Searching for the leak
Authors: Daniel Shepshelovich, Talia Diker‐Cohen, Meir Lahav
Journal: American Journal of Hematology (2014)

A 60-year-old woman was admitted for evaluation of a two day history of afebrile watery diarrhea, nausea, vomiting, and diffuse abdominal pain. She had not eaten outside her home, has not traveled recently and has not been exposed to animals. No one in her vicinity had similar symptoms. Although the differential diagnosis for abdominal pain, diarrhea, and vomiting is broad, I would first consider infectious gastroenteritis, the most common cause of acute diarrhea. A targeted medical history for recent travel, antibiotic treatment, similar symptoms in relatives or coworkers and eating out may offer diagnostic clues. Noninfectious causes of acute diarrhea in a 60-year-old patient include medications' side effects, ischemic colitis, and diverticulitis. Conditions causing chronic diarrhea might be confused with acute diarrhea early in their course. The patient's past medical history was significant for untreated stage II chronic lymphocytic leukemia (CLL) known for 3 years, with splenomegaly, stable lymphocytosis, and otherwise normal blood counts. She also had essential hypertension and hypertriglyceridemia. Her medications were ramipril, disothiazide, bezafibrate, and aspirin. Diarrhea in patients with CLL can have many etiologies. Acute diarrhea is commonly infectious and unrelated to CLL, with most pathogens being viruses (e.g., adenovirus, rotavirus, and Norwalk virus) or various bacteria (e.g., Escherichia coli, Clostridium difficile, Campylobacter jejuni, Salmonella, and Shigella spp.). Opportunistic pathogens (e.g., microsporidia and cryptosporidium) are more common after treatment with immunomodulating drugs (e.g., fludarabine). Noninfectious causes include chemotherapy-related diarrhea, which can be life threatening. CLL itself might rarely cause diarrhea through direct bowel involvement. On physical examination, the blood pressure was 90/55 mmHg, pulse 60 beats/min, temperature 35°C and respiratory rate 18. There was diffuse abdominal tenderness but no peritoneal irritation; the liver span was 12 cm in the midclavicular line; the spleen was palpated 4 cm below the rib line. Labs showed a white-cell count of 14,000 mm−3 (68% lymphocytes), hematocrit level at 37.5%, and platelet count at 120 mm−3. The serum sodium level was 133 mmol/l, potassium 4.3 mmol/l, urea 52 mg/dl, and creatinine 1.68 mg/dl (the patient's baseline creatinine level was 0.87 mg/dl). Arterial blood gas results were normal. The approach to a patient with acute diarrhea depends on its severity and the patient's comorbidities. This patient's hypotension and acute renal failure warrant further workup. Leukocytosis and thrombocytopenia could indicate severe infection, but could also be CLL-related. I would start with intravenous infusion of isotonic saline, order blood and stool cultures and proceed with hemodynamic and laboratory monitoring while rehydrating the patient. The patient received aggressive hydration therapy and was treated empirically with intravenous ciprofloxacin and metronidazole for a presumed intra-abdominal major infection. A computed tomography (CT) scan performed to rule out surgical conditions causing the profound abdominal tenderness showed no inflammatory focus. However, the scan demonstrated splenomegaly, a small-to-moderate amount of ascites and edema of the terminal ileum. Following hydration, the patients' condition rapidly improved. The diarrhea and abdominal pain subsided within 24 hr, and the blood pressure and renal function normalized. Blood and stool cultures were negative and the antibiotic treatment was stopped. The patient was discharged in good condition. The findings of ascites and edema of the terminal ileum are unusual for simple gastroenteritis. The rapid response to fluid administration and antibiotics is also unexpected for a severe gastrointestinal infection. Addisonian crisis could present with hypotension, diarrhea, and ascites. CLL itself could cause ascites, terminal ileitis, and diarrhea through direct bowel involvement. This patient's splenomegaly could suggest liver cirrhosis as a cause of ascites, although probably a manifestation of her CLL. Uncommon causes of diarrhea, ascites and terminal ileitis include yersinia and tuberculosis infections, Crohn's disease, eosinophilic gastroenteritis, and systemic mastocytosis. Three days after recovery, the patient was readmitted for recurrence of afebrile diarrhea, nausea, vomiting, abdominal pain, and hypotension. Physical examination again showed diffuse abdominal tenderness with no peritoneal irritation, splenomegaly, and shifting dullness. Laboratory results demonstrated leukocytosis, lymphocytosis, and increased levels of urea and creatinine. Electrolytes were normal. Abdominal ultrasound revealed fatty liver, splenomegaly, and mild ascites. Blood and stool cultures were negative, as was a test for Clostridium difficile toxin. The patient was treated with saline and ciprofloxacin with rapid clinical recovery and resolution of renal failure. She was discharged feeling well, without pain or diarrhea. Recurrence of hypotension and acute renal failure after complete resolution of infectious gastroenteritis is uncommon. A different diagnosis should be pursued as the events recur and cause hemodynamic instability. I would order an adrenocorticotropic hormone stimulation test to rule out adrenal insufficiency and blood levels of tryptase to test for mastocytosis, tap the ascites for albumin level, complete blood count, culture and cytology, and consider a colonoscopy with biopsy of the terminal ileum. Two days after the second discharge, the patient was readmitted for similar symptoms. CT scan findings were consistent with persistence of ascites and edematous small bowel loops. Colonoscopy and gastroscopy were unremarkable as was upper gastrointestinal and small bowel series. Recurrent hypotension, ascites and edematous bowel loops could all be caused by episodes of increased vascular permeability. Severe infection could be the etiology of such findings, but not of recurrent events. Moreover, in this patient blood and stool cultures were repeatedly negative. Nephrotic syndrome and protein loosing enteropathy, common causes of edema, are not cyclical and do not cause acute exacerbations. Carcinoid syndrome can cause hypotension but is rarely the cause of severe edema and shock. Detailed history for agents and conditions potentially causing anaphylaxis should be obtained. Acquired angioedema (AAE) and systemic capillary leak syndrome (Clarkson syndrome), both rare entities with somewhat increased prevalence in patients with hematologic malignancies, should be considered. Laboratory evaluation for systemic mastocytosis and carcinoid syndrome were negative. Complement studies showed undetectable levels of C4 at <1.36 mg/dl (reference 10–40) with normal levels of C3 at 117 mg/dl (reference 90–180). C1 esterase inhibitor (C1INH) level was low at 2.8 mg% (reference 15–33). C1q levels were low-normal at 13 mg% (reference 12.6–20.8). Of note, C1q levels were tested when the patient recovered and not during an angioedema episode. Adult new onset angioedema may be IgE-mediated, usually associated with urticaria and allergy-related symptoms. It can also be a side-effect of certain medications, particularly angiotensin converting enzyme (ACE) inhibitors. Angioedema, which is IGE-mediated or ACE inhibitor-induced cannot be diagnosed using complement studies and usually has predilection for the face, mouth, and upper airway. Bowel angioedema, however, is more commonly associated with C1 esterase deficiency. The latter has a hereditary form, which usually presents early in life, whereas the late-onset acquired form is usually malignancy-related, most commonly secondary to B cell lymphoproliferative disorders. Low C4 and C1 inhibitor levels support a diagnosis of C1 esterase deficiency. Given this patient's age at presentation, the lack of family history of angioedema, the underlying lymphoproliferative disease, and the complement studies results, it is reasonable to conclude that the patient has AAE, which is probably related to CLL. Ramipril was stopped, the patient responded to aggressive hydration therapy and her symptoms resolved. Rituximab monotherapy was initiated, four doses of 375 mg/m2 given at 1 week intervals. Acute therapy can include the administration of fresh frozen plasma or C1 inhibitor replacement. ACE inhibitors should be stopped. Androgens such as danazol and antifibrinolytics such as ε-aminocaproic acid were shown to be beneficial for some patients. Long-term therapy for recurrent episodes should be directed at the underlying lymphoproliferative disease. A year from the original diagnosis the patient had two similar episodes. Laboratory tests showed low levels of C1INH and C4 during each episode. Clinical improvement was achieved after the administration of hydration and anti-emetics. Rituximab monotherapy was readministered and she had no recurrences for 2 years. Then, laboratory follow-up showed a marked reduction in C1INH levels without any symptomatic manifestation. The patient was given rituximab in attempt to prevent another clinical crisis. She remained asymptomatic while levels of C1INH returned to normal. Over the following 5 years, the patient received three courses of "prophylactic" rituximab with normalization of C1INH level and without progressing to symptomatic attacks of angioedema. Abdominal pain and diarrhea are symptoms commonly faced by general practitioners, mostly indicating a transient treatable cause. However, recurrent episodes suggest a systemic disease. Here we present a case of recurrent diarrhea, abdominal pain, and hypotension turned out to result from acquired C1 esterase deficiency. The rare entity of C1 esterase deficiency has a hereditary form and an acquired form. These share the same clinical manifestations, namely recurrent episodes of angioedema of various organs. Patients may present with laryngeal edema, which is a medical emergency; swelling of subcutaneous tissues (e.g., face, extremities, and genitals); or swelling of abdominal organs (e.g., stomach, intestines, and bladder) leading to nausea, vomiting, and/or pain, which might even mimic a surgical emergency of peritonitis 1. Typical episodes last a few days. Although there is interpatient variability, in a given patient the duration, severity, and anatomic distribution of the symptoms are largely uniform 2. The patient presented in this report is a good example, repeatedly experiencing the same clinical symptoms years apart. Hereditary C1 esterase deficiency, also known as hereditary angioedema (HAE), has an autosomal dominant Mendelian mode of inheritance and is usually detected in the first or second decade of life in patients with family history of HAE. Acquired C1 esterase deficiency or AAE is detected in adulthood and there is no family history of the disease. Most data regarding the acquired form of the disease relies on case reports and case series. A recent Danish nationwide study identified only eight patients with AAE, who constituted less than 10% of the C1INH deficiency cohort 3. The diagnostic delay was on average 1 year and 8 months. Similarly, a British study showed an average diagnostic delay of 5 years 4. Many patients with AAE have an underlying lymphoproliferative disorder, ranging from relatively benign causes such as monoclonal B cell lymphocytosis or monoclonal gamopathy of unknown significance to acute B cell leukemia 3, 5, 6. AAE might be the presenting symptom 5. Rarely, nonlymphoproliferative diseases were reported to be associated with AAE, mostly systemic lupus erythematosus, acute hepatitis B infection, and human immunodeficiency virus infection 7, 8. Whereas HAE results from low levels or an abnormal function of the serine protease C1 esterase inhibitor, AAE entails the enhanced catabolism of the C1INH, sometimes associated with C1INH autoantibodies. Regardless of mechanism, the end result in both forms of the disease is an ongoing unopposed activity of the C1INH's substrate, C1, which results in depletion of a downstream target in the complement cascade, C4. Of note, the blood levels of the active form of C1, C1q, are usually normal in HAE but low in AAE. Therefore, in an appropriate clinical context, the laboratory diagnosis of C1 esterase deficiency involves measurement of C1 inhibitor, C1q and C4 levels: low levels of C4 and C1 inhibitor establish the diagnosis of the disease; then, low levels of C1q suggest the diagnosis of AAE, whereas normal levels of C1q generally support the diagnosis of HAE. Complement studies in our patient demonstrated low levels of C4 and C1INH, consistent with the diagnosis of C1 esterase deficiency. The C1 level was low-normal, which might suggest a hereditary form of the disease. However, for technical reasons C1 was tested after successful treatment and resolution of an acute episode, and therefore, might not represent the true level had it been obtained during the presentation of symptomatic angioedema. Moreover, our patient was 60 years old at presentation, had no family history of angioedema and had a diagnosed lymphoproliferative disorder, thus supporting a diagnosis of AAE rather than an unlikely late onset of HAE. In retrospect, recurrent episodes of abdominal pain, nausea, vomiting, diarrhea, and capillary leak syndrome manifested as hypotension and ascites in a patient with a chronic lymphoproliferative disorder have constituted a typical presentation of AAE in our patient. Just like in this case, it is intuitive to ascribe such symptoms on initial presentation to a common diagnosis like acute gastroenteritis. However, as the events recurred, the patients' physicians appropriately looked for a broader differential diagnosis including rare disorders, leading to establishment of a correct diagnosis approximately 1 month after the first presentation. A recent international consensus on angioedema has defined HAE-specific treatments 9. Medications for acute attacks include C1INH concentrates as well as the FDA-approved ecallantide, a kallikrein inhibitor, and icatibant, a selective bradykinin B2 receptor antagonist. If those are unavailable, fresh-frozen plasma can be used. For short-term prophylaxis, C1INH concentrates are preferred. Long-term prophylaxis options include 17α-alkylated androgens and the antifibrinolytics ε-aminocaproic acid and tranexamic acid 9. Treatment for AAE is less established, and can involve the same medications that are used for the hereditary form. Autoantibodies against C1INH might bring about a need for higher doses of C1INH plasma concentrate than in HAE. Although ecallantide and icatibant are not FDA-approved for acute attacks in AAE patients, both drugs have been reported to be efficacious for in this setting 9. AAE patients may be less responsive to androgens and experience more efficiency of antifibrinolytic treatment compared to HAE patients 7. Most importantly, when possible, the underlying disorder should be treated. Resolution of angioedema has been reported with the treatment of underlying disease, although recurrences have occurred despite appropriate treatment 9. Several studies have documented effective treatment of AAE patients with rituximab, a chimeric monoclonal antibody against CD20, regardless of a diagnosis of a lymphoproliferative disorder 6. Early publications reported that rituximab treatment resulted in normalization of C1INH and C4 levels and in long-term remission of angioedema attacks in several patients with severe AAE 10-12. However, the largest reported series to date of seven AAE patients who were treated with rituximab demonstrated inconclusive results: three complete remissions, two partial remissions, and two treatment failures 6. A recent article reported the efficacy of maintenance therapy with a different anti-CD20 monoclonal antibody, ofatumumab, in preventing recurrent episodes of angioedema in a patient with CLL 13, raising the possibility of potential efficacy of ofatumumab in patients that are refractory to rituximab. As AAE remains a rare disorder, there is paucity of evidence to guide patient management. Rituximab seems to be a promising prophylactic treatment for AAE in patients with lymphoproliferative disorders. However, rituximab can cause both acute reactions and late adverse effects 14 and there can be a high overall cost for such a lifelong maintenance treatment. We felt that considering our patient's relatively young age and given that her CLL per se did not necessitate treatment, lifelong rituximab maintenance was not appropriate. Therefore, we chose to follow C1INH as a marker for disease activity and to treat the patient whenever C1INH levels decreased, in attempt to prevent acute, potentially life-threatening, exacerbations of angioedema. Using this strategy has enabled us to expose our patient to considerably less doses of rituximab while keeping her asymptomatic (Fig. 1). To the best of our knowledge, this is the first report of prophylactic rituximab treatment of AAE guided by C1INH levels. Course of C1 inhibitor concentration (mg%) related to rituximab administration over a 6-year period.