Ep 168: A 52-Year-Old with Abdominal Pain and an Elevated Lipase

[MUSIC] >> This is Katarina Heithausen, Executive Editor of Harrison's Principles of Internal Medicine. Harrison's podcast is brought to you by McGraw-Hill's Access Medicine, the online medical resource that delivers the latest content from the best minds in medicine. Now, onto the episode. [MUSIC] >> Hi, everyone. Welcome back to Harrison's podcast. We're your co-hosts. I'm Dr. Kathy Handy. >> I'm Dr. Charlie Weiner, and we're joining you from the Johns Hopkins School of Medicine. >> Welcome to Harrison's podcast. Today's episode is a 52-year-old with abdominal pain and an elevated lipase. >> Kathy, today's patient is a 52-year-old man who's admitted to the hospital with three days of severe mid-abdominal epigastric pain and an elevated lipase. >> Right off the bat, sounds like he may have pancreatitis, but tell me more. >> So this is his second episode of presumed acute pancreatitis in the last six months. During the last hospital admission, no source was found and he was told he may have passed the gallstone. He was treated with fluids and discharged after five days. Since then, he's had mild to moderate chronic pain and has been avoiding fatty foods. This acute episode started about two days ago and the pain is not relented such that he's not taking any oral intake whatsoever. In the emergency department, his abdomen is diffusely tender with diminished bowel sounds. His vital signs are only notable for sinus tachycardia, but he does have postural hypotension and appears volume depleted. >> All right. We're going to admit him, start some IV fluids and we'll get some more studies. First, any additional history and in particular, any alcohol or gallstones? >> Okay. I see you're thinking about the risk factors for pancreatitis. Well, first off, he does not smoke or use alcohol. He does have a 15-year history of atopic rhinitis with nasal polyps and asthma that has been treated with topical steroids and a bronchodilator. Over the past three months, he's been noted to have a rising hemoglobin A1C, but he's never been treated for diabetes. On his last hospital admission, he had a right upper quadrant ultrasound that showed some gallbladder wall thickening but no gallstones or cholecystitis was demonstrated. He did not have additional pancreatic imaging at that time. >> Okay. Sounds like he may be developing chronic pancreatitis. Let's get some labs and imaging of his abdomen. >> His labs are notable for an elevated white cell count, elevated bilirubin, elevated alkaline phosphatase, but a normal liver synthetic function. Abdominal CT shows a diffusely enlarged or sausage-shaped pancreas with loss of the normal lobularity and signs of ductal obstruction. >> The question asks. >> The question is asking, which of the following tests is most likely to provide a diagnosis in this patient? Option A is CA 19-9. Option B is carcinohembryonic antigen or CEA. Option C is genetic testing for a CFTR mutation. Option D is IgG4 levels, and option E is sweat chloride. >> Okay. I know where you're going with this, but first, in a patient with obstructive jaundice and anatomic abnormalities, you do have to think hard about pancreatic cancer. The earlier you can diagnose pancreatic cancer, the more likely you can offer a curative surgery. CA 19-9 and CEA are both tumor markers that may be elevated in pancreatic cancer, but are neither specific nor sensitive. They should not be used for screening, but may have utility in specific patients and follow-up. >> Okay. Neither of those is the answer. What do you think is going on? >> I think this patient has autoimmune pancreatitis due to IgG4-related disease. The answer to this question is D, check IgG4 levels. >> What led you there? >> His history of atopy, nasal polyps, and asthma is classic. Plus, it would explain his prior episode of acute pancreatitis, and now his impending glucose intolerance or diabetes. It can mimic pancreatic carcinoma. Many patients have received the diagnosis after resective whoopal surgery. >> Tell me more about IgG4-related disease. >> Okay. IgG4-related disease is a fibro-inflammatory condition characterized by a tendency to form tumor-active or tumor-like lesions. IgG4-related disease can affect virtually any organ system. Commonly affected organs are the pancreas, biliary tree, major salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, and the retroperitoneum. The pathologic findings are consistent across all of the affected organs. >> What do you see at pathology? >> Path shows lymphoplasmicidic infiltrates with a high percentage of IgG4-positive plasma cells. Biopsy is not required in order to establish a diagnosis in classic cases, but most patients do undergo a biopsy at some point in the evaluation in order to exclude malignancy. The earliest reported manifestation of IgG4-related disease was autoimmune pancreatitis. Now it's clear it's a multi-organ disease. >> What is thought to be the pathogenesis of this disease? >> Well, first, it's typically a disease of middle-aged men like our patient. In contrast to most presumed autoimmune diseases, it is not more prevalent in women. The pathogenesis has not fully worked out. Despite the emphasis of IgG4 in the name, the IgG4 molecule is not believed to play a direct role in the pathophysiology of the disease within most organs. There is a thought that the role of IgG4 in this disease is actually a counter-regulatory mechanism rather than part of the primary inflammatory process. So in that case, what's thought to be driving the response? >> Again, not clear, but next-generation sequencing studies of CD4-positive T-cells have demonstrated a unique CD4-positive cytotoxic T-cell. This cell, also found in abundance at tissue sites of disease, makes interferon gamma, TGF-beta, and interleukin 1, all of which may contribute to the characteristic fibrosis found in this condition. The pronounced oligoclonal expansion of the CD4-positive cytotoxic T-cell at tissue sites suggests that this cell is a major disease driver. We don't know what may turn on this response. >> So stay tuned. How about the typical clinical presentation? You already mentioned pancreatitis. >> IgG4-related disease usually presents subacutely, even in the setting of multi-organ disease. Most patients do not have fevers or high elevations of C-reactive protein levels. Patients may present with pancreatic exocrine or endocrine failure. There can be some symptoms seen more commonly, like lymphadenopathy, tubulointestinal nephritis, and epatobiliary disease. And some that are a little bit less common, like aorticitis and retroperitoneal fibrosis. As I mentioned before, many patients with IgG4-related disease have allergic features, such as atopy, eczema, asthma, nasal polyps, sinusitis, and even sometimes a modest peripheral eosinophilia. IgG4-related disease also appears to account for a significant proportion of tumorous swellings, or pseudo-tumors, in many organ systems. >> What's the typical time course of this IgG4-related disease? >> Clinically apparent disease can evolve over months, years, or even decades before the manifestations within a given organ become sufficiently severe to bring the patient to medical attention. >> This really is one of those diseases that you'll never diagnose unless you actually know about it and then think about it. >> And that's why we're talking about it today. >> How do you diagnose it once you're suspicious? >> The majority of patients with IgG4-related disease have elevated IgG4 concentrations. However, the range of elevation varies widely. Serum concentrations of IgG4 as high as 30 or 40 times the upper limit of normal sometimes occur. Usually that's in patients with disease that affects multiple organ systems simultaneously. Approximately 30% of patients have normal serum IgG4 concentrations despite classic histopathologic and immunohistochemical findings. Such patients tend to have disease that affects fewer organs. Often the diagnosis is made from a typical clinical picture or from a biopsy to rule out malignancy. >> How do we treat IgG4-related disease? >> Treatment should be individualized based on how aggressive the disease is in that patient and if there's impending organ failure. Glucocorticoids are the first line of therapy based on experience with autoimmune pancreatitis. Although the clinical response to glucocorticoids is usually swift and striking, prolonged steroid free remissions are uncommon and the risk of steroid induced morbidity in this middle age to elderly patient population is high, particularly in those with baseline comorbidities and pancreatic involvement by the disease. Few data exist to support the utility of conventional steroids bearing agents in this disease. >> And then what do you do for patients who are either relapsing or have glucocorticoid resistant disease? >> For those patients, B cell depletion with rotuximab is an excellent second line therapy. The good news is that the rapidly evolving understanding of the pathophysiology suggests several novel targeted approaches to treating the disease, such as tyrosine kinase inhibitors or targeting B lymphocytes and the CD4 positive cytotoxic T cell. >> Again, more to come. Okay, let's close by saying something about the two other incorrect options, sweat chloride testing or genetic analysis for CFTR mutations. >> Those are both looking for cystic fibrosis, which may also present with chronic pancreatic insufficiency, but it's not the case in our patient. >> Yeah, so that was worth thinking about, at least. So the teaching points in today's case are that IgG4-related disease is a protean autoimmune disease which may present with pseudotumors, particularly in middle-aged men. It is often diagnosed in the evaluation of a patient with a suspected malignancy. Finding it is actually good news because it is treatable with corticosteroids or other immune modulators. >> You can find this question and other questions like it in the Harrison Self Review Book and you can read more about the topic in the Harrison's chapter on IgG4-related disease. Visit the show notes for links to helpful resources, including related chapters and review questions from Harrison's, available exclusively on Access Medicine. If you enjoyed this episode, please leave us a review so we can reach more listeners just like you. Thanks so much for listening. [BLANK_AUDIO]