p a t h o g e n e s i s o f the HV (veno-occlusive) l es ions is u n k n o w n . We h a v e s tudied 61 c irrhot ic l ivers r e m o v e d at t ransp lantat ion to clarify the prevalence, distribution, and p a t h o g e n e s i s o f v e n o u s les ions , as wel l as the as soc ia t ion of these les ions w i th o ther morpho log ica l features and cl inical morbidity. Int imal fibrosis that is h ighly sugges t ive of hea led HV or PV thrombos i s w a s found in at least 70% and 36% of livers, respect ively . The dis tr ibut ion o f HV les ions w a s patchy and largely conf ined to ve ins b e t w e e n 0.1 and 3 m m in diameter , sugges t ing mult i foca l origin in smal l veins. PV les ions w e r e more un i form t h r o u g h o u t the liver, sugges t ing origin in large ve ins w i th propagat ion to the smal l veins . HV les ions w e r e assoc ia ted wi th reg ions of conf luent f ibrosis (focal p a r e n c h y m a l ext inct ion) , and PV les ions w e r e assoc iated wi th reg ional var ia t ion in the s ize o f c irrhot ic nodules and a h is tory of b leeding varices. These observat ions sugges t that thrombos i s of m e d i u m and large PVs and HVs is a frequent occurrence in cirrhosis , and that these events are important in causing progress ion of cirrhosis . (HEPATOLOGY 1995;21:1238- 1247.)

C i r r h o s i s d e v e l o p s w h e n p a r e n c h y m a l i n j u r y is fol- l o w e d b y f i b r o u s o b s t r u c t i o n o f s i n u s o i d s a n d a d j a c e n t s m a l l p o r t a l v e i n s (PVs) a n d h e p a t i c v e i n s (HVs) . M o s t c i r r h o t i c l i v e r s h a v e a u n i f o r m p a t t e r n o f f i b ro us s e p t a

Abbreviations: PV, portal vein; HV, hepatic vein; FPE, focal parenchymal extinction.

From the Departments of 1Pathology, '~Medicine, and 3Surgery, The Toronto Hospital, University of Toronto; and the Canadian Liver Pathology Reference Centre, Toronto, Canada.

Received August 19, 1994; accepted October 25, 1994. The Canadian Liver Pathology Reference Centre is supported by the Cana-

dian Liver Foundation. This work was presented in part at the annual meeting of the American

Association for the Study of Liver Diseases, Chicago, IL, November 6, 1993 (HEPATOLOGY 1993; 18:112A), and at the biennial scientific meeting of the In- ternational Association for the Study of the Liver, Cancdn, Mexico, May 23, 1994 (HEPATOLOGY 1994; 19:139I).

Address reprint requests to: Ian R. Wanless, MD, Department of Pathology, The Toronto Hospital, 200 Elizabeth St, Toronto, Canada, M5G 2C4.

Copyright © 1995 by the American Association for the Study of Liver Diseases.

0270-9139/95/2105-000453.00/0

a n d r e g e n e r a t i v e n o d u l e s . H o w e v e r , w e h a v e n o t e d re- g i o n a l v a r i a t i o n in f i b ros i s in c i r r h o t i c l i v e r s t h a t is a s s o c i a t e d w i t h o b s t r u c t i o n of m e d i u m a n d l a r g e he - p a t i c v e s s e l s . T h e p u r p o s e of t h e p r e s e n t s t u d y is to d o c u m e n t t h e m o r p h o l o g i c a l a n d c l i n i c a l f e a t u r e s of t h e s e f o r m s of r e g i o n a l p a r e n c h y m a l h e t e r o g e n e i t y a n d o b s t r u c t i v e l e s i o n s in P V s a n d H V s i n c i r r h o t i c l i ve r s .

O u r r e s u l t s s u g g e s t t h e v a s c u l a r l e s i o n s a r e a r e s u l t of t h r o m b o s i s a n d r e g i o n a l p a r e n c h y m a l h e t e r o g e n e i t y is s e c o n d a r y to v a s c u l a r o b s t r u c t i o n . I n t r a h e p a t i c t h r o m b o s i s m a y h a v e a n i m p o r t a n t i n f l u e n c e on t h e n a t u r a l h i s t o r y of c i r r h o s i s .

M A T E R I A L S A N D M E T H O D S

Sixty-one cirrhotic l ivers removed at t ime of t r ansp lan ta - t ion were studied. The pa t ien ts were adul t s t r ea ted at The Toronto Hospi ta l in 1992 or 1993. The specimens were unse- lected, except t ha t l ivers with incomplete cirrhosis or cirrhosis caused by HV thrombosis were excluded. Twenty-four livers obta ined at autopsy from pa t ien ts wi thout cirrhosis served as controls. Livers were examined grossly for weight, configuration, size of nodules, appearance of large PVs and HVs and regional heterogenei ty in nodule size and parenchymal fibrosis.

Histological blocks were obtained prospectively. The ma in HVs were sampled wi thin 1 cm of the i r ostia, and the left and r ight PVs were sampled wi thin 1 cm of the hilum. The ma in PV was sampled in most cases. Other blocks were t aken from per iphera l left and r ight lobes to show parenchyma; regions of maximal fibrosis were sampled. A mean of 17 blocks were obtained per liver. These were embedded in paraffin, sectioned, and s ta ined with hematoxyl in-eosin and elas- t ic-trichrome. Iron, periodic a c i d - S c h i f f wi th diatase, and orcein s ta ins were performed on one block from each liver. Grad ing for ana tomic pa r a me te r s is summar ized in Table 1. In t ima l fibrosis and luminal nar rowing were graded (0 th rough 5) for each of the large veins (left, middle, and r ight HVs; left, r ight , and ma in PVs) and med ium HVs and PVs from left and r ight lobes. Veins were called large if they were grea te r t han 3 m m in d iamete r and medium if they were 0.2 to 3 m m in diameter . The gradings were defined as 1 (focal but definite in t imal fibrosis), 2 ( int imal fibrosis involving at leas t two-thi rds of the circumference with luminal nar rowing < 10%), 3 ( in t imal fibrosis wi th luminal nar rowing approxi- ma te ly 10% to 40%), 4 ( int imal fibrosis wi th luminal narrowing 40% to 80%), and 5 ( luminal nar rowing >80%). For medium veins, the most severe lesion found in each lobe de- t e rmined the grade for t ha t lobe. Acute thrombi were sought but not included in the grading of lumina l narrowing.

1238

HEPATOLOGY Vol. 21, No. 5, 1995 WANLESS ET AL 1239

TABLE 1. S u m m a r y of A n a t o m i c G r a d i n g S y s t e m

Focal Parenchymal Extinction (% of lobar involvement on Parenchymal Fibrosis (on stained sections

Grade Vascular Disease gross appearance) at 5>< magnification)*

1 Focal intimal fibrosis < 10 Occasional broad fibrous septa 2 Intimal fibrosis involving 2/3 of circumference, 10-33 Many broad fibrous septa

< 10% luminal narrowing 3 10%-40% luminal narrowing >33 4 40%-80% luminal narrowing 5 >80% luminal narrowing

Confluent fibrosis at least 5 mm across

* Grade 0 fibrosis equals cirrhosis with uniformly narrow septa.

Parenchymal fibrosis was graded in two ways. Focal parenchymal extinction (FPE) was defined as a grossly visible region of severe parenchymal loss and fibrous replacement and was graded (0 through 3) for each lobe according to the ap- proximate percentage of involvement as 1 (< 10%), 2 (10% to 33%), or 3 (>33%). Parenchymal fibrosis was also graded by mounting all elastic-trichrome-stained slides on a light box and viewing them with a 5× lens. The fibrosis score of each slide was recorded (0 through 3) as 0 (cirrhosis with uniformly narrow septa), 1 (occasional broad fibrous septa), 2 (many broad fibrous septa), and 3 (confluent fibrosis at least 5 m m across). The fibrosis grade for the liver was the mean score of all slides.

Coronal slices of whole right lobes from 10 selected cirrhotic livers were embedded in large paraffin blocks (up to 7 × 9 cm), and elastic-trichrome-stained sections were examined to determine the topographic distribution of venous intimal fibrosis and parenchymal fibrosis. The location of all HVs at least 0.2 mm in diameter was marked. The HV external diameter was measured with an eyepiece graticule, and the percentage of narrowing was estimated to the nearest 10%. The parenchymal fibrosis in the region of each vein was graded on the large glass slides as described previously. Fig-

. ure 7 was produced by recording the location of fibrosis on a plastic overlay, digitizing both the overlay and the dotted slide, and superimposing the images using CorelDRAW (Corel Corporation, Ottawa, Canada). PV obstruction was es- t imated in 4 livers. For all portal tracts having arteries at least 0.03 mm in diameter, the smallest dimension of the PV lumen and the smallest outside dimension of the largest adjacent artery were measured and the PV/artery ratio was calculated. This method was used because PVs are often shrunken or not visible after thrombosis.

Clinical records were reviewed, without knowledge of anatomic findings, for history of variceal bleeding, esophageal sclerotherapy, portacaval anastomosis, and splenectomy. As- cites was graded as 1 (mild, treated with salt restriction only), 2 (moderate, treated and controlled with diuretics), or 3 (severe, resistant to diuretics or requiring large-volume para- centesis). The apparent origin was hepatitis C virus (14), primary biliary cirrhosis (9), primary sclerosing cholangitis (9), alcohol (7), hepatitis B virus (7), al-antitrypsin deficiency (3), hemochromatosis (2), autoimmunity (2), obesity (1), biliary atresia (1), and cryptogenic (6). Variceal bleeding had been treated using sclerotherapy in 19 patients. Five had a remote surgical shunt procedure, 2 had transjugular intrahepatic portosystemic shunt insertion, and 9 had a splenectomy months or years before transplantation. The mean age was 49 (cirrhosis) and 69 (controls) with 66% and 46% men, respectively.

Statistical analysis was performed using Student's t-test (two-tailed) and X 2 test (two-tailed) or Fisher's exact test as computed by Microstat (Ecosoft Inc., Indianapolis, IN).

RESULTS

Prevalence of Lesions. Large I-IV disease (grades 3 t h r o u g h 5) was p r e sen t in one or more of the th ree ma jo r HVs in 10 l ivers (16.4%) (Fig. 1). At l eas t 80% n a r r o w i n g (grade 5) of an H V was p r e s e n t in 3 l ivers (4.9%). The p reva lence of lesions was s imi la r in the r ight , middle , and left veins, except t h a t g rade 4 and 5 lesions were not observed in the r igh t lobe. None of the controls h a d large H V disease g r e a t e r t h a n g rade 2.

M e d i u m H V disease (grades 3 t h r o u g h 5) was p r e sen t in 43 l ivers (70%) (r ight lobe, 36; left lobe, 33) (Fig. 1). None of the controls h a d m e d i u m H V disease g r e a t e r t h a n g rade 2. La rge H V disease cor re la ted wi th me- d ium H V disease in the s a m e lobe (Fig. 2). However , l a rge H V disease was u sua l ly less severe t h a n m e d i u m H V disease in the s a m e lobe.

La rge PV disease (grades 3 t h r o u g h 5) was p r e s e n t in 15 l ivers (25%), and g rade 5 lesions were found in 6.6% of l ivers (Fig. 3). M e d i u m PV disease (grades 3 t h r o u g h 5) was observed in 22 l ivers (36%) (r ight lobe, 20; left lobe, 10). The p resence of l a rge PV disease corre- l a ted ve ry closely wi th m e d i u m PV disease (Fig. 4). The re was no cor re la t ion be tween large PV disease and large H V disease or be tween m e d i u m PV disease and m e d i u m H V disease (da ta not shown).

100

80

60

40

20

Percent of livers with lesions p=0.4

FIG. 1.

Cirrhosis C o n t r o l Cirrhosis Control

Medium HV Large HV

BB5 BB4 D 3 D 2 E31 Grade of lesions

Prevalence of HV lesions in 61 cirrhotic livers and 24 noncirrhotic control livers.

1240 WANLESS ET AL HEPATOLOGY May 1995

4 . 4

o 3 . " " , 3

lm - W e-

( lee

" 0 . - - , , . , . , - , . , • • - J O

e e

e l e

eee eee

ee •

i

• e e

eee ee

e e e e • •

0 1 2 3 4 5 M e d i u m - s i z e d hepat ic ve ins

FIG. 2. Correlation between disease in large and medium HVs. Each dot represents the grading of medium HVs and large HVs in the same lobe (P < .01 [)/2 = 46.6; d f = 25]).

0 1 2 3 4 5 M e d i u m - s i z e d portal ve ins

FIG. 4. Correlation between disease in large and medium PVs. Each dot represents the grading of medium PVs and large PVs in the same lobe (P < .0001 [X 2 = 96.4; d f = 25]).

FPE was present in 33 livers (54%) (right lobe, 31; left lobe, 23; both lobes, 21). FPE correlated with medium HV disease and with large HV disease (Fig. 5). For example, data from the right lobe showed that 75% of those with medium HV disease (grades 3 through 5) had FPE, whereas only 16% with milder HV disease (grades 0 through 2) had FPE (P = 2 × 10-5). There was no association between medium PV disease and FPE, but there was a slight inverse relationship between large PV disease and FPE (31% of lobes had FPE i fPV was grades 2 through 5 vs. 52% i fPV was grades 0 and I; P = .047).

HV disease, FPE, and PV disease were found in cirrhosis of all origins (Fig. 6). There was no correlation

Percent of livers with lesions 100

80

60

40

20

0 Cirrhosis Control Cirrhosis

p=0.048

' . : . : . : . : . : . : . : . : . : .

Control

Medium PV Large PV m5 B=4 m3 E22 ~1

Grade of lesions

FIG. 3. Prevalence of PV lesions in 61 cirrhotic livers and 24 noncirrhotic control livers.

between gender or liver weight and any of the vascular parameters or fibrosis (data not shown).

Distribution and Quanti tat ion of Vascular Occlu- sion and Parenchymal Fibrosis. Examination of large coronal sections from 10 cirrhotic livers confirmed the initial observation obtained from small blocks that FPE occurred in regions having fibrous obliteration of medium HVs (Figs. 7 and 8). Some livers had regions of accentuated fibrosis with broad septa but less than total loss of cirrhotic nodules (Figs. 7C and 8C). Quantita- tion showed that regions of accentuated fibrosis, as well as FPE, were more likely to have narrowing of hepatic vein lumina (Fig. 9). The percentage of occlusion of a vessel was proportional to the severity of fibrosis in the region of that vessel. Thus, the mean percentage of occlusion of 0.20- to 0.39-mm veins was 13% with back- ground cirrhosis (fibrosis grade 0), 44% with mild to moderate accentuation of fibrosis (grades 1 and 2), and 56% with FPE (fibrosis grade 3). The prevalence of narrowing and the percentage of narrowing were higher in the smaller vessels (Fig. 9). Livers without FPE or accentuated fibrosis (i.e., fibrosis grade 0) had almost no disease in medium and large HVs. In one such liver examined with a large coronal section, only 3 of 66 medium HVs showed lesions.

Obstructed HVs occurred in clusters, suggesting that a single event could have caused all venous lesions in a cluster. Obstructed I-tVs were crowded together, con- sistent with loss of parenchymal volume in regions of FPE. The size of an FPE lesion correlated with the size of the largest regional HV having high-grade occlusion (>40%), with a ratio between 25 and 75 to 1 (i.e., a typical 10-mm region of FPE was associated with high- grade obstruction of a 0.2-mm HV). Marked deformity of a lobe was associated with high-grade occlusion in a vein at least 1 mm in diameter.

PV morphometry data from four livers are summa-

HEPATOLOGY Vol. 21, No. 5 ,1995 WANLESS ET AL 1241

5 M m

3 ~ A

K ~ X X X m •

E= 1 ==,

0 z"-

N

N

2 [JnF z z -

1 = = =

" 0 IZ l= , "

0 1 2 3 Focal parenchymal extinction

FIG. 5. Correlation between HV disease and FPE. Each dot represents the grading of HVs and FPE in the same lobe (for medium HVs P < .001 [X: = 39.0; df = 15]; for large HVs P < .01 [X 2 = 31.7; df = 15]).

rized in Fig. 10. Livers had either many lesions or almost none; case no. 4 had intimal fibrosis in 14% of PVs between 0.1 and 2.0 mm in diameter, whereas cases I through 3 had intimal fibrosis in 88%, 94%, and 65% of PVs, respectively. The percentage of occlusion was similar across the range of PV size from 0.1 to 2.0 mm in diameter (Fig. 10).

Anatomic Description. Lesions in HVs larger than 0.1 mm in diameter were characterized by patchy intimal fibrosis with focal and eccentric thickening and variable degrees of luminal obstruction, often with multiple lumina or fibrous bands forming webs (Fig. 11). The irregular intimal surface and patchy distribution were highly suggestive of healed thrombosis. Re- cent thrombi were rarely observed.

PV lesions were qualitatively similar to those of HVs, except that elastic fibers were less evident (Fig. 12), and the luminal surface tended to be more regular with single lumina. Webs were usually observed only in large PVs.

FPE was characterized by a marked increase in fibrosis compared with the neighboring parenchyma, and cirrhotic nodules were smaller or absent within the lesions (Fig. 13). The capsular surface was usually depressed, and the cut section was often congested. When FPE was large there was marked deformity and shrinkage of the lobe. The overlying capsule was often fibrotic and formed a thick "sugar-coating" in two livers. Regions of FPE were most frequent in the subcapsular region but occasionally were scattered in more central parenchyma. When many regions of FPE or accentuated fibrosis were almost confluent, the surviv- ing parenchyma formed clusters of cirrhotic nodules that were usually centered on a patent HV (venocentric nodules) (Figs. 7C, 8C, and 13B).

Histologically, FPE lesions invariably contained obliterated or sclerotic HVs and almost total absence of hepatocellular parenchyma (Fig. 13D). Clusters of ductules sometimes identified the location of effete cirrhotic nodules. Medium PVs were usually patent and dilated in regions of FPE.

Livers having obstruction of large PVs often had enlargement of the cirrhotic nodules in the regions sur- rounding large portal tracts (Fig. 14). This pat tern was observed in 4 of 10 livers with grades 4 and 5 large PV disease and in 1 of 5 livers with grade 3 large PV disease.

Clin ica l Features . There was a history of variceal hemorrhage in 25 patients (41%), and this correlated with PV disease (Table 2). For example, patients with grades 2 through 5 medium PV disease were 3.0 times more likely to have had bleeding varices than those

Percent of livers with lesions 100

80

60

40

20

Alcohol HCV PSC PBC

Etiology

ULarge HV mMedium HV ~ F P E right lobe I~Medium PV

Site of lesions

FIG. 6. The effect of etiology on the prevalence of various lesions. Alcohol-induced liver disease tended to have more lesions t han average, and biliary disease had less lesions t han average, but there are no statistically significant differences. Data is percentage of pat ients with large HV disease (grades 3 through 5 in ei ther lobe), medium HV disease (grades 4 or 5 in ei ther lobe), FPE (grades 2 or 3 in r ight lobe), and medium PV disease (grades 3 through 5 in ei ther lobe). Number of pat ients by disease: alcohol-induced liver disease, 7; hepatitis C virus, 14; PSC, 9; PBC, 9.


A

!! iiii iii!i iii iiiii i iii iiii i ii!iii !iiii i iiiiiiiiiii i i i! ii!iiii i!iiiiii iiiii i ii~ i i~*-'!i ~ i i i ii ~iiiiiiliiiiiiiiiiliiiiiiiiiiiiiiiiii!iiiiii~i ii~i!:!!!!::̧:̧!ii!!!~!ii~iiii!:!:! .......

patient data (Fig. 15) showed that many patients with bleeding varices had evidence of intrahepatic PV occlusion even when the main or first order PVs had less than 10% narrowing of their lumina. There was no correlation between HV disease and variceal bleeding (Table 2).

There was a history of ascites in 79% of patients; in 38% of patients ascites was severe (grade 3). Ascites

. . . . . . . . . . P " . . . . . . . . 7 . . . .

[ ] Cirrhotic parenchyma with broad fibrous septa

Focal parenchymal extinction (densely fibrotic liver)

o 0 0 0 0 0 O • o o 0 •

Normal 10-70% <'10% >70%

> 1.0 mm

0,6-'1,0 mm

0,2-0.6 mm

Vein diameter

Percent occlusion of hepatic veins

FIG. 7. Diagrams mapping the location of all HVs at least 0.2 mm in diameter, luminal occlusion, and focal accentuation of parenchymal fibrosis. (A and B) Pat ient with cirrhosis and severe FPE. The pat ient was a 42-year-old man with hepati t is C virus cirrhosis, severe bleeding varices, and no ascites. (A) Right lobe. The HVs with high-grade obstruction are clustered and crowded together in regions of severe FPE. The main HVs were widely patent but with mild int imal fibrosis. (B) Left lobe. Many HVs with no int imal fibrosis are located in regions without FPE. (C) Pat ient with cirrhosis related to hemochromatosis. There is no well-defined region of FPE but widespread geographic accentuation of fibrosis tha t correlates with the location of HV lesions. Veins greater t han 0.3 mm in diameter have part ial occlusion suggesting recanalized thrombus, but many HV between 0.1 and 0,3 mm in diameter have high-grade obstructive lesions.

with grades 0 or 1 PV disease (53.8% vs. 18.2%; P = .012). This relation was still present after the 12 patients with prior splenectomy and/or portacaval anastomosis were excluded. Examination of individual

FIG. 8. Liver slices adjacent to those analyzed in Fig. 7. (A) Marked FPE involves half of the cross sectional area. (B) The left lobe has minimal FPE (left). (C) Cirrhosis with minimal FPE but with large geographic areas showing moderate accentuation of fibrosis and some residual small cirrhotic nodules. The regions without accentuation of fibrosis are often centered on the hepatic venous drainage.

HEPATOLOGY Vol. 21, No. 5, 1995

A Percent of hepatic veins with intimai fibrosis 100

80

60

40

20

0 none mild moderate severe

Fibrosis in the region of each vein

D1.0-3 .0 lB0.4-0.9 ==0.2-0.39

Vein diameter (mm)

R " - Percent of hepatic veins with > 40% occlusion 70

60

50

40

30

20

10

none mild moderate severe

Fibrosis in the region of each vein

D1.0-3.0 IB0.4-0.9 ==0.2-0.39

Vein diameter (ram)

FIG. 9. Morphometric data on 534 HVs pooled from 10 livers. The veins are grouped according to diameter and degree of parenchymal fibrosis in the region of each vein. (A) Data for percentage of HVs with any intimal fibrosis indicates that almost all HVs in regions of accentuated fibrosis show intimal fibrosis. P < .0001 for comparison between grades of fibrosis in veins 0.2 to 0.39 mm, P < .0001 for comparison between grades of fibrosis in veins 0.4 to 0.9 mm, P < .03 for comparison between grades of fibrosis in veins 1.0 to 3.0 mm, and P < .02 for comparison between vein sizes (all grades of fibrosis together). (B) Data for percentage of HVs with at least 40% occlusion indicates that t tV occlusion is most severe in smaller veins that are located in regions of accentuated fibrosis. P < .0001 for comparison between grades of fibrosis in veins 0.2 to 0.39 mm, P < .0001 for comparison between grades of fibrosis in veins 0.4 to 0.9 mm, and P < .0001 for comparison between vein sizes (all grades of fibrosis together).

correlated with hepatic capsular thickening, but there was no significant correlation with other morphological features including FPE, fibrosis grade, HV or PV lesions, or nodule size (Table 3).

WANLESS ET AL 1243

DISCUSSION

Vascular obstruction in cirrhosis is prominent in PVs and HVs less than 0.2 mm in diameter. The present s tudy quanti tates lesions in larger PVs and HVs. Inti- mal fibrosis with at least 10% luminal narrowing in- volved HVs in 70% of cirrhotic livers and PVs in 36%.

In other studies, PV thrombosis was found in 0.6% to 16.6% of cirrhotics by angiography or ultrasonogra- phy, 1-5 and grossly visible PV fibrosis or acute thrombi were found in 39% of cirrhotic livers at autopsy. ~ Thus, the finding ofPV intimal fibrosis in 36% of our patients is similar to other reports when the whole liver was available for study. Much of the PV disease found in the present s tudy would not be clinically detectable with current ultrasound techniques.

The pat tern of disease in medium and large PVs could be explained by a small number of thrombotic events (one or few) beginning in a large vein with prop- agation to small veins, followed by recanalization of the larger veins. 3'5'7's This is supported by the fairly uniform distribution of PV lesions from one region to another and from one vessel size range to another and the observation that splenic and mesenteric vein lesions are often present in continuity with PV lesions. ~ Multiple layers of intimal fibrosis in some livers suggests that recurrent thrombosis may occur.

Narrowing of large HVs has been documented veno- graphically in patients with cirrhosis. 9-14 Veno-occlusive lesions of HVs less than 0.2 mm in diameter have been found in up to 74% of cirrhotic livers examined at autopsy. ~5-17 The present s tudy may be the first to quanti tate lesions in HVs of medium size (0.2 to 3 mm). In our material, veno-occlusive lesions of small veins

Mean ratio of portal vein / artery 5

4

2

0 <0.06 0.06-0.12 0.12-0.20 >0.2

Duct diameter (mm) rTCase 1 inCase 2 ==Case 3 ==Case 4

FIG. 10. Morphometric data on 334 portal tracts in 4 livers. The ratio of the PV diameter to the arterial diameter is used as an esti- mate of PV occlusion. Liver from case no. 4 has no evidence of PV disease and thus represents a control for cases 1 through 3 that had widespread PV intimal fibrosis. Cases no. 1 and no. 3 had widely patent large PVs and case no. 2 had 80% occlusion of the main PV. The estimated mean percentage of decrease in luminal diameter (compared with case no. 4) was approximately 45% for case no. 1 and 20% for cases no. 2 and no. 3. The data show that decreased luminal diameter after thrombosis is constant for medium PVs (from 0.1 to 2.0 mm) and that occlusion of the large PVs may differ mark- edly from that in the medium branches.


were often observed in continuity with lesions in medium veins.

The pathogenesis of HV lesions in cirrhosis is generally stated to be unknown. The lesions described here

FIG. 12. PV lesions from 2 different cirrhotic livers. (A) Large PV is 3 mm in diameter with marked intimal fibrosis and multiple lumina, suggestive of organized and largely recanalized thrombus (grade 3). The main PV in this liver was occluded by 80% by similar intimal fibrosis. (Elastic-trichrome stain; original magnification x30.) (B) Medium PV is 0.3 mm in diameter with moderate intimal fibrosis (grade 3). The main PV in this liver was occluded by 50% and the main left and right PVs were occluded by 10%. (Elastic- trichrome stain; original magnification x70.)

FIG. 11. HV lesions from 3 different cirrhotic livers. (A) HV 1.0 mm in diameter largely occluded with partially recanalized thrombus (grade 5). (Movat-pentachrome stain; original magnification x50.) (B) HV 0.3 mm in diameter showing focal intimal fibrosis with irregular intimal contours (grade 4). (Elastic-trichrome stain; original magnification x60.) (C) HV 0.07 mm in diameter showing subtotal fibrous obliteration (grade 5) and increased elastic fibers. (Elastic-trichrome stain; original magnification x300.)

in medium and large HVs are most likely produced by thrombosis. The entire spectrum of postthrombotic disease is present, including (1) occasional coexistence of acute thrombosis and intimal fibrosis; (2) partial recanalization leaving irregular intimal excrescences, multiple lumina, and webs; (3) multiple layers of fibrosis suggesting recurrent events; (4) clustering of lesions in a single venous drainage zone; and (5) severe obliteration most prominent in the smallest veins.

The sequence of events in HVs can be inferred from various observations. Experience with the liver in congestive heart failure suggests that thrombi begin in sinusoids, propagate to veins, and terminate at junc- tions with larger veins, in which high flow rates are encountered is (Fig. 16). Thrombi may be initiated by intimal inflammation and/or stasis in the smallest veins and sinusoids. Phlebitis of terminal hepatic ve- nules is readily observed in alcohol-induced hepatitis and in chronic hepatitis of various origins. Thrombi in


FIG. 13. Examples of FPE in 4 livers. (A) Mild FPE with small lesion measuring 0.4 cm across (alcohol-induced liver disease). (B) Severe FPE (right) with veno-centric region containing congested and recently infarcted cirrhotic nodules (alcohol-induced liver disease). (C) Severe FPE with marked deformity of the right lobe (hemochromatosis). (D) Microscopic appearance of a small region of FPE with depressed capsular surface (left) and several partially obliterated HVs measuring 0.2 to 0.3 mm in diameter. (Masson's trichrome stain; original magnification × 15.)

veins larger than 0.2 mm in diameter may recanalize almost completely, but some residual obstruction likely increases susceptibility to recurrent thrombosis. The distribution of HV lesions is patchy, suggesting that multiple separate thrombotic events commonly occur.

In cirrhosis nodule size is generally uniform. How- ever, PV thrombosis is associated with a regenerative response characterized by enlargement of cirrhotic nodules adjacent to major portal systems. This "porto-centric" pat tern is analogous to that observed in response to PV obstruction occurring in noncirrhotic livers, when it has been called partial nodular transformation or macronodular transformation. 19-21

Although fibrosis in cirrhosis is often uniform, regional accentuation of fibrosis, called atrophy, collapse, focal broad scar, confluent hepatic fibrosis, or massive subcapsular fibrosis has been noted in a minority of livers. 22-2s Rubin et a129 described "postnecrotic" cirrhosis with regions of collapse and broad septa in patients with alcohol-induced disease. A single case report de- scribes a liver with alcohol-induced cirrhosis having atrophy of the left lobe in association with left HV

FIG. 14. Cirrhosis showing superimposed variation in nodule size apparently because of PV thrombosis. This gives an appearance of porto-centric nodules. Note healed thrombosis of the PV with multiple lumina.


TABLE 2. P r e v a l e n c e o f H i s t o r y o f B l e e d i n g V a r i c e s C o r r e l a t e d With V a s c u l a r L e s i o n s

Grade 0-1 Grade 2-5 Vessel Lesions Vessel Lesions

(%) (%) P

All patients, n = 61 Medium PV 18.2 53.8 Large PV 26.7 54.8 Medium HV 33.3 41.4 Large HV 23.1 45.8

Excluding prior portacaval anastamosis and splenectomy, n = 49

Medium PV 10.5 46.7 Large PV 25.0 42.9 Medium HV 33.3 32.6 Large HV 23.1 36.1

TABLE 3. P r e v a l e n c e o f A s c i t e s C o r r e l a t e d With V a r i o u s H e p a t i c L e s i o n s

Low-Grade High-Grade Lesion (%) Lesion (%) P

Capsular thickening* 41.9 77.8 .012 FPEt 55.5 71.4 NS

.012 Large HVs$ 56.9 70.0 NS

.046 Medium HVs$ 61.1 58.1 NS NS Large PVs$ 58.7 60.0 NS NS Medium PVs$ 61.5 54.6 NS

.016 NS NS NS

NOTE. The data are expressed as the percentage of pat ients having a history of bleeding varices among those with low-grade or high- grade vascular lesions in ei ther the left or r ight lobes.

Abbreviation: NS, not significant.

thrombosisJ ° It is likely that all these lesions represent FPE superimposed on established cirrhosis. Hales et al 2~ found HV obliteration within such lesions and sug- gested the venous lesions were secondary to the scars. We confirm the association of extinction and HV lesions, but it seems more likely that the venous lesions are primary and the extinction is secondary.

The clinical significance of secondary HV thrombosis in cirrhosis is not certain. There is no evidence from our data to suggest that lesions of medium or large HVs are important in the genesis of ascites. However, most of our patients had moderate to severe ascites so that a type 2 error may have occurred.

5 A u) C "3 4 A

NOTE. The data are expressed as the percentage of pat ients having moderate to severe ascites among those with low-grade or high- grade lesions.

Abbreviation: NS, not significant. * Low grade = 0; high grade = 1 through 3. t Low grade = 0-1, high grade = 2-3, in ei ther the left or r ight

lobes. $ Low grade = 0-2, high grade = 3-5, in e i ther the left or r ight

lobes.

>

2

L-

Lesions in medium and large PVs correlated with a history of variceal bleeding. It is possible that PV thrombosis contributes to the development of clinical portal hypertension in patients with cirrhosis by in- creasing resistance in the large and medium PVs or by causing obliteration of small intrahepatic collateral veins. Patients with cirrhosis and partial or complete obstruction of the PV often have bleeding varices at presentation, 3'31 although we are not aware of controlled studies defining the importance of PV thrombo-

J

eins A e A • •

ee A ewe.. ee • ~ R ~ Focal parenchymal extinction

ee (me • &

• A A

0 1 2 3 4 5 Medium-sized portal veins

FIG. 15. Correlation of lesions in large and medium PVs for pa- t ients without history of portacaval anastomosis or splenectomy (n = 49). Triangles and circles represent pat ients with and without a history of bleeding varices, respectively. Grades 0 through 2 and many grade 3 large PV lesions are unlikely to be visible on ultrasound.

veins

FIG. 16. Diagram of distribution of (A) HV and (B) PV thrombosis. Thrombus usually propagates in the direction of blood flow, ex- plaining the multifocal distr ibution of HV lesions and the uniform distribution of PV lesions.


sis i n p a t i e n t s w i t h c i r rhos i s . A n a l t e r n a t e i n t e r p r e t a - t i on of ou r d a t a is t h a t p a t i e n t s w i t h severe p o r t a l h y p e r t e n s i o n c a u s e d b y c i r rhos i s a re p r e d i s p o s e d to h a v e s e c o n d a r y P V t h r o m b o s i s b e c a u s e of m a r k e d s ta - sis, h y p o t e n s i o n , or effects of t h e r a p e u t i c m a n e u v e r s . Howeve r , e x a m i n a t i o n of ou r d a t a a f t e r r e m o v i n g pa- t i e n t s w i t h h i s t o r y of s p l e n e c t o m y or p o r t a c a v a l a n a s t o - mos i s d id n o t r e m o v e t he a s s o c i a t i o n b e t w e e n PV disease a n d b l e e d i n g var ices . A role for s c l e r o t h e r a p y is m o r e di f f icul t to exc lude b e c a u s e few p a t i e n t s w i t h o u t s c l e r o t h e r a p y a re a v a i l a b l e to se rve as cont ro ls . M e s e n - te r ic t h r o m b o s i s h a s b e e n d i a g n o s e d s h o r t l y a f t e r s c l e r o t h e r a p y i n s eve ra l p a t i e n t s , b u t t h i s is a r a r e c o m p l i c a t i o n t h a t w a s c l in i ca l ly f o u n d on ly once in a se r ies of 799 s c l e r o t h e r a p y p rocedure s . 32

Acknowledgment: We t h a n k K. E k e m for exce l l en t t e c h n i c a l a s s i s t a n c e .

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