Involvement of the Pancreas in Lupus

A Case Study
By Susan A. Boackle, M.D. Assistant Professor of Medicine and Immunology, University of Colorado at Denver and Health Sciences Center, Denver, CO

Introduction

Pancreatitis (inflammation of the pancreas) can be the first symptom of lupus and can be life-threatening. The signs and symptoms of acute pancreatitis in people with lupus are similar to those in individuals without lupus, but the management is quite different. The following case illustrates the complexity involved in the management of a person with lupus-associated pancreatitis.

Case History

Medical History

A 34-year-old woman with a three-year history of lupus presented with a five-day history of constant, dull epigastric pain, intermittent sharp epigastric pain radiating to the back, and nausea. She denied recent alcohol ingestion. Her initial lupus symptoms included only fatigue and arthritis. She was unable to tolerate hydroxychloroquine due to the development of corneal edema, and she had been managed chronically with low-dose steroids.

Eighteen months prior to this presentation she had severe abdominal pain, elevated liver function tests, and elevated pancreatic enzymes. She was then diagnosed with lupus-associated hepatitis and pancreatitis, and was treated with high-dose steroids. She was unable to tolerate mycophenolate mofetil due to an allergic reaction, or methotrexate due to elevated liver function tests. Her prednisone was tapered, and at the time of this visit she was being treated with azathioprine and low-dose steroids only.

Physical Examination

The patient had no fever. She had a raised red rash over her chest, oral ulcers, mild synovitis in the small joints of her hands, and diffuse abdominal tenderness that was worse in the epigastric region, without rebound tenderness. Cardiac and pulmonary exams were normal.

Laboratory Test Results

• Pancytopenia present: white blood cells 1.2, hemoglobin 9.7, hematocrit 29.1, and platelets 127,000.
• Manual differential showed 63 percent segmented neutrophils, 10 percent bands, 16 percent lymphocytes, 7 percent monocytes, 1 percent metamyelocytes, and 3 percent myelocytes.
• AST 231;
• ALT 136;
• Albumin low;
• total bilirubin normal.
• Amylase 137 on admission, increased to 385 during hospitalization.
• Lipase 107 on admission, increased to 459 during hospitalization.
• Urinalysis negative for protein or cells; Erythrocyte sedimentation rate 38.
• Anti-dsDNA > 300;
• C3 and C4 were low; chest X-ray showed a mild pleural effusion.

Diagnostic Impression

The differential diagnosis included active flare of lupus associated with pancreatitis, hepatitis, and pancytopenia; infection; portal vein thrombus; and biliary obstruction.

Management and Clinical Course

Abdominal CT scan showed stranding suggestive of inflammation at the root of the mesentery, and a small amount of pelvic free fluid. The pancreas appeared normal. There was no biliary ductal dilatation. Abdominal ultrasound showed unobstructed hepatic vessels without thrombus (blood clot), no gallstones, and no splenomegaly. Bone marrow biopsy was consistent with peripheral destruction/sequestration as the cause for the patient's peripheral cytopenias. Repeated blood cultures were negative. Direct Coombs was negative. Triglycerides were mildly elevated at 184.

The patient was started on high-dose steroids for a presumed lupus flare. Her leukopenia did not respond, and she was given two doses of G-CSF. After the results of the bone marrow biopsy were obtained, intravenous cyclophosphamide therapy was initiated in the hospital, and she was treated with this therapy monthly for six months, then every three months for 18 additional months. A gonadotropin- releasing hormone analogue (leuprolide acetate) was given prior to her first few doses of cyclophosphamide to protect from cyclophosphamide-induced ovarian damage; this was subsequently discontinued at the patient's request because of the development of perimenopausal symptoms. Prednisone was slowly tapered.

The patient is now two years out from this episode. She is currently being treated with oral prednisone 4 mg/day and is on no other cytotoxic or immunosuppressive drugs. Besides fatigue, she is having no symptoms of active lupus. Her anti-double-stranded DNA is 47, her C3 is mildly decreased at 78, and her C4 is normal. She has had normal complete blood counts, normal liver function tests, and a normal lipase with a persistent mild elevation of her amylase. Her menses had been regular and were associated with signs of normal fertility until recently, when her menstrual cycles have become irregular.

Discussion

Pancreatitis in lupus presents in a similar fashion as pancreatitis in non-lupus patients. Most people have epigastric pain, sometimes radiating to the back, and the majority have nausea or vomiting. About half have fever. Although imaging studies are often done to rule out other causes of abdominal pain, the diagnosis is usually based on laboratory evidence of elevated levels of serum amylase and lipase. Abnormal liver function tests and hypoalbuminemia are commonly seen in lupus-associated pancreatitis.

The incidence of pancreatitis in lupus cannot be easily determined from the literature, although it is believed to be rare. Most people with lupus-associated pancreatitis have other symptoms and signs of active lupus, as our patient did. Her blood count abnormalities reflected her increased disease activity, as did the presence of synovitis, serositis, and oral ulcerations. However, it is still necessary to rule out a mechanical etiology with appropriate imaging studies. In addition, triglycerides must be measured to rule out hypertriglyceridemia as a cause for pancreatitis, and recent consumption of alcohol must be evaluated.

Finally, non-essential medications that potentially have pancreatic toxicity, such as azathioprine and thiazide diuretics, should be discontinued. This latter point is difficult, however, as both azathioprine and prednisone can cause pancreatitis, whereas these are also commonly used treatments for active lupus. Case reports of lupus patients presenting with pancreatitis suggest that, in general, corticosteroids and azathioprine do not trigger acute pancreatitis or cause increased mortality. In our patient's case, her azathioprine was discontinued.

Mild elevations of serum amylase levels can occur in lupus patients in the absence of pancreatitis. These patients typically do not have abdominal pain and their lipases are normal. The etiology of elevated serum amylase may represent subclinical pancreatic or intestinal injury from vasculitis. Alternatively, it may be due to macroamylasemia, which results when renal excretion of amylase is impaired because amylase is bound to other macromolecules like immunoglobulins and polysaccharides. The diagnosis of macroamylasemia can be confirmed by determining the molecular weight of the serum amylase by gel electrophoresis. An amylase-clearance to creatinine-clearance of <1% in a 24 hour collection of urine can also be suggestive.

Treatment of lupus-associated pancreatitis is similar to that of non-lupus-associated pancreatitis, with intravenous hydration, resting the pancreas by permitting no oral intake, antibiotics if indicated, and sparing use of analgesics. In addition, lupus patients with pancreatitis are usually treated with steroids with and without cytotoxic agents, including azathioprine, cyclophosphamide, and mycophenolate mofetil. For example, our patient responded well to steroids alone for her first presentation of pancreatitis, but her second presentation required more aggressive therapy. Because she had a previous allergic reaction to mycophenolate mofetil, and we were concerned about the pancreatic and hepatic toxicity of azathioprine, we chose to use cyclophosphamide to treat her pancreatitis.

Pancreatitis complications occurred in approximately 60 percent of the patients reported in the literature. The mortality rate is approximately 25 percent. These surprisingly high figures may reflect the bias inherent in case reports. Higher mortality may occur in patients who present with pancreatitis as the initial manifestation of their lupus, possibly because the initiation of the appropriate immunosuppressive therapy is delayed. In addition, mortality is believed to be higher in individuals with symptoms of active lupus, particularly in those who also have problems with their central nervous system or heart.

This case also illustrates the difficulties inherent in treating young women with lupus with our current armamentarium of medications. Neither we nor the patient wished to use cyclophosphamide because of its potential toxicities, particularly its effects on fertility, which are increased in women in their 30s. However, we believed that this was the best option available to her at that time, due to her previous problems with other potentially useful medications and the severity of her presentation. We attempted to protect her ovarian function with leuprolide acetate. The timing was difficult, though, as it is best given several weeks before beginning cyclophosphamide, and this is often difficult to do in acutely ill patients needing immediate therapy.

Although this patient is in clinical remission now after two years of treatment with cyclophosphamide, the question remains about how we will manage her should she have another flare of her lupus. She will remain on a low dose of prednisone indefinitely due to her inability to tolerate other steroid-sparing agents. After her last few doses of cyclophosphamide, she began to develop leukopenia and it is possible that her bone marrow would not tolerate another course of cyclophosphamide. There are a number of clinical trials in progress or being planned to test targeted biologic agents for lupus, and we are hopeful that in the future, more effective and less toxic therapy will be available for patients such as her.

Summary

Lupus-associated pancreatitis is uncommon, but because of its high complication and mortality rates, it should be suspected in anyone with lupus who reports abdominal pain. Non-lupus causes of pancreatitis must be ruled out, and appropriate immunosuppressive therapy initiated promptly.

Glossary

alanine transaminase (ALT) - an enzyme that is measured to look for liver damage
amylase - any of a group of enzymes that catalyze the hydrolysis of starch and glycogen or their intermediate hydrolysis products
aspartate transaminase (AST) - an enzyme that when present in abnormally high levels in the blood is a diagnostic indication of heart attack or liver disease
biliary ductal dilatation - enlargement of the bile ducts in the liver; could be present if gallstones were blocking the bile ducts
CT scan - computed tomography
cytopenias - low blood cell counts
epigastric - the upper portion of the mid-abdomen
G-CSF - granulocyte colony-stimulating factor
leukopenia - low white blood cell count
lipase - any enzyme (as one secreted by the pancreas) that catalyzes the breakdown of fats and lipoproteins, usually into fatty acids and glycerol
mesentery - membranes that connect the intestines and their appendages with the wall of the abdominal cavity
pancytopenia - an abnormal reduction in the number of red blood cells, white blood cells, and blood platelets
pelvic free fluid - fluid that is present in the pelvis on CT scan (normally there is none); sometimes a sign of inflammation, but could represent blood as well as other causes
peripheral destruction/sequestration - indicates that the blood cells were being destroyed or sequestered (seized) after they left the bone marrow; in this case the bone marrow itself was pumping out plenty of blood cells, thus there was no evidence of bone marrow suppression
rebound tenderness - a sensation of pain felt when pressure (as to the abdomen) is suddenly removed
serositis - inflammation of the lining of the lungs, heart, or abdomen, resulting in fluid collections in these spaces
splenomegaly - abnormal enlargement of the spleen stranding-an appearance of the fat on CT scan; usually associated with inflammation
synovitis