What is the appropriate investigation and differential diagnosis for an 85-year-old lady with a history of Chronic Obstructive Pulmonary Disease (COPD) and Rheumatoid Arthritis (RA) on Methotrexate, presenting with recurrent left upper quadrant pain, nausea, and mild elevation of Alanine Transaminase (ALT), raised Alkaline Phosphatase (ALP), and elevated C-Reactive Protein (CRP), despite treatment with Famotidine and Cyclizine?

From the Guidelines

For an 85-year-old lady with persistent left upper quadrant pain, nausea, elevated inflammatory markers, and declining functional status, I recommend urgent comprehensive investigation starting with abdominal imaging, given the mild elevation of ALT and raised ALP, which may indicate liver or biliary pathology, as suggested by the multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders 1. The patient's symptoms and laboratory results, including a CRP of 200, indicate a potential inflammatory or infectious process that requires prompt evaluation.

• The differential diagnosis includes splenic pathology (infarct, abscess), gastritis/peptic ulcer disease (possibly related to methotrexate use), pancreatic disease (pancreatitis, malignancy), left colonic pathology (diverticulitis, malignancy), and less commonly, left-sided pyelonephritis or renal pathology.
• Given her immunosuppression from methotrexate and age, infection or malignancy must be considered, and the experts emphasised considering other causal factors, including non-steroidal anti-inflammatory drugs, obesity, and alcohol, as noted in the study 1. Order an abdominal CT scan with contrast (if renal function permits) to evaluate for potential splenic, gastric, pancreatic, or colonic pathology.
• Additionally, arrange an upper GI endoscopy to assess for gastritis, ulceration, or malignancy that may be causing her symptoms despite famotidine use. Further investigations should include a complete blood count, comprehensive metabolic panel, amylase/lipase, urinalysis, and blood cultures if febrile.
• Consider temporarily holding methotrexate until diagnosis is established, as it may contribute to GI symptoms or mask infection, according to the recommendation to stop methotrexate if there is a confirmed increase in ALT/AST greater than three times the upper limit of normal (ULN) 1. For symptom management while investigating, consider ondansetron 4mg every 8 hours for nausea as an alternative to cyclizine, and acetaminophen 500mg every 6 hours for pain.
• The elevated CRP of 200 suggests an inflammatory or infectious process requiring prompt evaluation, and her deteriorating condition warrants expedited investigation. Nutritional assessment and support are crucial given her declining oral intake and functional status.

From the FDA Drug Label

Methotrexate causes hepatotoxicity, fibrosis and cirrhosis, but generally only after prolonged use. Acutely, liver enzyme elevations are frequently seen. These are usually transient and asymptomatic, and also do not appear predictive of subsequent hepatic disease Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in the rheumatoid arthritis population.

The patient's mild elevation of ALT and raised ALP, along with the clinical presentation of left upper quadrant pain and nausea, may suggest hepatotoxicity related to methotrexate use 2.

• Differential diagnoses may include:
  • Methotrexate-induced hepatotoxicity
  • Other causes of liver enzyme elevation (e.g. viral hepatitis, autoimmune hepatitis)
  • Gastrointestinal disorders (e.g. peptic ulcer disease, gastroesophageal reflux disease)
• Investigation should include:
  • Liver function tests (LFTs) to monitor for persistent abnormalities
  • Imaging studies (e.g. ultrasound, CT scan) to evaluate for liver disease or other abdominal pathology
  • Consideration of methotrexate dose reduction or discontinuation if hepatotoxicity is suspected 2
• Next steps:
  • Closely monitor the patient's LFTs and clinical symptoms
  • Consider consulting a gastroenterologist or hepatologist for further evaluation and management
  • Evaluate the need for alternative treatments for rheumatoid arthritis if methotrexate is discontinued 2

From the Research

Patient Presentation and Initial Assessment

The patient is an 85-year-old lady with a history of COPD and rheumatoid arthritis, presenting with recurrent left upper quadrant (LUQ) pain and nausea for 2 months. She has been taking methotrexate for her rheumatoid arthritis. Initial treatment with famotidine and cyclizine has not provided relief, and she is intolerant to proton pump inhibitors (PPIs) due to side effects.

Laboratory and Physical Examination Findings

Blood tests indicate mild elevation of alanine transaminase (ALT), raised alkaline phosphatase, and a C-reactive protein (CRP) level of 200. Physical examination reveals a soft abdomen with no masses, but mild tenderness to palpation in the LUQ.

Differential Diagnoses

Based on the patient's presentation and laboratory findings, potential differential diagnoses include:

• Gastrointestinal disorders (e.g., peptic ulcer disease, gastroesophageal reflux disease)
• Hepatobiliary disorders (e.g., cholecystitis, hepatitis)
• Pancreatic disorders (e.g., pancreatitis)
• Renal disorders (e.g., pyelonephritis, nephrolithiasis)
• Musculoskeletal disorders (e.g., costochondritis, rib fracture)

Investigation and Management

To further investigate the patient's condition, the following steps can be taken:

• Imaging studies: Consider abdominal ultrasound, computed tomography (CT) scan, or magnetic resonance imaging (MRI) to evaluate the liver, pancreas, kidneys, and gastrointestinal tract 3.
• Laboratory tests: Repeat blood tests to monitor liver function, inflammatory markers, and other relevant parameters.
• Physical examination: Continue to monitor the patient's abdominal tenderness and other physical examination findings.
• Medical history: Take a comprehensive patient history to identify any potential underlying causes of the patient's symptoms 4.

Role of Imaging Studies

Imaging studies can play a crucial role in diagnosing and managing abdominal disorders. Abdominal ultrasound, CT scan, and MRI can help identify liver, pancreatic, and renal disorders, as well as gastrointestinal disorders 3, 5. The choice of imaging study depends on the suspected diagnosis and the patient's clinical presentation.

Use of CRP Levels

CRP levels can be useful in predicting the presence of postoperative complications after major abdominal surgery 6. In this patient, the elevated CRP level may indicate an underlying inflammatory process. Combining CRP levels with abdominal CT scans can help predict the macroscopic appearance of encapsulating peritoneal sclerosis (EPS) patients prior to surgery 7.