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Pancreatitis with arthropathy and subcutaneous fat necrosis.

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arthritb
and
rheumatism
Official Journalof the American Rheumatism Association Section of the Arthritis Foundation
PANCREATITIS WITH ARTHROPATHY AND
SUBCUTANEOUS FAT NECROSIS
Evidence for the Pathogenicity of Lipolytic Enzymes
H. ALEXANDER WILSON, ALI D. ASKARI, DEWEY H. NEIDERHISER, A. MYRON JOHNSON,
BRIAN S. ANDREWS. and LANSING C. HOSKINS
normal. No associated proteinase inhibitor or significant
immunologic abnormality was detected. Certain properties of adipose cells and lipolytic enzymes may help
explain the characteristically selective necrosis of fat
cells observed in this syndrome.
The occurrence of peripheral fat necrosis in
exceptional cases of pancreatic disease is not well understood. We report studies on such a patient with arthropathy and subcutaneous nodules. Examination of serial
serum samples demonstrated striking elevations of the
pancreatic enzymes phospholipase A, 3-3.4 unitdm1
(normal 0.17-0.41); lipase, 7-39 Sigma-Tietz units/ml
(normal < 1); immunoreactive trypsin, 912-3,207 ng/ml
(normal 12-41). The distinguishing characteristic of the
patient’s synovial fluid was a marked elevation of hydrolized fatty acids (680 mg/dl versus 19 & 19 in control
inflammatory joint fluids). Synovial fluid fatty acid
distribution was identical to values for tissue fat. In
contrast, serum fatty acid levels and distribution were
Pancreatitis or pancreatic neoplasm occasionally presents as a systemic illness characterized by
fever, necrotizing subcutaneous nodules, arthropathy,
visceral effusions, and osseous intramedullary fat necrosis (1-7). While the finding of selective fat cell
necrosis in affected tissues is diagnostic (2), the cause
of tissue injury distant from the pancreas is not well
understood. Pathogenesis generally has been attributed to the release of lipolytic enzymes. Observations
supporting this view include a disproportionately high
incidence of acinar cell (exocrine) carcinomas among
cases due to malignancy (3,
and the acute onset of
peripheral fat necrosis after rupture of a pancreatic
pseudocyst (3). However, no direct evidence has been
reported previously for increased lipolytic activity in
peripheral tissues, and only lipase elevation in serum
and tissue fluids has been shown (8). Recent studies
have focused attention on putative immunologic abnormalities (4) or proteinase inhibitor deficiency (9) in
such patients.
This study was undertaken primarily to clarify
the relationship of lipolytic enzymes to peripheral
tissue injury in a patient with pancreatitis and disseminated fat necrosis. Striking serum elevations of lipase,
phospholipase A, and trypsin were documented. The
distinguishing characteristic of the patient’s synovial
fluid was a marked elevation of hydrolyzed fatty acids,
thus demonstrating lipolysis in an involved tissue.
Presented at the VIII Pan-American Congress of Rheumatology, Washington, DC, June 1982
From the Department of Medicine, Cleveland Veterans
Administration Medical Center and Case Western Reserve University School of Medicine; the Department of Pediatrics, University of
North Carolina at Chapel Hill; and the Department of Medicine.
University of California, Irvine.
Supported in part by t h e Veterans Administration, the
Cystic Fibrosis Foundation, and by Grant 2 ROI AM1 1766 from the
National Institutes of Health. Dr. Wilson is an Investigator of the
Arthritis Foundation.
H. Alexander Wilson. MD: Arthritis Investigator: Ali D.
Askari, MD: Associate Professor; Dewey H. Neiderhiser, PhD:
Assistant Professor; A. Myron Johnson, MD: Associate Professor,
Department of Pediatrics, University of North Carolina at Chapel
Hill; Brian S. Andrews, MD: Associate Professor, Department of
Medicine, University of California, Irvine; Lansing C. Hoskins.
MD: Associate Professor, Department of Medicine, Case Western
Reserve University.
Address reprint requests to H. Alexander Wilson, MD,
Building 5, Room 228. National Institutes of Health, Bethesda, MD
20205.
Submitted for publication July 6, 1982; accepted in revised
form September 30, 1982.
Arthritis and Rheumatism, Vol. 26, No. 2 (February 1983)
121
WILSON ET AL
122
These findings are discussed with reference to lipolytic
enzyme kinetics and certain properties of adipose
cells.
CASE REPORT
A 48-year-old man was admitted to the Cleveland Veterans Administration Medical Center. Six
weeks previously he had noted pain and erythema
below the right ankle and extending over the dorsum
of the foot to the medial two metatarsophalangeal
joints. Both ankles became painful and swollen. The
week before admission. he developed intermittent
fever and polyarthralgia. Abdominal symptoms were
limited to mild anorexia. He acknowledged chronic
alcohol abuse.
On initial examination. he was dehydrated and
malnourished. The pulse was 120 and the temperature
was 38.6"C. Bowel sounds were normal and there was
no abdominal tenderness or organ enlargement. Pain
resulted from palpation of the wrists, elbows. knees,
ankles, and most finger joints. Periarticular erythema
was prominent. Erythema also was present over the
dorsum of the left foot, and an abscess below the
medial malleolus drained yellow-brown odorless fluid.
Laboratory evaluation included a hematocrit of 26%, a
leukocyte cell count of 19,0OO/pl(2% eosinophils). and
an erythrocyte sedimentation rate of 90 mdhour.
Rheumatoid factor (latex fixation) was positive at
1 :80, serum aspartate aminotransferase was 182 units
(normal < 41) and alkaline phosphatase was 372 units
(normal < 115). Results of the following studies were
normal or negative: uric acid. bilirubin, hemolytic
complement, and antinuclear antibodies. Cultures of
blood, urine, and abscess exudate were sterile.
On the fourth hospital day, multiple nontender
erythematous nodules appeared on the chest and legs.
Biopsy of a nodule showed fat cell ghosts characteristic of pancreatitis-induced fat necrosis. Serum amylase
was 1.260 Somogyi unitsldl (normal 60-200) and serum
lipase was 34.4 Sigma-Tietz units/ml (normal < I ) .
Two days later an effusion appeared in the left knee.
Aspiration yielded a thick yellow fluid with the following characteristics: leukocyte cell count 1,20O/plwith
80% mononuclear cells, glucose 100 mg/dl, protein 3.6
gm/dl, amylase 2.400 Somogyi units/ml. lipase 5 Sigma-TietL unitslml. Fat globules were identified by
Sudan 111 staining.
Ultrasound examination, intravenous cholangiogram, barium contrast studies, and liver scan failed
to identify a specific pancreatic lesion. The patient was
treated with nasogastric suction, intravenous fluids,
and hyperalimentatian. Articular symptoms ameliorated, but new crops of subcutaneous nodules appeared
and progressed to extensive areas of confluent fat
necrosis despite therapy with tetracycline, a lipase
inhibitor (10). He remained febrile and was intermittently disoriented. During the second and third months
of hospitalization, cultures from various sites of subcutaneous fat necrpsis grew Escherichia coli despite
therapy with gentamicin and ampicillin or cephalothin.
The same organisrp, sensitive to all prescribed antibiotics, was then cultured from the left knee and from
the blood. Terminally, he developed respiratory insufficiency.
Postmortem examination limited to the thorax
and abdomen revealed a well circumscribed 5 cm
pseudocyst in the head of the pancreas in communication with a patent pancreatic duct and extensive fat
necrosis involving the peripancreatic, renal pelvic, and
retroperitoneal adipose tissue. Bilateral, confluent
bronchopneumonia was present.
MATERIALS AND METHODS
Materials. Fasting serum samples were obtained
from the patient and from 5 healthy donors. Patient joint and
subcutaneous nodule fluids were obtained by closed aspiration, as were control synovial fluids from patients with
arthritis secondary to other causes (Table I ). Specimens not
assayed at once were stored preservative-free at -70°C.
Lipid analyses. Fatty acids in serum, synovial fluid,
and subcutaneous aspirate were extracted into chloroform/
methanol ( I : I). Total and nonesterified fatty acids were
separated by thin layer chromatography (TLC) as previously
described ( I 1). methylated with boron trifluoride, and quantified on an F & M gas chromatograph (Hewletr Packard.
Avondale, PA) (12). The lower limit of detection for this
method was 0. I mg fatty acid/ml serum. Phospholipids were
separaled by T L C and measured by their phosphorus content (12).
Serum enzyme assays. Phospholipase A activity was
measured by the release of lysophosphatidylcholine after
incubation of equal volumes of serum with a solution containing 0. I mM di( l-'4C~oleoylphosphatidylcholine
(582,000
dpm/pmole. Applied Science Laboratory. State College.
PA). 4.5 mM sodium deoxycholate (Sigma Chemical Co., St.
Louis. MO), and 0.5 mM calcium in O.IM Tris buffer, pH
7.4. Incubations were performed at 37°C for I hour. The
reaction was stopped with chloroform/methanol and the
lipids separated by T L C ( I 1 ), The distribution of radioactivity was measured in a Beckman LSlOO scintillation counter.
One unit of enzyme activity was defined as that amount
releasing 1 nmole of lysophosphatidylcholine from 100
nmole of dioleoylphosphatidylcholinein 1 hour. 1,ipase was
measured by thc method of Tietz (13) using a lipase kit
(Sigma).
Protease activity was measured using azoalbumin
PANCREATITIS AND ARTHROPATHY
123
Table 1. Lipid concentration and percent distribution in patient serum, synovial fluid, and
subcutaneous nodule compared with controls*
Serum
Fatty acids (mgldl)
Total
Esterified
Nonesterified
Distribution (%)8
Myristic (14:O)
Palmitic (16:O)
Palmitoleic (16: I )
Stearic (18:O)
Oleic (18:l)
Linoleic (18:2)
Arachidonic (20:4)
Phospholipids
( u g phosphorus/ml)
Synovial fluid
Cutaneous nodule
Control
Patient
Control
Patient
Patient
276 2 30
260 2 29
1 6 ? 13
247 2 67
229 f 68
18 2 2
117 2 31
99 t 35
19 2 19
770t
90
680t
5.900
2,600
3,300
2*0
27 2 5
5 2 3
8 2 1
34 2 3
18 2 10
5?2
8
25 2 2
3 2 1
102 I
32 2 2
30 f 4
2
19t
6t
8
55t
3
22
9
4
53
9
8
3
24
3
9
24
31
6
2 1
I
2 1
2 1
23
2 4
2 4
2
100 2 18
8
1O t
8
54 2 7 t
* Values are expressed as mean 2 SD. Control synovial fluids were obtained from 4 patients with the
following diagnoses: 2 with gout, 1 with rheumatoid arthritis, 1 with osteoarthritis. Control serum
samples were obtained from 5 healthy male donors and compared with 3 serial samples from the
patient.
t More than 2 SD above or below mean of controls.
8 Distribution is shown for total fatty acids. Percent distribution of phospholipids in control (and in
patient) serum were: phosphatidylcholine, 47 ? 3 (53 2 10); sphingomyelin, 18 ? 4 (18 2 6);
lysophosphatidylcholine, 10 2 3 (8 2 5 ) ; phosphatidylethanolamine, 4 f 2 (3 2 3); polar lipids
remaining at the origin of the thin layer chromatography plate, 21 (18).
8 Not detected (less than 0. I mglml).
(Sigma) as substrate (14). One unit of protease activity per
ml of serum was defined as that amount which caused an
increase of 0.001 in the optical density at 440 nm of trichloroacetic acid-soluble reaction products after 4 hours at 3TC,
pH 8.0. Immunoreactive trypsin-trypsinogen was determined (courtesy of Dr. C. Largman) as described (15).
Proteinase inhibitors. Proteinase inhibitors were
quantified by electroimmunoassay (16). The inhibitors assayed were al-antitrypsin, a*-macroglobulin, inter-a-trypsin
inhibitor, a,-antichymotrypsin, and C 1 inhibitor. Monospecific antisera were obtained from Atlantic Laboratories
(Scarborough, ME). Pi(al-antitrypsin) phenotyping was performed by isoelectric focusing (17) using polyacrylamide gel
plates from LKB Instruments (Rockville, MD).
Immunologic studies. C3 and C4 were measured by
endpoint nephelometry (18) using monospecific antiserum
(Meloy Laboratory, Springfield, VA). Properdin factor B
was measured by rate nephelometry (19) using the Beckman
(Fullerton, CA) immunochemistry analyzer. Immune complexes were assayed by the Raji cell radioimmunoassay (20)
and by a modified 1251-Clqbinding radioimmunoassay (21).
RESULTS
Analysis of fatty acid content in the patient’s
synovial fluid, compared with synovial fluids from
patients having inflammatory rheumatic diseases (control fluids), demonstrated a marked increase in lipids,
due entirely to elevation of the nonesterified fatty acid
(NEFA) fraction (Table I). Lipids in the aspirate of a
subcutaneous nodule were also predominantly nonesterified. In both fluids, the percent distribution of the
fatty acids was identical to standard values for tissue
fat (22). In contrast, the lipids present in control
synovial fluids were esterified (85%) and reflected
normal serum distribution. Except for minor shifts in
the distribution of individual fatty acids, the patient’s
total serum fatty acid values were comparable with
those of healthy controls, as were the NEFA fractions.
Serum phospholipid concentrations from the patient
were low but the percent distribution of individual
phospholipids was normal.
Serial examination of the patient’s serum
showed persistent elevation of lipolytic and proteolytic enzymes (Table 2). Lipase levels were 7-39 times
the normal level and phospholipase A activity was
tenfold higher than values measured in controls. Trypsin, determined by a radioimmunoassay which measures predominantly the zymogen and inhibitor bound
forms (15), was also strikingly elevated. Serum proteolytic activity was twice the levels observed in normal
individuals.
Five serum samples were examined for a proteinase inhibitor deficiency and for immune complexes. Alphal-antitrypsin levels were elevated, and the Pi
124
WILSON ET AL
Table 2. Pancreatic enzymes in patient serum
~
Enzyme*
Initial
Lipase (8)
(Sigma-Tietz units/ml)
Phospholipase A (3)
(units/ml)t
Protease ( I ) (units/ml)
Trvpsin (3) (ndml)
Course
34.4
7-39
3.4
3.0-3.4
1.376
~~~~
18
912-3.207
Normal
values
=I
0.17-0.41
8-10
12-41
* Values in parentheses indicate number of patient samples assayed.
Normal ranges for phospholipase A and protease established in 5
healthy controls.
t Hydrolysis of labeled substrate. Calculated total units of enzyme
activity (labeled plus endogeneous phospholipid) were: patient, 3 I35; controls, 2.8-6.6. The assay conditions chosen favor measurement of phospholipase A2 but do not exclude phospholipase A ,
activity .
phenotype was the common M. Alphaz-macroglobulin
values, however, were moderately low (87-147 mg/dl,
normal 160-410), and correlated inversely with immunoreactive trypsin determinations (r = 0.85). No significant abnormality was present in the other inhibitors
assayed. Values for complement components (C3, C4,
properdin factor B) were normal or elevated. Immune
complexes, measured by the Raji cell and Clq binding
radioimmunoassays, were detected at low levels in
only I serum.
DISCUSSION
Clinical observations (1-33-7) and studies of
experimentally induced pancreatitis (8) have suggested
that the subcutaneous fat necrosis and arthropathy
associated with pancreatitis results from the action of
lipolytic enzymes of pancreatic origin. We present
novel findings which satisfy two requirements for
establishing this hypothesis. Persistent serum elevations of phospholipase A, trypsin, and, as previously
reported, lipase are shown (8). The finding of phospholipase A elevation is of particular interest due to its
potential for the initiation of tissue necrosis by cleavage of membrane glycerophospholipids (23). Secondly, both synovial fluid and a subcutaneous nodule were
found to have strikingly high levels of hydrolyzed fatty
acids, demonstrating lipolytic enzyme activity in involved tissues. Nonesterified fatty acids at concentrations considerably lower than those present in patient
synovial fluid are cytotoxic for a variety of cell types
including leukocytes (24). Hence, once free in tissues,
NEFA would be expected to perpetuate inflammation.
An intriguing aspect of this syndrome, its infrequent occurrence even in severe pancreatitis (2),
needs further clarification. An enzyme inhibitor deficiency could account for this low incidence, and an
association between disseminated fat necrosis and q antitrypsin deficiency has been proposed (9). Circulating trypsin is predominantly bound to az-macroglobulin (25) and rapidly cleared by the reticuloendothelial
system (26). Our finding of an inverse correlation
between depressed cY2-macroglobulinand elevated immunoreactive trypsin implies accelerated clearance of
enzyme complexed inhibitor. Increased proteolytic
activity, consistent with elevated levels of immunoreactive trypsin, was present in patient serum, but this
appears to be a consistent feature of severe pancreatitis (27). A serum proteinase inhibitor deficiency was
excluded in our patient. The findings reported here
suggest that a lipolytic inhibitor deficiency might be a
more attractive candidate.
Selective necrosis of fat cells is the pathologic
hallmark of this syndrome. Certain properties of adipose tissues and pancreatic lipolytic enzymes may
help explain this selectivity.
Lipolytic enzymes act preferentially in waterlipid interfaces. Catalysis requires both the adsorption
of the enzyme to the substrate-containing interface
and hydrolysis within the plane of the interface. Because both adsorption and hydrolysis are highly sensitive to lipid composition and packing, these enzymes
react only with a narrow range of lipid conformations
(28,29). In serum, lipoproteins are the interface to
which lipolytic enzymes must adsorb before lipid
hydrolysis may occur. The normal serum triglycerides
and reduced phospholipids in our patient are consistent with the composition and high packing density of
lipoprotein components (30). Under these conditions,
pancreatic lipase and phospholipase A cannot bind
readily to the interface and catalysis is limited to the
protein-phospholipid surface layer. Available data
(31-33) indicate that lipid conformations in plasma
membranes exclude enzyme adsorption. In the present
case, we were unable to show cytotoxicity in patient
serum for cultured endothelial cells by a chromium
release assay. A relatively unique lipid array in fat cell
membrane, however, might permit enzyme adsorption.
A second mechanism for selective fat cell necrosis is suggested by special ultrastructural characteristics of adipocytes adjacent to capillary endothelial
cells. These fat cells appear to be connected with the
vascular lumen by a continuous membrane leaflet (34).
At the endothelial surface, lipoproteins are degraded
by a membrane-bound lipoprotein lipase and the re-
125
PANCREATITIS AND ARTHROPATHY
sultant hydrolysis products are driven inward by coupled reesterification within the adipocyte (34). Free
fatty acids are known to enhance (35) or enable (36)
the adsorption t o interfaces of lipolytic enzymes from
the pancreas. Thus, serum lipases adsorbed to the
degradation products of lipoproteins could be transported to the adipocyte, and their accumulation result
in cell lysis. This mechanism for selective fat cell
necrosis is compatible with the occasional reports
(7,37) of a discrepancy between serum lipase values
and clinical deterioration in patients with this syndrome, and with the observation in experimental pancreatitis-induced fat necrosis that the earliest ultrastructural changes occur within the fat cell (38).
Finally, we wish t o emphasize certain clinical
considerations. Review of previous reports on this
syndrome indicates that, as in our patient, symptoms
or signs of pancreatitis frequently are absent (2). Both
nonsteroidal arltiinflarnmatory agents and immunosuppressive drugs have proven inefficacious. Once extensive fat necrosis is present, infection even by relatively
drug-sensitive bacterial species becomes difficult t o
treat. Diagnostic and therapeutic maneuvers in such
patients would appear best directed toward defining a
remediable lesion in the pancreas.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
ACKNOWLEDGMENTS
We thank Dr. Corey Largman for performing the
assay for immunoreactive trypsin, Drs. Nortin M. Hadler
and Thomas M. Chused for helpful comments on the manuscript, and Drs. Edward C. Dennis and Howard L. Brockman for improving the discussion of lipolytic enzyme kinetics. Dr. Brockman called our attention to the pertinence of
studies on lipid packing density in serum lipoproteins and
lipid transport across capillary endothelium.
16.
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