The liver-spleen scan as a quantitative liver function test: Correlation with liver severity at peritoneoscopy

The Liver-Spleen Scan as a Quantitative Liver Function Test: Correlation With Liver Severity at Peritoneoscopy JOHN C. HOEFS, 1 FELIX WANG, 2 GARY KANEL,2 AND PHILIP BRAUNSTEIN3

Sulfur colloid distribution o n liver-spleen s c a n is det e r m i n e d by the p e r f u s e d Kupffer cell mass. T h e perf u s e d Kupffer cell m a s s is p r o p o r t i o n a l to t h e p e r f u s e d h e p a t o c y t e mass, but is less affected by a c u t e c h a n g e s in h e p a t o c y t e function. Thus, sulfur colloid distribution p a r a m e t e r s (precisely m e a s u r e d by q u a n t i t a t i v e livers p l e e n s c a n [QLSS]) m a y be a n e x c e l l e n t test o f t h e perf u s e d h e p a t i c mass. A l t h o u g h n o gold stav d~rd exists for confirmation, a close c o r r e l a t i o n s h o u l d exist b e t w e e n liver d i s e a s e s e v e r i t y a s s e s s e d at p e r i t o n e o s c o p y a n d sulfur colloid distribution~ P e r i t o n e o s c o p y s e v e r i t y (scored as total p e r i t o n e o s c o p y s c o r e [PS]; range, 0-5) w a s a s s e s s e d in 76 patients w h o also h a d QLSS. Multivariate e q u a t i o n w e r e g e n e r a t e d to e s t i m a t e liver dise a s e s e v e r i t y f r o m t h e QLSS. T h e s e w e r e t h e n applied p r o s p e c t i v e l y in 20 c o n s e c u t i v e p a t i e n t s to validate t h e s e equations. In 76 patients, 62 w e r e e v a l u a t e d bec a u s e o f c h r o n i c liver d i s e a s e (CLD) a n d i n c l u d e d t h o s e w i t h micronodulAr (20) a n d m a c r o n o d u l a r (20) cirrhosis w i t h v a r i o u s degrees o f s e v e r i t y (Child's A, 16; B, 29; C, 17). Multivariate a n a l y s i s y i e l d e d a n u m b e r o f c o m b i n a t i o u s o f QLSS p a r a m e t e r s that c o r r e l a t e d w i t h periton e o s c o p i c severity. T h e s e e q u a t i o n s w e r e u s e d to estim a t e liver d i s e a s e severity. E s t i m a t e s o f liver d i s e a s e severity ( e s t i m a t e d PS [EPS]) c o r r e l a t e d well w i t h t h e PS in t h e s e 76 p a t i e n t s (r = .9064; r 2 = .8216; P < .0001). Adding h i s t o l o g i c a l fibrosis to t h e QLSS p a r a m e t e r s yields an e q u a t i o n for e s t i m a t i n g PS that w a s e v e n m o r e effective (r = .9462; r 2 = .8953; P < .001). H o w e v e r , validation o f m u l t i v a r i a t e e q u a t i o n s r e q u i r e s c o n f i r m a t i o n o f their v a l u e in a s e c o n d population. A p p l y i n g t h e s e equations to a p r o s p e c t i v e g r o u p o f 20 patients w h o subse-

Abbreviations: CLD, chronic liver disease; ALD, alcoholic liver disease; NALD, nonalcoholic liver disease; QLSS, quantitative liver-spleen scan; PS, peritoneoscopy score; TFS, total hepatic fibrosis score; SL, spleen length; (L/L + S)t, liver/(liver plus spleen) ratio of tetal counts; (L/L + S)p, liver/(liver plus spleen) ratio of pixel counts; PfF ratio, ratio of (L/L + S)t and (L/L + S)p; T - P, difference between (L/L + S)t and (L/L + S)p; LBI, liver/bone index; LSI, liver/spleen index; SS, severity score; RR, redistribution ratio; ACT IND, activity index; EPS, estimated PS; EPS AVG, average of EPS; ETP TFS, estimate of peritoneoscopic severity. From the 1Department of Medicine, Division of Gastroenterology, Liver Disease Program; 2Department of Nuclear Medicine, Division of Radiological Sciences; and 3Department of Pathology, Division of Liver Unit Laboratories, University of California Irvine, CA. Received July 18, 1994; accepted April 10, 1995. Address reprint requests to: John C. Hoefs, MD, Associate Clinical Professor, UCI Medical Center, Director, Liver Disease Program, Department of Medicine/GI Division, 101 City Dr South, Bldg 53, Rt 81, Orange, CA 92668. Copyright © 1995 by the American Association for the Study of Liver Diseases. 0270-9139/95/2204-001453.00/0

quently h a d p e r i t o n e o s c o p i c e v a l u a t i o n p r o d u c e d a similar c o r r e l a t i o n for QLSS p a r a m e t e r s a l o n e for e s t i m a t i n g s e v e r i t y (r = .870; r ~ = .757; P < .0001), a n d this w a s i m p r o v e d w h e n t h e e q u a t i o n i n c l u d i n g histological fibrosis w a s a d d e d (r = .936; r 2 = .877; P < .001). We believe t h e s e data s u p p o r t t h e QLSS as a quantitative e s t i m a t e o f the p e r f u s e d h e p a t i c m a s s that c o r r e l a t e s w i t h liver disease s e v e r i t y at p e r i t o n e o s c o p y . (HEPATOLOGY 1995;22:1113-1121.)

Fibrotic chronic liver disease (CLD) is characterized by a progressive decrease in the functional hepatic mass and by abnormalities in the vascular perfusion of this mass. The perfusion abnormalities are caused by (1) intrahepatic shunting lv and (2) a relatively fixed intrahepatic resistance that lowers portal blood flow,s-9 limits the postprandial increase in portal flow, 1°12 and limits the reflex increase in hepatic arterial flow when portal flow decreases. 13-14The relationship between the reduced hepatic mass and hepatic perfusion determines the degree of expressed hepatic functional abnormalities and is associated with the severity of liver disease. Presumably, the maximal perfuseable hepatic mass is the ultimate limitation to hepatic functional reserve. Quantitative tests of hepatic function are thought to assess the functional mass by measuring the blood flow-dependent hepatocyte function, such as indocyanine green clearance, 1'2'15 lidocaine clearance, TMand galactose elimination capacity 17 or blood flow-independent hepatocyte functional capacity, such as the aminopyrine breath test.17-19 Quantitative tests are valuable, but individual variability in hepatocyte function caused by genetic and environmental factors (i.e., acute flare of liver disease) limits the clinical reliability of these tests in measuring differences in liver disease severity caused by fibrosis between patients with CLD. The quantitative functional tests are not clearly better t h a n more routine tests. The blood flow-dependent tests of quantitative liver function measure the perfused hepatocyte mass. An alternative strategy would be to measure the perfused Kupffer cell mass. Kupffer cell function is less affected by the activity or etiology of the liver disease, 2°23 the extraction capacity of the individual Kupffer cell is great, 2t perfusion of hepatocytes and Kupffer cells are similar, because the extraction ratios are closely correlated 1-~ and the ratio of Kupffer cells to hepatocytes is

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n o r m a l in p a t i e n t s with alcoholic liver disease (ALD) a n d nonalcoholic liver disease (NALD). 23 F u r t h e r m o r e , t h e p e r f u s e d Kupffer cell m a s s is t h e m a i n d e t e r m i n a n t of s u l f u r colloid distribution by liver-spleen scan sugg e s t i n g the possibility of simple e x t e r n a l m e a s u r e m e n t of s u l f u r colloid d i s t r i b u t i o n as a n e s t i m a t e of the perfused h e p a t i c mass. The r e c e n t ability to q u a n t i t a t e s u l f u r colloid d i s t r i b u t i o n w i t h the S P E C T liver-spleen scan 25 on a G e n e r a l Electric 400 AC/T w i t h a STAR II (Milwaukee, WI) h a s s t i m u l a t e d us to r e a s s e s s the liver-spleen scan as a q u a n t i t a t i v e t e s t of t h e p e r f u s e d h e p a t i c mass. I n o u r desire to test this hypothesis, it h a s become clear t h a t t h e r e is no gold s t a n d a r d test to use for comp a r i s o n a n d validation. However, a q u a n t i t a t i v e t e s t of the p e r f u s e d h e p a t i c m a s s s h o u l d correlate with the severity of liver disease as a s s e s s e d a n a t o m i c a l l y by fibrosis. The best a n a t o m i c a s s e s s m e n t of liver disease severity is derived at peritoneoscopy w h e r e h e p a t i c size, the presence of cirrhosis by surface a s s e s s m e n t , a n d histology are combined. 26-29 Therefore, we correlated q u a n t i t a t i v e liver-spleen scan (QLSS) p a r a m e ters with peritoneoscopy a s s e s s m e n t in 76 p a t i e n t s a n d derived e q u a t i o n s from m u l t i v a r i a t e a n a l y s i s to predict severity of CLD. Prospective e s t i m a t i o n of peritoneoscopic severity in 20 p a t i e n t s c o r r e l a t e d with m e a s u r e d severity s u p p o r t i n g the possibility t h a t Q L S S m e a s u r e m e n t of s u l f u r colloid d i s t r i b u t i o n is a v a l u a b l e q u a n t i t a t i v e liver function test.

HEPATOLOGYOctober 1995 TABLE 1. Demographic, Clinical, and Laboratory Evaluation in Patients

Group Number Age Men/women Type cirrhosis Micronodular Macronodular CLD: ALD/NALD Child's NA* Child's A B C Child's score (62 and 19 patients) Bilirubin (mg %) Prothrombin time (sec >control) Albumin (g %) Total protein (g %) SGOT (IU/L) SGPT (IU/L) Creatinine (mg %) Sodium (meq/L) Alkaline phosphatase (IU/L) WBC (cell/mm3 × 103) Hematocrit (%) Hemoglobin (g %) Platelets (cell/mm3 × 103)

A 76 52 ± 11 53/23

B 20 46 ± 16 9/11

20 20 19/43 14

8 8 3/16 1

16 29 17 7.8 ± 2.4 3.2 ± 3.9 2.2 _+ 2.6 2.9 + .8 6.5 ± 1.1 119 _+ 145 69 ± 83 1.0 ± .8 136 ± 6 182 ± 115 6.9 ± 4.4 35 ± 6 11.6 ± 2.1 197 ± 147

4 6 9 8.6 ± 3.1 4.0 ___3.8 2.2 ± 1.7 3.1 ± .7 7.2 ± 1.0 146 ± 119 92 ± 79 1.2 ± 1.1 137 ± 5 294 ± 254 6.5 ± 3.3 36 ± 6 11.9 _+2.3 169 _ 109

* NA, Child's criteria not applicable if CLD not present.

PATIENTS AND METHODS

This study evaluates QLSS parameters in 2 groups of patients with characteristics recorded in Table 1. Group A consists of 76 patients with a further subdivision into alcoholic liver disease, 19 nonalcoholic liver disease, 43 subacute flare of NALD,4 normals with nonportal hypertensive ascites, 1° and normals with hepatic infiltration or hepatic tumors (without significant tumor bulk). 4 The peritoneoscopic assessment was semiquantitated into a total peritoneoscopy score (PS) (described later). This score was correlated with QLSS parameters, and multivariate equations for estimating PS developed. An additional group B consists of 20 consecutive prospectively acquired patients with CLD who had both QLSS and peritoneoscopy. The estimated PS calculated from the QLSS was compared with the measured PS for validation of the equations derived from group A patients. The clinical evaluation included routine blood tests and determination of Child's classification based on a scale of 1 through 3 for ascites (none, easily treated, refractory)/bilirubin (<2, 2-2.9, ->3 mg %)/albumin (>3.5, 3.0-3.5, 2-2.9, <3.0 g %)/prothrombin time (<4, 4-5.9, ->6 sec > mean control) and hepatic encephalopathy (none, mild, difficult). Patients without liver disease were not graded for Child's classification and considered "O" in the regression analysis regardless of clinical problems such as tuberculous ascites or elevated bilirubin as in one patient with Rotor's syndrome. Assessment o f PS. The object of the PS was to semiquantitatively judge the severity of liver disease based on the amount of fibrosis and the amount of functioning tissue. Thus, peritoneoscopy allowed us to judge the size of the liver while minimizing sampling error for the liver biopsy. A small liver with marked fibrosis was considered more severe than

a large liver with a similar degree of fibrosis on biopsy, because the amount of remaining normal tissue is less. The degree of fibrosis was estimated either by a histological fibrosis score or by a hepatic surface score. The hepatic surface was graded 0, if normal; 1, for a blunt leading edge, light color, or abnormal light reflex; 2, for a granular tan surface with a blunt leading inferior hepatic edge; and micronodular cirrhosis when the majority of nodules were less than 5 mm in size. When obvious macronodules ->5 mm in diameter were present, a grade of 3 was given for obvious indistinct nodules that ran together to form an irregular surface; grade 4 for poorly developed but distinct nodules and grade 5 for well developed sharply demarginated distinct nodules. The surface score was used in patients with macronodular cirrhosis since sampling error is occasionally a major problem 26-29 and sinusoidal collagen is usually not a major contributor to the fibrosis score. The distinctiveness of the nodules is related to contraction of scar tissue around regenerative nodules. 2v'29Total hepatic fibrosis was assessed histologically for patients with a surface score 0 to 2 or with micronodular cirrhosis, because sampling error was then thought to be minimized. In these patients, the histological estimate of hepatic fibrosis equaled the total hepatic fibrosis score (TFS) as previously reported 25'3° divided by two. The TFS is twice the degree of portal fibrosis (score 0 through 5; 0, normal; 1-2, degrees of fibrosis; and 3-5, degrees of cirrhosis) plus the sinusoidal collagen score (0-7.5). The hepatic size was judged separately for the left and right lobe (Appendix) and used to modify the peritoneoscopy score as described later. Hepatic size was not used in the total peritoneoscopy score if the TFS was ---4 and the surface score -<2; thus the PS was then equal to the TFS/2 in these

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TABLE 2. The Liver/Spleen Scan Organ Size, Pixel, and patients. Previous experience has shown that biopsy representation of precirrhotic fibrosis is an adequate staging of Volumetric Parameters in 76 Group A Patients and 20 liver disease if sampling error is eliminated by the surface Group B Patients appearance, because the functional mass can assumed to be Group A Group B normal and that hepatic enlargement with fat or tumor only confuses assessment of this stage. For patients with greater Right lobe (cm) 16.3 _+4.0 15.9 _+4.3 than 4 TFS or macronodular cirrhosis at peritoneoscopy, the Left lobe (cm) 13.5 +_ 3.2 13.0 _+ 3.1 liver size score was graded 2 for larger than normal size, 3 (Right + .5 left) lobe (cm) 23.1 _+ 5.2 22.4 +_ 5.6 for normal, 4 for small, and 5 for very small. Given the same Spleen length (cm) 14.8 _+4.0 15.3 _ 4.4 percent of fibrosis, the total amount of functioning tissue LSI 58.8 _+ 24.0 59.0 _+ 24.9 decreases as the liver becomes smaller. A PS for each lobe LBIp 80.3 _+ 24.6 85.2 _+26.6 was calculated as TFS/2 or as the average of the fibrosis (or LBIt 85.5 _+26.2 80.5 _+ 20.6 surface) score and size score depending on the conditions SSp 69.6 + 22.8 72.1 _+24.0 previously stated. The total PS equaled two times right lobe SSt 72.2 +_ 23.2 69.8 _+ 21.4 peritoneoscopy score plus the left lobe peritoneoscopy score (L/L + S)p .34 _+ .14 .31 +_ .10 divided by three. (I_/L + S)t .47 _+ .22 .47 _+ .22 QLSS Parameters. The size of the right and left lobes by P/T ratio .81 +_ .41 .89 _+ .67 QLSS was estimated as the length from the mid right hepatic RR .46 _+ .44 .50 + 50 dome to the most inferior descent of the right and left lobe Activity index -17.4 +_34.1 -11.2 _+ 32.3 respectively on the anterior planar scan. Total hepatic size TFS 6.7 _+3.7 7.0 _ 3.6 was estimated from the right lobe length plus ½the left lobe PS 3.1 _+ 1.6 3.5 _+ 1.2 length. The spleen length (SL) was the maximal length in any orientation from the posterior planar view. The rest of the QLSS parameters of the liver, spleen, and a portion of the bone marrow were calculated from SPECT analy- for j u d g i n g the v a l u e of t h e Q L S S p a r a m e t e r s relative sis 25 (General Electric) for total quantitative counts and for to a k n o w n q u a n t i t y . F i g u r e 1A t h r o u g h 1D shows the pixel counts from the posterior planar view. The liver/(liver plus r e l a t i o n s h i p of t h e P S to L B I p , LSI, SSp, a n d RR. spleen) ratio of total counts ([L/L + Sit) and pixel counts ([L/L Multivariate Analysis for QLSS Correlation With + S]p), the ratio of these two (P/T ratio), and difference between these two (T - P) were calculated. A liver/bone marrow index PS. M u l t i v a r i a t e l i n e a r r e g r e s s i o n a n a l y s i s u s i n g P S (LBI) = log (total liver counts/bone marrow counts); liver/spleen as t h e d e p e n d e n t v a r i a b l e w a s p e r f o r m e d u n d e r the index (LSI) = (L/L + S). 100/(1 - .025. [spleen length - 6]); conditions listed below: 1. M u l t i v a r i a t e a n a l y s i s w i t h o r g a n sizes. I n c l u d i n g and severity score (SS) = (LBI + LSI)/2 reflect quantitative estimates of sulfur colloid distribution. The LBI using pixel RR, yields t h e e q u a t i o n (r = .9118; r 2 = .8313; P bone marrow counts was labeled LBIp (LBIp = log [total liver < .0001) f o r m u l a 1: P S = 4.342 - 2.008RR - .0209SSt counts/pixel bone marrow counts × 104]) and using the total + 18.15/RL. Deletion of t h e R R from t h e a n a l y s i s proSPECT bone marrow counts LBIt(LBIt = log [total liver counts/ duces a similar h i g h correlation (r = .9116; r 2 = .8310; 10 × total bone marrow counts/frame]). The respective severity P < .0001) f o r m u l a 2: P S = - . 0 6 4 2 L B I P - 9.556 log scores are designated SSp and SSt. The redistribution ratio (RR) was calculated from pixel counts as previously described 1'25 (1/SSp) - 6 . 9 8 7 (L/L + S)t + 20.51/RL + 3.71 (T - P) and activity index (ACT IND) = LBIp - (.702 LSI + 46) - 7.652. (PS) 2 w a s also significant w i t h the m u l t i v a r i × 100)/LBIp reflecting the relative dominance of sulfur colloid ate e q u a t i o n (r = .8833; r 2 = .7804; P < .0001) f o r m u l a distribution to bone marrow (negative) values or spleen (posi- 3: (PS) 2 = 313/(R + .5L) - 14.8 log RR - 9.6. 2. M u l t i v a r i a t e a n a l y s i s u n d e r special conditions. tive) values. Statistical Analysis. Univariate linear regression analysis Occasional p a t i e n t s will h a v e a d d i t i o n a l d a t a or special was used to assess correlation between parameters. Multi- conditions in w h i c h e i t h e r m o r e or less i n f o r m a t i o n is variate analysis was used to determine independent corre- available t h a n expressed in the above equations. T h u s , lates with the PS. Group A subgroup means were compared the degree of histological severity can be u s e d to enby a t-test and estimated PS (EPS) with measured peritoneosh a n c e severity e s t i m a t e s . F u r t h e r m o r e , some p a t i e n t s copy scores in the same patient by paired t-test. P < .05 was considered significant. All analyses were performed in the lack a spleen or pixel bone m a r r o w data. E q u a t i o n s for t h e s e special conditions are f o u n d in Table 5. SSPS/PC. RESULTS

Correlations Between PS and QLSS Parameters. The m e a n +__ SD of QLSS a n d p e r i t o n e o s c o p y scores are listed in Table 2 a n d in s u b g r o u p s in Table 3. T h e univ a r i a t e correlations of PS, (PS) 2, a n d histological T F S to Q L S S p a r a m e t e r s in all 76 p a t i e n t s are s h o w n in Table 4. The T F S c o r r e l a t e d well (P < .0001) w i t h peritoneoscopic severity as expected from clinical experience a n d b e c a u s e of inclusion of T F S in the peritoneoscopy score (PS = .367 T F S + .629; r = .868; r 2 = .753). However, c o m p a r i s o n w i t h the T F S offers a s t a n d a r d

Correlation of EPS With Measured PS in 76 Patients. The E P S calculated from the f o r m u l a s above

a n d in Table 6 c o r r e l a t e d significantly w i t h the m e a s u r e d v a l u e in this g r o u p of 76 p a t i e n t s ( r e p r e s e n t a t i v e e x a m p l e s in Fig. 2). The m e t h o d of e s t i m a t i n g t h e P S can be d e t e r m i n e d b y t h e f o r m u l a n u m b e r after EPS. The a v e r a g e of the E P S 1 a n d E P S 3 is t e r m e d E P S AVG. F o r t h e E P S 1 , the correlation w i t h P S w a s signific a n t (r = .9118; r 2 = .8313; P > .0001): P S = .9995EPS1 + .0038; or E P S as the a v e r a g e (EPS AVG) of f o r m u l a s 1 a n d 3 (r = .9182; r 2 = .8438): P S = 1.0387EPS AVG - .1598. The E P S a v e r a g e in c o m b i n a t i o n w i t h T F S c o r r e l a t e d well w i t h p e r i t o n e o s c o p y severity (r = .9462;

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HEPATOLOGY October 1995

TABLE 3. LSS P a r a m e t e r s in Group A P a t i e n t Subgroups: ALD; NALD S u b d i v i d e d into T h o s e With CLD With or Without a S e v e r e Flare; a n d N o r m a l Liver W i t h o u t a n d With T u m o r or I n f d t r a t i o n Normals

NALD

ALl) No. (cm) R i g h t lobe (cm) Left lobe (cm) (Right + ½ left lobe) (cm) S p l e e n l e n g t h (cm) LSI LBIp LBIt SSp SSt (L/L + S)p (L/L + S)t P f r ratio Activity i n d e x RR TFS PS Child's score

17 14 24 14 57 62 66 59 61 .26 .45 .59 -50 .17 9.2 3.9 9.2

19 _+ 5 _+ 4 _+ 6* _+ 3* _+ 19" + 18" _+ 19" _+ 18" _+ 18" _+ .09 _+ .16 _+ .15 _+ 32* _+ .08* _+ 2.2* _+ .7* _+ 2.5

CLD 15 13 21 16 49 79 83 64 66 .30 .37 .98 -7 .35 7.5 3.7 7.3

CLD With Severe Flare

Hepatic Normal

Hepatic Infiltration or Tumor

7 16_3 13_+2 23_4 15___3" 56_+ 17" 68 _+ 14" 75 _+ 19" 62_+ 14" 66 _+ 16" .34 -- .13" .43 _+ .13" .80 ___ .18*T - 3 3 _+ 21" .27 _+ .20* 8.3 _+ 3.0* 3.7 _+ .7* 10.6 - 1.8

10 18_+2 14_+2 26_+2 11_+ 1 90_+ 11 118 _+ 10 121 ___ 11 104_+6 106 - 9 .51 _+ .11 .78 --+ .10 .66 _+ .08 10 _+ 18 1.26 _+ .44 .8 _+ .9 .2 _+ .2 NA

4 20_~4 15_+2 28_+5 9_+2 86_+9 107 _+ 11 129 _+ 24 97_+4 107 _+ 11 .59 _+ .0 .79 _+ .0 .76 _+ .1 .1 _+ 18 1.14 _+ .3 0 .3 _ .2 NA

36 _+ 3* _+ 3 _+ 4* + 4* _+ 21" _+ 18" _+ 17" _+ 19" __+ 18" _+ .09* _+ .19" _ .52t _+ 27~ _+ .20*¢ _+ 2.2* _+ .9* _+ 2.0

Abbreviation: NA, n o t applicable. * S i g n i f i c a n t difference f r o m n o r m a l s (P < .05). t S i g n i f i c a n t difference f r o m A L D (P < .05).

r 2 = .8953) formula 10: PS = .6922EPS AVG + .1783TFS - .2983 EPS 10 (or EPS AVG[TFS]) correlated with PS (r = .945). Table 6 shows the mean _+ SD of the estimated PS in subcategories in these 76 patients. Prospective Estimation of Liver Disease Severity by EPS in 20 Patients and Comparison With Actual P S . The 20 patients with peritoneoscopy after QLSS had comparison of the peritoneoscopy results with those predicted by QLSS and by biopsy alone. There was no significant difference in t-test analysis of PS to

TABLE 4. U n i v a r i a t e A n a l y s i s o f QLSS P a r a m e t e r a n d H i s t o l o g i c a l F i b r o s i s (TFS) With P e r i t o n e o s c o p i c P S Assessment of Liver Disease Severity

R i g h t lobe size Left lobe size (Right + ½ left) size Spleen length SSp SSt LSI LBIp LBIt Activity i n d e x RR TFS Child's score Bilirubin Prothrombin time Albumin

TFS

PS

(PS) 2

-.166 -.027 -.136 .312 -.664 -.686 -.544 -.699 -.718 -.410 -.800 -.463 .163 .290 -.603

-.424 -.295 -.418 .458 -.839 -.841 -.743 -.829 -.810 -.474 -.856 .860 .627 .271 .413 -.645

-.471 -.378 -.481 .401 -.839 -.838 -.751 -.821 -.798 -.497 -.772 .800 .620 .249 .395 -.620

any of the estimated peritoneoscopy scores (Table 7)

(representative examples in Fig. 3). In this analysis, the TFS permits an estimate ofperitoneoscopic severity (ETP TFS) for comparison with the QLSS parameters. The linear regression correlation between PS and EPS values was highly significant (P < .001) (Table 7). For example, PS = .801EPS AVG + .923; r = .884 (Fig. 3A), and is a better estimate of PS than using TFS alone: PS = .618EPS TFS + 1.49 (r = .661) (Fig. 3B). Combining QLSS parameters with the score of histological fibrosis (TFS) (Fig. 3C and 3D) in estimating the PS improved the correlation (PS = .790EPS4 + .825) (r = .942; r 2 = .887) and PS = .861EPS10 + .758 (r = .936; r 2 = .877). Thus, the severity of liver disease as assessed by peritoneoscopy could be estimated effectively by QLSS alone or by QLSS parameters in combination with histological fibrosis. DISCUSSION

We view the distribution of sulfur colloid between liver, spleen, and bone marrow as a means of quantitation of the perfused functional hepatic mass independent of hepatocyte function p e r se. The ability to precisely measure sulfur colloid distribution using SPECT analysis of the LSS has allowed us to evaluate the correlation with clinical and histological parameters that should correlate with the perfused functional mass, although no truly gold standard is available for comparison to prove this point. However, parameters that correlate with liver disease severity and prognosis should correlate with sulfur colloid distribution. Other studies of SPECT-derived parameters from liver-spleen scan have proven as effective as other quantitative liver

HEPATOLOGYVol. 22, No. 4, 1995

HOEFS ET AL

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40

60

LSI

5~

.pl| •

•

:'i.

|

j

M

.

-=

i

1 60

80

100

120

140

0.4

•

O.8

1.2

1.6

2

2.4

RR

~p

.. m

!

140

o."

s

P~

120

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.'l M

:

100

- ~i

•

!

4O

80

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u i

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l.~Ip

"'i.~;, ~" I.

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ml w mw

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I I

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FIG. 1. The main sulfur colloid distribution parameters that correlated with the total PS are shown: (A) LSI, (B) LBIp, (C) SSp, (D) RR, and (E) liver size (R + .5L).

y

{R+~*L)(CM)

function tests in the evaluation of patients with diffuse liver disease, sl's2 One specific parameter of liver disease severity not previously evaluated for correlation with QLSS is peritoneoscopic assessment that allows determination of hepatic size, histology, and means of minimizing sampling error in those patients with macronodular cirrhosis. Peritoneoscopy with liver biopsy is the single most precise estimate of clinical severity. 26 Thus the major finding of this study is the excellent correlation of sulfur colloid distribution parameters with our peritoneoscopy assessment. We tried to maximize the information obtained from the QLSS by using both pixel and volumetric parameters and by generating multivariate equations that

would allow us to use independent factors to predict the PS from QLSS. When this equation was applied to the population from which it was derived, the correlation was excellent and linear, as expected. However, the validity was established by the excellent correlation of the estimated PS with the measured PS in 20 patients evaluated prospectively (Table 7). This supports studies that show a good correlation of sulfur colloid distribution by QLSS with histological fibrosis, Child's classification, and prognosisY Sulfur colloid distribution seems to be a quantitative test of the perfused hepatic mass and deserves further study to determine its role in the evaluation of liver patients. Peritoneoscopy evaluation of severity was considered

1118

H O E F S E T AL

HEPATOLOGY O c t o b e r 1995

Analysis Under Special Conditions C o r r e l a t i n g PS With QLSS P a r a m e t e r s a n d Organ S i z e s

TABLE 5. M u l t i v a r i a t e

F o r m u l a No. I n c l u d i n g h i s t o l o g i c a l fibrosis (TFS) w i t h a n d w i t h o u t u s e of t h e R R W i t h R R (r = .9632; r 2 = .9277) PS = .2553TFS - .006488LBIt + 36.59/(R + .5L) + . 6 1 7 8 P f r - .7316RR + .110 W i t h o u t RR (r = .9653; r 2 = .9319) PS = .2755TFS - .00889LBIt + 75.24/(R + .5L) + 1 . 1 2 5 P f r - 2 . 8 ( I J L +S)p + .0663(R + .5L) 1.9743 log (1/LSI) - 5.63 P S c o r r e l a t i o n w i t h o u t u s i n g s p l e e n size or s p l e e n d e r i v e d p a r a m e t e r s (no RR, LSI, or SS) (r = .8469; r 2 = .7172) PS = 5.415 - .0476LBIp + 23.11/RL PS c o r r e l a t i o n w i t h o u t u s e of p i x e l bone m a r r o w d e r i v e d p a r a m e t e r s (r = .8688; r 2 = .7549) PS = 5.397 - . 0 2 5 6 6 L B I t - 4.412(L/L + S)p + 21.25/RL PS c o r r e l a t i o n w i t h o u t u s e of l i v e r or s p l e e n size, b u t w i t h s p l e e n d e r i v e d p a r a m e t e r s (LSI a n d SS) W i t h RR (r = .8985, r 2 = .8072) PS = 5.9666 - 1.8847RR - .027SST W i t h o u t RR (r = .8969; r 2 = .8044) PS = 6.173 - .06565LBIp + .016911ACT I N D 3.99(L/L + S)p - 2.2122 log (ULSI)

4

5

6

7

8 9

NOT E . (P < .0001 for all e q u a t i o n s )

the gold standard in this study rather than liver biopsy. Histological fibrosis should theoretically be a good test of liver disease severity, because fibrosis is a major determinant of the hepatic perfusion problem and, eventually, of the reduction in hepatic cell mass. However, histological evaluation is limited by sampling error, particularly in patients with macronodular cirrhosis and by subjective interpretation. 2629 The correlation coefficient of hepatic fibrosis with peritoneoscopic assessment is .8126 and is similar to other gold standard measurements. 27'33-41 In this study, we accepted histological evaluation of fibrosis if sampling error was minimized by evaluation of the hepatic surface. In fact, the discrepancy between TFS and PS was primarily caused by low estimates of hepatic fibrosis in four patients in Group A and two patients with obvious advanced mac-

ronodular cirrhosis in group B, presumably because of sampling error of large (> 1 cm diameter) nodules. This is similar to other studies. 26-29Thus, we used a surface score to estimate fibrosis in patients with macronodular cirrhosis, rather than accept this sampling error. The surface appearance of the nodules is related to the contraction of scar tissue and has prognostic value because of this. 29'42 Furthermore, cirrhosis in a large liver might actually have a normally perfused functional mass if hepatic size is increased. Regardless of the amount of scar tissue, it is equally important to know the perfused functional mass that is partially related to hepatic size. Peritoneoscopy evaluation of hepatic size also has prognostic value for this reason. 42 Thus, peritoneoscopy does appear to be an adequate gold standard, and it is encouraging that the QLSS correlates well with this assessment. The QLSS need not be used in isolation of other clinical information. Compared with liver biopsy, the QLSS has the advantage of assessing the whole liver function from sulfur colloid distribution and estimation of hepatic and spleen size. However, combining QLSS information with information present on liver biopsy m a y be even more effective in estimating liver disease severity. The TFS on liver biopsy combined with QLSS parameters allowed a better correlation with the evaluation at peritoneoscopy than biopsy or QLSS alone. The combination of QLSS and blind liver biopsy may be as precise as peritoneoscopy in the evaluation of liver disease severity. Other factors must be considered when using the QLSS to estimate liver disease severity. The redistribution ratio was one of the best QLSS parameters evaluated in this study. However, investigations have concluded that pixel-derived parameters are less effective estimates of liver disease severity than volumetric related parameters in groups of patients with liver disease of diverse origins, although the RR is a semiquantitative pixel parameter that is nearly as effective.1 The primary reason for the decreased effectiveness of pixelrelated parameters is the decrease in hepatic pixel counts that occurs with infiltrative disease, such as fatty liver, that is not related to total hepatic counts. 25 When infiltrative disease is excluded or made less likely (as in this study), the RR is comparable to volu-

TABLE 6. C o m p a r i s o n o f E P S in S u b g r o u p s of P a t i e n t s Normals NALD

Liver ALD No. PS EPS1 EPS2 E P S AVG EPS4 E P S 1 0 (TFS + E P S AVG)

3.9 3.8 3.9 3.9 3.9 3.8

19 +_ .7 _+ .6 _+ .8 _+ .6 + 1.0 _+ .8

CLD

3.7 3.6 3.4 3.6 3.7 3.7

36 _+ .9 _+ .9 ± 1.0 _+ .8 _+ 1.0 _+ 1.0

CLD and Flare

3.7 3.6 3.6 3.7 3.7 3.6

7 _+ .7 _+ .7 _+ .8 _+ .6 +_ .7 _+ .9

Normal

.2 .7 .9 (1.0 .5 .6

10 ___ .2 _+ .9 ± .4* _+ .8)* _+ .3 _+ .3*

* S i g n i f i c a n t l y (P < .05) d i f f e r e n t c o m p a r e d w i t h t h e m e a s u r e d v a l u e s to t - t e s t a n d p a i r e d t - t e s t a n a l y s e s .

Hepatic Infiltration or Tumor .3 .8 1.2 (1.3 .5 .5

4 _+ .2 _+ .8 _+ .7* _ .8)* _ .2 _+ .2

HEPATOLOGYVol. 22, No. 4, 1995

HOEFS ET AL

1119

6'

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FIG. 2. The EPS correlated well with the actual PS in the original data set of 76 patients using equations with and without estimates of histological fibrosis (see text for definition of different EPS equations).

o 2I r = .9458

0

-2

2

PS EPS1 EPS1 + TFS EPS2 EPS2 + TFS EPS3 EPS3 + TFS EPS AVG EPS AVG + TFS EPS TFS

3.5 3.2 3.2 3.2 3.2 3.3 3.2 3.3 3.2 3.2

_+ 1.2 + 1.5 _ 1.4 _+ 1.3 +_ 1.3 _+ 1.3 _+ 1.4 _+ 1.4 _ 1.4 _+ 1.4

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liver disease severity. A number of patients do not have spleens. Therefore, we derived calculations not dependent on parameters requiring spleen size for application to this patient population as well. Likewise, organ sizes are related to patient size and infiltrative diseases, perhaps adding inaccuracies in the EPS calculation in some circumstances when these parameters are used. Therefore, estimated PS derived from sulfur colloid distribution ratios alone have been included. We believe that QLSS estimates of perfused functional capacity will have application in patients with infiltrative liver disease, in those patients with marked deviations from mean patient size, and in those with splenectomy. APPENDIX

Regression Equations of Correlating EPS With Measured PS

Mean + SD

:

EI~I@ ( E I ~ A V G + TI~)

+_ S D o f E P S o f S e v e r i t y W e r e n o t b y P a i r e d t-Test A n a l y s i s F r o m t h e Patients: The Linear Regression EPS With PS Are Shown Below

Formula for EPS

q

a=

-1

metric estimates of sulfur colloid distribution in correlation with liver disease severity and in the ability to estimate the peritoneoscopy evaluation of liver disease severity. This effectiveness is unlikely to be reproduced in diverse patient groups, which is why we excluded the RR in part of our analysis. Special considerations are present in some patients that require modification in calculation of estimated

TABLE 7. T h e M e a n s Significantly Different M e a s u r e d P S i n 20 Correlation of the

r2 = .8945

Validation of Peritoneoscopic Estimates of Hepatic Size. The peritoneoscopic e s t i m a t i o n of hepatic size is an im-

Slope

Intercept

r

r 2

.751 .838 .850 .887 .888 .875 .833 .773 .618

1.053 .765 .821 .670 .542 .690 .756 .814 1.498

.901 .934 .881 .905 .903 .942 .914 .946 .661

.813 .873 .777 .819 .816 .887 .835 .895 .437

NOTE. The formulas for estimating severity (EPS) were more effective than liver biopsy estimates in comparison with measured peritoneoscopy severity estimates. The combination of biopsy and liver parameters was more effective than either alone.

p o r t a n t variable in this study, because it helped to j u d g e the functional m a s s at any given degree of fibrosis. Only 1 person (JH) assessed the size of left an d r i g h t lobe at peritoneoscopy by the criteria described later. Therefore, i n t r a o b s e r v e r and i n t e r o b s e r v e r v a r i a t i o n could not be assessed. The e s t i m a t i o n of size does not include thickness, b u t descent of t he inferior margin. This is si m i l ar to our e s t i m a t e s of hepatic size by liver-spleen scan. Hepatic size at peritoneoscopy correlated closely (P < .001) with QLSS e s t i m a t e s in c e n t i m e t e r s for r i g h t lobe (y = 30.0 - 3.87x; r = .879), left lobe (y = 23.6 1 - 3.34x; r = .805) and total (right lobe plus ~ left lobe) (y = 43.2 - 5.96x; r = .880). All p a t i e n t s j u d g e d to h a v e a large liver by peritoneoscopy (size score of 2) were above t he normal r an g e of total size (range, 20-28 cm) by QLSS and n e a r l y all p a t i e n t s j u d g e d to h a v e a very small liver (size score of 5) were below this range. Overall, t h e correlation was excellent.

1120

HOEFS ET AL

HEPATOLOGYOctober 1995

5.

)

•

•

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•

PS = .6181 EPSTFS + .I.4984

PS = .8328 EPSAVG + .7562

1

0

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4

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EPSAVG + TFS

Seven p a t i e n t s h a d t h e i r livers weighed at a u t o p s y or t r a n s p l a n t a t i o n sometime after peritoneoscopy a t a r a n g e of 1 to 35 months, w i t h six being less t h a n 16 months. The correlation for all p a t i e n t s of h e p a t i c weight in g r a m s divided by the p a t i e n t ' s ideal body weight in pounds compared w i t h t h e peritoneoscopy a s s e s s m e n t of size was y = - 2 . 5 6 x + 18.2; r = .705; P < .05. In the four p a t i e n t s assessed less t h a n 1 y e a r after peritoneoscopy, t h e correlation was still significant: y -- - 3 . 3 8 x + 22.9; r = .923; P < .05. J u d g m e n t of size a t peritoneoscopy would a p p e a r to be a d e q u a t e using our criteria. The peritoneoscopy e s t i m a t e s of hepatic size included separ a t e e s t i m a t e s for r i g h t a n d left lobe. Hepatic size criteria for r i g h t lobe was based on t h e following: (1) l e n g t h in centimeters from dome to inferior m a r g i n of liver (large, > 2 0 cm; normal, 16 to 20 cm; small, 13 to 15 cm, a n d very small, < 13 cm); (2) r e l a t i o n s h i p of most inferior hepatic edge descent to insertion of t h e falciform l i g a m e n t (large, g r e a t e r t h a n normal; normal, 5 to 6 cm below insertion; small, a p p r o x i m a t e l y even with insertion; a n d v e r y small, t a p e r s from t h e insertion t o w a r d the dome); a n d (3) r e l a t i o n s h i p of most inferior hepatic edge descent to t h e r i g h t costal m a r g i n (large, > 3 finger b r e a d t h s below r i g h t costal margin; normal, 0 to 2 finger b r e a d t h s below r i g h t costal margin; small, superior to r i g h t costal margin; a n d very small, tucked up in the r i g h t u p p e r q u a d r a n t t a p e r i n g t o w a r d the dome). Hepatic size criteria for the left lobe were b a s e d on the following: (1) length in centimeters from t h e d i a p h r a g m in the midline to g r e a t e s t inferior descent (large, > 12 cm; normal, 8 to 12 cm; small, 6 to 8 cm; a n d very small, < 6 cm); (2) relationship to the falciform l i g a m e n t (large, inferior to insertion; normal, even with insertion; small, does not reach or t a p e r s from the insertion; a n d very small, atrophic); a n d (3) r e l a t i o n s h i p to xiphoid (large, > 2 finger b r e a d t h s below xiphoid; normal, 0 to 2 finger b r e a d t h s below xiphoid; small, does not reach xiphoid; and very small, s u b s t a n t i a l l y superior to xiphoid a n d atrophic).

0

2 EPS4

4

6

FIG. 3. The prospective comparison of the EPS with the actual PS in 20 patients showed significant correlations with or without inclusion of histological fibrosis (see text for definition of different EPS equations).

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