16 November 2023

An international study led by research group leaders Mirjam Christ-Crain and Julie Refardt shows which test leads to a reliable diagnosis when drinking by the liter becomes a medical issue.

One symptom, two disease patterns

Excessive fluid intake can be a medically harmless habit, but it can also indicate a rare hormonal disorder. Drinking more than three liters per day with a corresponding increase in urine excretion is considered too much. This drinking by the litre is called "polydipsia-polyuria syndrome" and is usually developed over time through habit or is a concomitant of a mental illness.

In rare cases, however, the cause may be a deficit of arginine vasopressin (AVP). AVP is a hormone produced in the pituitary gland that controls water and salt balance. Individuals with AVP deficiency cannot concentrate urine and therefore lose large amounts of fluid. Accordingly, they feel a strong sense of thirst and must drink a lot to avoid dehydration.

Wrong diagnosis can be fatal

The distinction between a "harmless" form of frequent drinking and an AVP deficiency is extremely important, as the therapy is fundamentally different. AVP deficiency is treated with substitution of AVP while people with primary polydipsia are offerd behavioral therapy with the aim of slowly reducing the amount they fluid intake. Incorrect treatment can have life-threatening consequences, as inappropriate therapy with AVP can lead to water intoxication.

In recent years, the two research group leaders Mirjam Christ-Crain and Julie Refardt together with several national and international study groups have worked intensively on test methods to distinguish between these two disease patterns. A test in which AVP release is stimulated by means of a salt infusion has shown very high reliability. However, because of the strong salt increase, constant monitoring of treated patients and half-hourly salt measurements in the blood are necessary. A subsequently much simplified and more tolerable test using arginine infusion also showed very high reliability in diagnosis. Arginine, a conditionally essential amino acid, also stimulates the release of AVP.

Clarity in diagnosis

The international study now available directly compared the two tests. The results on 158 participants show that saline infusion correctly diagnosed more than 95% of patients. The test using arginine infusion led to the correct diagnosis in just under 75% of cases. Thus, the researchers recommend the test with saline infusion as the "gold standard" for a reliable differentiation between polydipsia and AVP deficiency.

Polydipsia Vasopressin deficit
CARGOx trial
Stimulation of copeptin with arginine or hypertonic saline for diagnosis of arginine vasopressin deficiency

ClinicalTrials.gov NCT03572166

Principle Investigators 
rof. Mirjam Christ-Crain, PD Dr. med. Julie Refardt, Endocrinology, Diabetes and Metabolism, University Hospital Basel

Study design
International, multicenter, randomised, crossover, noniferiority trial

Study sites
7 centers in Switzerland, The Netherlands, Germany, Italy, United Kingdom, Brazil


Project duration

DKF Scientific Services
Methodological consulting, statistics, data management, monitoring

Read original publication
Arginine or Hypertonic Saline–Stimulated Copeptin to Diagnose AVP Deficiency, Julie Refardt, M.D., Ph.D., et al., November 16, 2023, N Engl J Med 2023; 389:1877-1887, DOI: 10.1056/NEJMoa2306263