Acute Acalculous Cholecystitis in a Multiple Sclerosis Patient Treated with Natalizumab
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.314544
Source of Support: None, Conflict of Interest: None
Keywords: Acalculous cholecystitis, immunosuppression, multiple sclerosis, natalizumab, parvovirus B19Key Message: Disease-modifying drugs in Multiple Sclerosis have changed the course of the disease. However, they are not free of risks, and several adverse effects are described. Acalculous cholecystitis had been related before with Alemtuzumab, but not with Natalizumab. A proper follow-up of patients taking this type of drugs is critical to avoid unexpected events, some of them due to infections.
Acute acalculous cholecystitis (AAC) is an inflammatory disease of the gallbladder in the absence of cholelithiasis. It accounts for around 10% of acute cholecystitis cases. A multifactorial pathogenesis is suspected, including biliary stasis, increased viscosity, and gall bladder ischemia. Mortality rates are high, particularly in the elderly and critically-ill patients. Infections and immunosuppression predict a poor outcome. Diagnosis relies on high clinical suspicion and imaging due to its nonspecific presentation and lack of definitive laboratory tests.
Natalizumab is a humanized monoclonal antibody used in Multiple Sclerosis (MS). It binds to α4b-1 integrin sites, blocking leukocyte adhesion to the vascular endothelium and limiting immune cells' access to the central nervous system. Its use is associated with an increased risk of opportunistic infections. Progressive Multifocal Leukoencephalopathy is amongst its most feared complications.
We report a 37-year-old woman admitted to our clinic with a history of abdominal pain, dyspnea, facial and leg swelling, and 10-Kg weight gain over 3 weeks. She was diagnosed with RR-MS 9 years ago. For the last six years, she is being treated with intravenous Natalizumab 300 mg every 4 weeks. Previous treatment included Interferon beta 1b.
She first presented to the Emergency Room with malaise, mild fever, joint pain, and a self-limited bright red rash on her trunk. By that time, there was an outbreak of B19V infection at her son's primary school, so serologic tests were conducted. IgM and IgG antibodies tests were positive. She was started on Acetaminophen 1 g every 8 h and discharged. She consulted again 2 weeks later due to worsening of symptoms, diarrhea, and abdominal pain on the right upper quadrant. General condition improved after treatment with Dipyrone 575 mg every 8 h and a short course of prednisone and was again discharged. The following days she received a new Natalizumab cycle (63rd cycle). After a total of 3 weeks with symptoms, she was eventually admitted to our clinic.
Physical examination on admission showed mucocutaneous pallor, edema, and intense right hypochondrial pain on palpation. Blood tests revealed normocytic anemia: red cell count 2.75 x 106/μL (3.90-5.20 x 106/μL), hemoglobin 8.7 g/dL (12.0-16.5 g/dL), hematocrit 24.1% (36.0-46.0%), MCV 87.7 fL (80.0-100.0 fL), MCH 31.5pg (26.0-34.0 pg), with normal leukocyte and platelet counts. Mild acute kidney injury with creatine 1.08 mg/dL (0.51-0.95 mg/dL), and lightly increased ALT with no other signs of impaired hepatic function: AST 26 U/L (0-35 U/L), ALT 46 U/L (0-35 U/L), GGT 32 U/L (0-38 U/L), FA 62 U/L (30-120 U/L), with a high sensitivity C reactive protein of 2.78 mg/dL (0.0-0.5 mg/dL). Patient tested negative for JC-virus, human immunodeficiency virus (VIH), Cytomegalovirus (CMV), Epstein-Barr (EBV) and Hepatitis A, B and C (HAV, HBV, HCV).
Due to the patient's worsening condition, a red blood cell transfusion and an urgent endoscopy were performed. No signs of active or recent bleeding were found. Chest radiography showed bilateral pleural effusion. Abdominal echography revealed a distended gallbladder and a thickened wall, with no signs of sludge nor gallstones. These findings were compatible with AAC [Figure 1].
A laparoscopic cholecystectomy was performed on the fourth day of hospitalization due to severe uncontrolled abdominal pain. The pathology report confirmed the diagnosis of cholecystitis. Unfortunately, tissue processing and technical limitations prevented the sample from being tested for viral infection. The patient showed significant improvement of her health condition over the following days. She was discharged on day twelve, and a new cycle of Natalizumab was scheduled for the next month.
Parvovirus B19 is a common pathogen in school-aged children. Its classical manifestation is erythema infectiosum, though it can also present with a flu-like syndrome in adults. Red cell-aplasia has been documented in immunocompromised hosts.
Barring immunosuppressive therapy, our patient lacked conventional risk factors for AAC, such as prolonged fasting, diabetes, atherosclerotic disease, trauma, recent surgery, sepsis, or other critical illnesses. This is why the authors believe B19V infection played a big role in this case. Cases of AAC associated with other viruses like HAV, HBV, EBV, CMV, or Flavivirus, have also been reported.,
In certain cases, an early cholecystostomy gives time to stabilize the patient's condition and later proceed to elective surgery. In our case, the patient's condition rapidly improved after laparoscopic cholecystectomy. Immunoglobin therapy, a targeted treatment for B19V, was not used in our case.
Alemtuzumab-related cases of AAC have been reported in MS patients, but to date, none has been linked with Natalizumab. Considering the highly variable interval between drug administration and the development of symptoms, two different mechanisms have been suggested. In those with very short latency, an infusion-associated reaction might be the cause. Nevertheless, in those who suffer a delayed AAC, an opportunistic infection due to immunosuppression is the prime suspect. The latter would be in line with in our case, given the long-term treatment with Natalizumab.
No Natalizumab-related AAC cases have been reported since its commercialization in 2004. The possibility of AAC under Natalizumab therapy is an important issue to consider, given the complications it may cause.
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