Differential Diagnosis for 1 Month of Persistent Vomiting
For a patient with 1 month of persistent vomiting, the differential diagnosis must systematically address gastrointestinal motility disorders, disorders of gut-brain interaction (DGBI), medication-induced causes (especially opioids and cannabis), metabolic/endocrine disorders, malignancy-related obstruction, and psychiatric conditions including eating disorders. 1, 2
Primary Diagnostic Categories
Gastrointestinal Motility Disorders and DGBI
Cyclic Vomiting Syndrome (CVS) should be considered if the patient has experienced at least 3 discrete episodes in the past year (with 2 in the prior 6 months), each lasting less than 7 days, separated by at least 1 week of complete wellness. 1, 3 Episodes are stereotypical with prodromal symptoms including impending doom, panic, anxiety, or diaphoresis, and personal or family history of migraines strongly supports this diagnosis. 1, 3
Cannabinoid Hyperemesis Syndrome (CHS) is a critical diagnosis requiring prolonged (>1 year) and heavy cannabis use (>4 times weekly, often daily) preceding symptom onset. 1, 4, 3 Key diagnostic features include stereotypical episodic vomiting resembling CVS and compulsive hot-water bathing behavior (reported in 71% of cases). 4 Resolution requires cannabis cessation for at least 6 months or duration equal to 3 typical vomiting cycles. 1, 4
Rumination syndrome, chronic unexplained nausea and vomiting are increasingly recognized differential diagnoses of foregut DGBIs with vomiting-like presentation that should not require parenteral nutrition except in life-threatening malnutrition. 1
Gastroparesis should be evaluated with gastric emptying studies only when specifically suspected, though few CVS patients have delayed emptying and results are uninterpretable during acute episodes or with concurrent cannabis/opiate use. 1, 4
Medication and Substance-Induced Causes
Opioid bowel dysfunction can mimic or exacerbate gastrointestinal dysmotility and invoke opioid-induced nausea and vomiting via multiple peripheral and central mechanisms. 1 At its most extreme, opioid bowel dysfunction may mimic features of chronic intestinal pseudo-obstruction (CIPO). 1 Motility testing and diagnoses should be reserved until controlled opioid withdrawal has been achieved. 1
Other medications including digoxin, phenytoin, carbamazepine, and tricyclic antidepressants should have blood levels checked as potential culprits. 1
Metabolic and Endocrine Disorders
Addison's disease, hypothyroidism, and hepatic porphyria can mimic CVS and should be excluded through targeted testing based on individual patient history. 1, 4
Hypercalcemia is a treatable cause that should be identified. 1
Malignancy-Related Causes
Malignant bowel obstruction is common in advanced cancer, especially ovarian and colorectal cancers. 1 Emergency surgical intervention is not generally necessary but is appropriate in patients with reversible cause, good performance status, and lack of complicating factors; stents are an appropriate alternative in many situations. 1
Gastric outlet obstruction may benefit from treatment with corticosteroids, with alternative options including endoscopic stenting or insertion of a decompressing G-tube. 1
Psychiatric and Eating Disorders
Avoidant/Restrictive Food Intake Disorder (ARFID) has significant overlap/comorbidity with DGBIs. 1 The commonest ARFID presentation in DGBIs associated with malnutrition is fear avoidance of foods due to previous symptom associations. 1 All patients with non-CIPO gastrointestinal neuromuscular disorders or DGBI should be screened for ARFID as well as shape and weight-motivated eating disorders such as anorexia nervosa and bulimia. 1
Hypermobility Disorder/hypermobile Ehlers-Danlos Syndrome (HD/hEDS) is an emerging condition with increasing referrals, strongly associated with functional dyspepsia and irritable bowel syndrome. 1 There is large overlap with fibromyalgia and chronic fatigue/myalgic encephalomyelitis with core features of chronic pain due to peripheral and central sensitization. 1
Essential Diagnostic Workup
Initial Laboratory Testing
- Complete blood count, serum electrolytes and glucose, liver function testing, lipase, and urinalysis 1, 2, 5
- Thyroid-stimulating hormone level 5
- Urine pregnancy testing in women of childbearing age 5
- Targeted testing for Addison's disease, hypothyroidism, and hepatic porphyria when clinically indicated 1, 4
Imaging Studies
- One-time esophagogastroduodenoscopy to exclude obstructive lesions that may account for vomiting 1, 4
- Repeated esophagogastroduodenoscopy or upper gastrointestinal imaging studies should be avoided 1, 4
- If esophagogastroduodenoscopy is performed soon after recent vomiting, recognize epiphenomena (mild gastritis, erythematous streaking, Mallory-Weiss tear, esophagitis) as not being causal 1, 4
- Gastric emptying scans should not be ordered routinely 1, 4
- Brain imaging and neurology referral if any localizing neurologic symptoms are present 1
Critical History Elements
- Cannabis use pattern: duration, frequency (>4 times weekly suggests CHS), temporal relationship to symptom onset, and hot-water bathing behavior 1, 4, 3
- Opioid use: current and recent use, as withdrawal may be necessary before accurate diagnosis 1
- Episode pattern: timing, duration, stereotypical nature, prodromal symptoms, and symptom-free intervals 1, 3
- Triggers: stress, sleep deprivation, fasting, specific foods 1
- Associated symptoms: migraines, anxiety, depression, autonomic dysfunction 1
- Eating patterns: fear avoidance of foods, restrictive diets (gluten-free, low-FODMAP) that may increase ARFID risk 1
Critical Pitfalls to Avoid
Do not dismiss cannabis use: Many patients with CHS remain uncertain about the role of cannabis and attribute symptoms to food, alcohol, stress, or existing GI disorders. 4 However, cannabis use in CVS patients is typically occasional and often postdates the onset of episodic vomiting (making cannabis non-causal). 1, 4
Do not assume hot water bathing equals CHS: This behavior occurs in nearly half of CVS patients without cannabis use. 3
Do not order repeated imaging: Avoid repeated esophagogastroduodenoscopy or upper GI imaging studies that may only show epiphenomena of recent vomiting. 1, 4
Do not routinely order gastric emptying scans: Few CVS patients have delayed emptying, results during episodes are uninterpretable, and cannabis or opiate use complicates interpretation. 1, 4
Do not initiate parenteral nutrition prematurely: In the absence of severe progressive life-threatening malnutrition, parenteral nutrition should be avoided in patients with DGBIs, opioid bowel dysfunction, and eating disorders. 1 Multidisciplinary team biopsychosocial holistic and rehabilitative approaches with persistent dietitian-overviewed oral feeding and/or enteral nutrition should be prioritized. 1
Management Considerations
Prophylactic therapy is indicated for moderate-severe CVS (>4 episodes per year, each lasting >2 days, with emergency department utilization or hospitalizations). 1 Tricyclic antidepressants are strongly recommended as first-line prophylaxis. 1
For nonspecific persistent nausea and vomiting, dopamine receptor antagonists (prochlorperazine, haloperidol, metoclopramide, olanzapine) or benzodiazepines for anxiety-related nausea can be used. 1 For persistent symptoms, titrate dopamine receptor antagonists to maximum benefit and tolerance, adding 5-HT3 receptor antagonists, anticholinergic agents, antihistamines, corticosteroids, antipsychotics, or cannabinoids as needed. 1
Neuromodulators such as mirtazapine can be helpful in increasing food tolerance and body weight in patients with DGBI with significant weight loss. 1
Referral to allied health services including psychology, psychiatry, sleep specialists, and substance use specialists can help address comorbid conditions such as anxiety, depression, migraines, sleep disorders, and substance use that substantially improve symptoms and quality of life. 1