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MedGenMed. 2005; 7(2): 14.
Published online 2005 June 20.
PMCID: PMC1681551
Copyright ©2005 Medscape
A Multisystem Illness Involving Pancreas, Bile Ducts, and Salivary Glands
Venu Julapalli, MD, Fellow in Gastroenterology, Daniel Ball, MD, Clinical Assistant Professor, and Ravi Shivshankar, MD, Clinical Associate Professor
Venu Julapalli, Baylor College of Medicine, Houston, Texas;
Contributor Information.
Richard Goodgame, MD, Professor of Medicine
Richard Goodgame, Department of Medicine, Gastroenterology Section, Baylor College of Medicine, Houston, Texas;
Disclosure: Venu Julapalli, MD, has disclosed no relevant financial relationships.
Disclosure: Daniel Ball, MD, has disclosed no relevant financial relationships.
Disclosure: Ravi Shivshankar, MD, has disclosed no relevant financial relationships.
Disclosure: Richard Goodgame, MD, has disclosed no relevant financial relationships.
Case Presentation
The patient is a 46-year-old man with a complicated history of biliary tract, pancreatic, and salivary gland disease.
Prior to the onset of this illness the patient was healthy. He had no excessive alcohol or tobacco use, no substance abuse, no travel, and had a stable family and finances. There was no relevant family history of serious diseases. Three years ago, the patient abruptly developed epigastric and right upper quadrant abdominal pain, nausea, and vomiting. He had persistent symptoms over the next few weeks, during which time he visited his local emergency department several times. After 1 month he developed jaundice. This began a series of interactions with multiple physicians and hospitals that is best summarized as 3 problems, as described below:
Biliary disease: Cholestatic jaundice developed 3 years ago and endoscopic retrograde cholangiopancreatography (ERCP; Figure 1Figure 1 and and2)2Figure 2) showed multiple biliary strictures suggestive of sclerosing cholangitis.
Figure 1
Figure 1
Figure 1
Figure 2
Figure 2
Figure 2
Liver biopsy showed periductular neutrophilic infiltrates, bile plugging (Figure 3Figure 3), and mild periportal fibrosis around the bile ducts (Figure 4Figure 4) without hepatitis or cirrhosis. These findings supported the diagnosis of bile duct obstruction, as may be seen with sclerosing cholangitis.
Figure 3
Figure 3
Figure 3
Figure 4
Figure 4
Figure 4
In the following year, the patient underwent multiple attempts at balloon dilation and stenting of dominant strictures in the biliary tree. Multiple brushings and biopsies of the ducts were performed, and no malignancy was found. During this period he lost 40 pounds. Two years ago all attempts at instrumentation of the biliary strictures was abandoned. Two months ago he was referred to our hospital. An ERCP was performed (Figure 5Figure 5 and and6).6Figure 6). Results showed a high-grade stricture in the distal common bile duct, marked dilation of the biliary system, and multiple intra- and extrahepatic ductal irregularities. Brushings and biopsies of the stricture were negative for malignancy.
Figure 5
Figure 5
Figure 5
Figure 6
Figure 6
Figure 6
Pancreatic disease: Although the patient had pancreatic-type pain at the onset of his illness 3 years ago, the initial imaging studies did not show impressive changes in the pancreas. The biliary abnormalities attracted more attention, but the abdominal pain never resolved. Two years ago, he had worsening pancreatic-type pain that prompted an abdominal MRI (Figure 7Figure 7). Results of MRI showed a diffusely enlarged pancreas with a small halo of pancreatic edema.
Figure 7
Figure 7
Figure 7
Given the common bile duct stricture and 40-pound weight loss, a pancreatic malignancy was suspected. Pancreatic biopsy was performed (Figures 8Figure 8–10Figure 10), and results showed pancreatic fibrosis and mild inflammation that was nonspecific. No malignancy was found.
Figure 8
Figure 8
Figure 8
Figure 10
Figure 10
Figure 10
One year ago the patient underwent endoscopic ultrasound because of persistent pain. Results of imaging were suggestive of a hypoechoic mass in the pancreatic neck. Fine-needle aspiration of this lesion revealed no malignancy. Two months ago the patient was referred to our hospital. MRI of the pancreas (Figures 11Figure 11 and and12,12Figure 12, T1, post-gadolinium; transverse – Figure 11Figure 11; coronal – Figure 12Figure 12) showed a diffusely enlarged “sausage-like” pancreas with a surrounding halo of inflammation. No definite mass was seen.
Figure 11
Figure 11
Figure 11
Figure 12
Figure 12
Figure 12
Salivary gland disease: One year ago the patient noted bilateral, painful swelling of both submandibular salivary glands; this was associated with the sicca syndrome (dry mouth and eyes). A Schirmer test showed absent tearing. Biopsy of the submandibular gland showed chronic sialadenitis.
A complete physical examination showed weight of 170 pounds and height of 68 inches. Vital signs were normal. There was no jaundice or stigmata of chronic liver disease. There were only 2 abnormal physical findings: bilateral, firm swelling of both submandibular glands, and mild epigastric tenderness.
Routine laboratory tests were ordered; complete blood count, urinalysis, and electrolytes were normal. Results of serum chemistries were as follows: total protein, 8.7 g/dL; albumin, 4.2 gm/dL; total bilirubin, 1.6 mg/dL; direct bilirubin, 0.9 mg/dL; alkaline phosphatase, 142 U/L; alanine aminotransferase, 187 U/L; aspartate aminotransferase, 265 U/L; and amylase, 100 mg/dL.
Diagnostic Questions
The goal of describing this patient's complicated course is to aid the clinician in recognizing the disease underlying these clinical findings. There are 3 clinical situations that should prompt the consideration of this elusive diagnosis. The diagnostic questions below serve to emphasize these clinical “prompts.”
  • What is the cause of the unusual appearance of the pancreas in this patient's MRI (Figure 11Figure 11)?
    The unusual appearance of the pancreas on MRI shows many of the features of a newly recognized pancreatic disease that is being diagnosed with increased frequency: autoimmune pancreatitis. CT and MRI scans of patients with autoimmune pancreatitis characteristically reveal a diffusely enlarged, “sausage-like” pancreas without peripancreatic fat infiltration, pseudocysts, parenchymal atrophy or calcification, or intraductal stones.[1] MRI may show a hypoenhancing peripancreatic rim that may represent peripancreatic inflammatory tissue.[2] Review Figure 11Figure 11 and try to appreciate “sausage-like” and “halo.” Focal enlargement of the head of the pancreas may also occur and mimic pancreatic cancer.[3] The characteristic finding on pancreatogram is diffuse or segmental irregular narrowing of the main pancreatic duct with minimal dilatation upstream of any segmental narrowing.[1] The best pancreatogram we have on our patient is from a magnetic resonance cholangiopancreatography (MRCP) performed 6 months ago (Figure 13figure 0702_504037-f13). It shows multiple irregularities with no distal enlargement.
    figure 0702_504037-f13
    figure 0702_504037-f13
    The combination of diffuse pancreatic enlargement on CT/MRI (which can be seen in acute pancreatitis) with narrowing of the pancreatic duct is peculiar to autoimmune pancreatitis. Our patient exhibited many of these imaging characteristics over different periods, including both focal and diffuse enlargement of the pancreas, a hypoenhancing peripancreatic rim, and no parenchymal atrophy or calcification. The variable patterns may have reflected the heterogeneous pattern of inflammatory infiltrates and fibrosis seen in this disease.[1]
  • What is the relationship between the pancreatic disease and the 2 other aspects of this patient's illness – the biliary and salivary findings?
    The term “autoimmune pancreatitis” implies an autoimmune mechanism for chronic inflammation of the pancreas. In autoimmune pancreatitis there is reportedly an immune reaction against carbonic anhydrase type II or lactoferrin by Th1-type CD4+ T cells.[1] These antigens are also found in salivary glands and the bile duct; this may account for the association of autoimmune pancreatitis with primary sclerosing cholangitis and Sjogren's syndrome.[1] Like many autoimmune diseases, the clinical manifestations of autoimmune pancreatitis are variable and reflect the anatomic targets of involvement, including the pancreatic parenchyma and duct, biliary duct, and extrapancreatic tissues.
    Our patient had prominent features of biliary involvement. He presented with obstructive jaundice secondary to biliary ductal strictures. Most patients with autoimmune pancreatitis show cholestasis on liver function tests.[4] These abnormalities in our patient prompted liver biopsy which showed changes that could be seen in any cause of extrahepatic biliary obstruction. He also had extrapancreatic involvement of his submandibular glands, which prompted submandibular salivary gland biopsy. The inflammatory changes found were nonspecific. But the combination of pancreatitis, sclerosing cholangitis, and chronic sialadenitis should, from now on, lead clinicians to strongly consider autoimmune pancreatitis.
  • What should be the reflexive diagnostic response when suspected pancreatic cancer is accompanied by a negative biopsy?
    Autoimmune pancreatitis frequently mimics pancreatic cancer. Focal enlargement of the head of the pancreas with cholestatic liver chemistries is common.[3] Mass lesions in other parts of the pancreas also occur.[3]
    In one series of 17 patients from Korea,[4] 65% presented with painless jaundice as the major symptom, 35% had nonspecific mild abdominal pain, 35% had weight loss, and 76% were diagnosed with diabetes mellitus within a year of the diagnosis of autoimmune pancreatitis. All of these symptoms could suggest pancreatic cancer. Many patients have narrowing of the intrapancreatic portion of the common bile duct as well, secondary both to the extrinsic compression by the inflamed pancreatic head and inflammatory involvement of the distal common bile duct itself. These were prominent features in our patient. Cancer was so strongly suggested that pancreatic tissue was obtained on 2 occasions, with negative results. The characteristic histologic finding of autoimmune pancreatitis is a periductal lymphoplasmacytic infiltrate, associated with fibrosis, that is heterogeneous in extent and severity.[1] We suspect that sampling error produced nondiagnostic results in our patient.
    This clinical situation – suspicion of pancreatic cancer but negative results – should prompt the clinician to order the diagnostic test for autoimmune pancreatitis: serum level of IgG4. This key laboratory test distinguishes autoimmune pancreatitis from other diseases of the pancreas and biliary tract. Serum IgG4 accounts for only 3% to 6% of total IgG in the serum of normal subjects.[5] IgG4 can be elevated in nonpancreatic conditions such as atopic dermatitis, some parasitic diseases, and pemphigus variants.[5] Hamano and colleagues[5] compared serum IgG4 levels in 20 patients with autoimmune pancreatitis with the following controls: 20 age- and sex-matched healthy subjects; 45 patients with ordinary chronic pancreatitis (alcoholic in 36 cases and idiopathic in 9 cases); 70 patients with pancreatic cancer; 20 patients with primary biliary cirrhosis; 8 patients with primary sclerosing cholangitis; and 11 patients with Sjogren's syndrome. Patients with autoimmune pancreatitis had serum IgG4 levels that were significantly higher than those found in the normal subjects (P < .001) and in subjects with the other diseases. Using a cut-off of 135 mg/dL, the sensitivity and specificity of serum IgG4 for distinguishing autoimmune pancreatitis from pancreatic cancer were 95% and 97%, respectively.
    Our patient had a markedly elevated serum IgG4 level of 988 mg/dL (normal range, 7-89 mg/dL). His total serum IgG was elevated (2230 mg/dL) almost entirely due to the IgG4 component. Taken together with the other clinical findings, these values secure the diagnosis of autoimmune pancreatitis.
Management Question
The reason for adding the prompts to your diagnostic algorithms, as discussed in the previous section, is because this patient's disease is well known to respond to specific therapy.
  • 4. 
    What therapy may cure this patient's pancreatic, biliary, and salivary disease?
    The satisfaction of correctly diagnosing autoimmune pancreatitis lies in its dramatic response to corticosteroids. – which is in contrast to the poor options in medical management available for other forms of chronic pancreatitis, primary sclerosing cholangitis, and pancreatic cancer. Clinical, biochemical, and radiographic improvement are all seen within 2-4 weeks of beginning corticosteroid therapy. The usual dosage is 30-40 mg/day of prednisone for 1-2 months, followed by tapering by 5 mg every 1-2 weeks. A maintenance dose of 5-10 mg may be needed to prevent relapse.[1] Radiographic indicators of response include a reduction in pancreatic size, loss of the hypoenhancing rim, and normalization of the pancreatic duct.[1] Reduction in serum IgG4 levels in response to steroid therapy also correlates well with clinical and radiographic resolution.[5] If improvement is not evident within 2-4 weeks of steroid treatment, the diagnosis of autoimmune pancreatitis should be questioned, and exploratory laparotomy should be considered.[1]
    The long-term prognosis of autoimmune pancreatitis is not well defined. There is some evidence that the rate of relapse is very low, based on a mean of 56 months of follow-up.[1]
Clinical Course and Outcome
Our patient was started on 30 mg/day of prednisone and within 2-3 weeks had resolution of his abdominal pain and reduction of his submandibular gland swellings. Repeat MRI of his abdomen 6 weeks after initiation of steroid therapy showed a reduction in the size of the pancreas and a decrease in biliary ductal dilatation (Figures 14Figure 14 and and1515Figure 15).
Figure 14
Figure 14
Figure 14
Figure 15
Figure 15
Figure 15
Discussion
Autoimmune chronic pancreatitis is an increasingly recognized cause of pancreatitis. The history of autoimmune pancreatitis is well summarized in a recent review article.[1] Pancreatitis associated with hypergammaglobulinemia and not associated with alcohol consumption was first described by Sarles and colleagues in 1961. The term “autoimmune pancreatitis” was first coined by Yoshida and colleagues in 1995. Most of the literature on this disease has come from Japan, although this may represent a geographic difference in recognition rather than in prevalence.[1]
Our patient's clinical manifestations were quite consistent with those described in the literature. Most reported patients have been male. In the 17 Korean patients, the male:female ratio was 15:2.[4] The clinical manifestations are variable and reflect the anatomic targets of involvement, including the pancreatic parenchyma and duct, biliary duct, and extrapancreatic tissues. Most patients do not manifest recurrent acute pancreatitis. In addition, they have normal or only mildly elevated amylase and lipase levels.[4] The presence of a positive antinuclear antibody is widely variable, and ranges from 11% to 83%.[1] The key diagnostic test is the serum IgG4 level. A good case could be made for ordering this test in all of the following clinical situations: unusual CT and MRI appearance of the pancreas; suspected pancreatic cancer; chronic pancreatitis; or benign biliary strictures. On the basis of the pancreatic pathology, the disease is sometimes called lymphoplasmacytic pancreatitis. However, clinicians should be able to diagnose and treat this condition without biopsy. The dramatic response to corticosteroid therapy, as was seen in our patient, emphasizes the importance of proper and early diagnosis.
Contributor Information
Venu Julapalli, Baylor College of Medicine, Houston, Texas;
Daniel Ball, Baylor College of Medicine, Houston, Texas;
Ravi Shivshankar, Baylor College of Medicine, Houston, Texas;
References
1. Kim KP, Kim MH, Song MH, Lee SS, Seo DW, Lee SK. Autoimmune chronic pancreatitis. Am J Gastroenterol. 2004;99:1605–1616. [PubMed]
2. Irie H, Honda H, Baba S, Kuroiwa T, et al. Autoimmune pancreatitis: CT and MR characteristics. AJR Am J Roentgenol. 1998;170:1323–1327. [PubMed]
3. Tabata M, Kitayama J, Kanemoto H, Fukasawa T, Goto H, Taniwaka K. Autoimmune pancreatitis presenting as a mass in the head of the pancreas: a diagnosis to differentiate from cancer. Am Surg. 2003;69:363–366. [PubMed]
4. Kim MH, Kim KP, Lee YJ, et al. 17 Cases of autoimmune chronic pancreatitis. Korean J Intern Med. 2003;65:S94.
5. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–738. [PubMed]
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