Tiopronin-induced reversible bilateral parotid gland enlargement in a patient with alcoholic cirrhosis

Abstract

Rationale:

Drug-induced parotid gland enlargement is uncommon, and reports associated with tiopronin are extremely rare in both domestic and international literature. The mechanism remains unclear, and its rapid onset may easily lead to misdiagnosis as allergic reactions or other salivary gland diseases. Timely recognition and management are crucial to avoid unnecessary interventions.

Patient concerns:

A 63-year-old man with alcoholic cirrhosis was admitted to our department for further management. Tiopronin was administered intravenously for hepatoprotective purposes. Approximately 20 minutes after the initiation of the infusion, the patient developed painless bilateral parotid gland swelling.

Diagnoses:

Emergency drug withdrawal was carried out immediately, and an ultrasound examination demonstrated bilateral parotid gland enlargement without obvious inflammatory changes or ductal dilation, consistent with acute noninflammatory sialadenosis.

Interventions:

The tiopronin infusion was discontinued promptly. No additional interventions were administered. The patient was monitored closely with serial physical examinations.

Outcomes:

During the evening ward round on the same day, a significant reduction in parotid swelling was observed. Two days later, bilateral parotid gland enlargement had nearly completely resolved without specific treatment.

Lessons:

Tiopronin-induced acute parotid gland enlargement is extremely rare. This case highlights the importance of considering drug-induced sialadenosis as a differential diagnosis when acute parotid swelling occurs shortly after drug administration. Early identification and discontinuation of the suspected agent can lead to rapid resolution, avoiding unnecessary interventions. Clinicians should be aware of this potential reaction and strengthen pharmacovigilance during tiopronin use.

1. Introduction

Tiopronin (N-(2-mercaptopropionyl)-glycine) is a second-generation thiol-binding agent recognized for its antioxidant properties, widely used in various liver diseases, cystinuria, and rheumatoid arthritis,^[1] especially employed for hepatoprotection and anti-fibrosis in patients with chronic liver disease.^[2,3] It is generally well tolerated, but reported adverse effects include dermatologic reactions,^[4,5] oral ulcerations,^[6] myasthenia,^[7] interstitial pneumonia,^[8] minimal change disease,^[9] and hematologic changes.^[10] Drug-induced salivary gland swelling is rare, with documented associations for iodine-containing contrast agents, antihypertensives, antiepileptics, and certain antibiotics.^[11-13] However, there have been almost no case reports of tiopronin causing parotid gland swelling in previous literature.

Considering the complexity associated with comorbid conditions and polypharmacy in patients with cirrhosis, the early identification and documentation of novel adverse drug reactions are critically important. We herein present a case of acute bilateral parotid gland swelling temporally associated with tiopronin therapy in a patient with alcoholic cirrhosis, which resolved swiftly upon drug withdrawal.

2. Case presentation

The patient was a 63-year-old man from Qingdao, China, who was admitted to the gastroenterology ward on August 11, 2025 due to “fatigue accompanied by decreased appetite for over a month, and yellowing of the skin and mucous membranes for over 10 days.” He has a 40-year history of chronic alcohol consumption, averaging 100 to 150 mL of liquor or approximately 1000 mL beer daily. He denied tobacco use. His past medical history was unremarkable for viral hepatitis, autoimmune disease, or metabolic disorders. There was no family history of liver disease or malignancy.

One month prior to admission, the patient began experiencing progressive fatigue, anorexia, and malaise. Ten days before hospitalization, jaundice became apparent, accompanied by dark urine and dyspepsia with intolerance to fatty foods. He reported an unintentional 4 kg weight loss over the preceding month. On admission, vital signs were stable. Physical examination revealed generalized jaundice and scleral icterus, without stigmata of chronic liver disease such as spider angiomas, palmar erythema, or ascites. Abdominal palpation disclosed no hepatosplenomegaly. No lymphadenopathy was detected.

Initial laboratory evaluation showed elevated liver enzymes: aspartate aminotransferase (114.26 U/L), alanine aminotransferase (65.43 U/L), alkaline phosphatase (258.81 U/L), gamma-glutamyl transpeptidase (430.11 U/L), total bilirubin (103.63 µmol/L), and direct bilirubin (71.71 µmol/L), with a decreased albumin level (29.07 g/L). Coagulation profile demonstrated mild prolongation of prothrombin time. Complete blood count revealed mild anemia (hemoglobin 100 g/L), a low white blood cell count (2.77 × 10⁹/L), and normal platelet counts. Electrolyte analysis showed hyponatremia (133.80 mmol/L) and hypochloremia (96.90 mmol/L). Urine component analysis indicated positive urine bilirubin (++). Serological tests for hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus antibody were all negative. Autoimmune panels, including antinuclear antibody, anti-mitochondrial antibody, and anti-Sjögren’s syndrome type A and type B antibodies were negative.

Transient elastography revealed a liver stiffness of 28.3 kilopascals (kPa) and a controlled attenuation parameter of 270 decibels per meter (dB/m), consistent with cirrhosis and hepatic steatosis. Abdominal ultrasound confirmed cirrhotic liver morphology and revealed incidental bilateral renal cysts without evidence of portal vein thrombosis or ascites. Based on the symptoms, signs, and auxiliary examination results, the patient was diagnosed with decompensated alcoholic cirrhosis, hepatic steatosis, hypoalbuminemia, and electrolyte imbalance.

Therapy was initiated with intravenous administration of glycyrrhizic acid preparations, infusion of albumin, and replenishment of electrolytes. As the results of the reexamination tests changed, on the third day of treatment, the treatment plan was adjusted to intravenous tiopronin (200 mg daily) for continued treatment. The administered tiopronin preparation was a lyophilized powder for intravenous infusion, each vial containing 100 mg tiopronin; each 100 mg vial was reconstituted with 2 mL of 5% sodium bicarbonate injection, and the daily total dose of 200 mg was further diluted in 250 mL isotonic sodium chloride solution for continuous intravenous drip over 60 minutes. No other new intravenous medications were co-administered in the same infusion line during tiopronin delivery, eliminating mixing drug interactions as a confounding trigger factor. About 20 minutes after using tiopronin, the patient suddenly developed painless swelling on both cheeks, with the lump being soft to touch and without redness, swelling, or fever; the oral mucosa was intact. The drug was immediately discontinued. An emergency salivary gland ultrasound revealed diffuse enlargement of bilateral parotid glands, with preserved echotexture and vascularity, and no evidence of sialolithiasis, abscess formation, or focal mass lesions (Fig. 1).

Figure 1.

Result of salivary gland ultrasound examination. Salivary gland ultrasound revealed diffuse enlargement of bilateral parotid glands, with preserved echotexture and vascularity, and no evidence of sialolithiasis, abscess formation, or focal mass lesions.

Given the absence of infectious signs and negative autoimmune and viral markers, a drug-related adverse reaction was suspected. Tiopronin was determined to be a potential causative factor; therefore, its use was discontinued, while other treatment measures continued. Remarkably, the swelling gradually decreased around 5 hours after the drug was stopped and resolved completely within 48 hours without additional interventions. Moreover, the patient’s liver function indices improved gradually, and he was discharged in stable condition after 7 days of hospitalization. The overall clinical course is summarized in the flow diagram (Fig. 2).

Figure 2.

Timeline of the entire clinical process.

3. Discussion

3.1. Current knowledge and rarity of cases

Parotid gland enlargement is a relatively common clinical finding, presenting a broad differential diagnosis encompassing infectious, autoimmune, obstructive, neoplastic, metabolic, and pharmacological causes.^[14] Drug-induced parotid gland enlargement remains rare and often goes unrecognized, with documented cases linked to iodinated contrast agents, antihypertensives, and antiepileptics.^[11-13]

Tiopronin has an established safety profile for gastrointestinal and dermatological adverse reactions.^[15] However, a comprehensive search of the PubMed, Embase, and Web of Science databases revealed no prior reports of tiopronin-associated parotid swelling. By contrast, when we reviewed the drug instructions from the Mayo Clinic, penicillamine, another thiol-containing agent, has been implicated in a small number of cases of reversible parotid gland enlargement, which suggests that the sulfhydryl moiety might be a common molecular determinant in this rare adverse reaction.^[16] The reporting of such cases is crucial for broadening the known adverse effect spectrum of widely used medications and for guiding early recognition in future clinical encounters.

The diagnostic reasoning in this case was greatly facilitated by a clear temporal association between the initiation of tiopronin and the onset of swelling, the lack of clinical or laboratory evidence of infection or autoimmune disease, and the complete resolution upon drug withdrawal. These features are consistent with a probable causal relationship on the Naranjo Adverse Drug Reaction Probability Scale. According to the scale (Table 1),^[17] tiopronin scored 6 (classified as “probable”), Therefore, tiopronin was suspected as the mainly probable cause of this adverse reaction.

Table 1.

Naranjo adverse drug reaction (ADR) evaluation scale.

Related questions	Yes	No	Unknown	Score
1. Are there any previous conclusive reports on this ADR?	1	0	0	1
2. Does the ADR occur after the use of the suspected drugs?	2	−1	0	2
3. Does the ADR resolve after the suspected drug is withdrawn or after the use of an antagonist?	1	0	0	1
4. Does the ADR reoccur following reexposure to the suspected drug?	2	−1	0	0
5. Are there alternative causes that can cause the reaction independently?	−1	2	0	2
6. Does the ADR reappear after the application of placebo?	−1	1	0	0
7. Does the drug reach toxic levels in the blood or other body fluids?	1	0	0	0
8. Is the ADR aggravated (relieved) with the increase (decrease) of dose?	1	0	0	0
9. Has the patient previously been exposed to the same or similar drugs and experienced similar reactions?	1	0	0	0
10. Is there any objective evidence that confirms the reaction?	1	0	0	0
Total score				6

Total score ≥ 9: definite; 5–8: probable; 1–4: possible; ≤0: doubtful.

ADR: adverse drug reactions.

3.2. Mechanism underlying tiopronin-induced parotid gland enlargement

To date, no direct mechanistic studies have investigated how tiopronin may induce salivary gland enlargement. However, insights can be extrapolated from other drug-induced sialadenopathies and from the known pharmacological properties of thiol-containing compounds. Several plausible mechanisms may be considered.

First, a hypersensitivity or immune-mediated reaction is possible. Tiopronin contains a free sulfhydryl group, which may function as a hapten and bind to glandular proteins, eliciting an idiosyncratic immune response.^[18,19] Some drugs directly act on mast cells, causing degranulation of mast cells and release of inflammatory cytokines such as serotonin, histamine, and kinin, which can cause angioedema.^[20] This could result in local interstitial edema without overt inflammation, resembling the pathophysiology of iodide mumps, a well-recognized but rare adverse reaction to iodinated contrast media characterized by reversible, nonsuppurative glandular swelling.^[21]

Second, autonomic dysregulation of salivary gland function may play a role. Salivary secretion is tightly regulated by both parasympathetic and sympathetic inputs.^[22] Drugs that interfere with cholinergic or adrenergic pathways can alter vascular permeability and glandular fluid dynamics.^[23] Increased capillary leakage and altered secretory tone may manifest clinically as transient, non-tender swelling.

Third, biochemical alteration of salivary proteins may contribute. Thiol drugs such as penicillamine are known to interact with disulfide bonds in mucins and other salivary proteins.^[24-26] This structural modification increases the viscosity of saliva and may promote ductal stasis, leading to sialadenosis rather than true sialadenitis. By analogy, tiopronin may exert similar effects through its sulfhydryl reactivity. The short administration duration in this case is insufficient to induce persistent ductal stasis, which we believe may explain the complete resolution of swelling within 48 hours after drug withdrawal without residual sialadenosis lesions.

Fourth, the clinical background of cirrhosis, combined with plasma oncotic pressure decline induced by hypoalbuminemia and hyponatremia that disrupt cellular and vascular homeostasis, expedites fluid extravasation into the interstitium, renders salivary glands susceptible to interstitial edema, and may ultimately lead to rapidly developing painless bilateral glandular enlargement within tens of minutes after infusion. The temporal correlation between tiopronin initiation and swelling suggests the drug acted as a trigger in a susceptible host environment.

Interestingly, while a search of international databases revealed no prior reports linking tiopronin to salivary gland enlargement, we discovered that several case reports had been published in Chinese medical journals. This difference might reflect the differences in drug indications and usage patterns. Since tiopronin is widely used in China for the treatment of chronic liver diseases, while it is mainly used for the treatment of cystinuria in other countries, and currently, most of the tiopronin available in the international market is in the form of oral preparations, while in China it is mainly in the form of intravenous preparations. Intravenous tiopronin achieves higher instantaneous blood drug concentration compared with oral preparations, which explains the higher incidence of salivary gland adverse reactions reported in Chinese clinical practice. Moreover, publication bias and language barriers might also be reasons because Chinese case reports are often difficult for international readers to access. Finally, it cannot be ruled out that genetic or racial susceptibility factors may play a role. The genetic variations of enzymes involved in thiol metabolism (such as γ-glutamyl transpeptidase) or drug transport proteins may affect an individual’s susceptibility, but further pharmacogenomic studies are needed to confirm this. These factors highlight the importance of cross-regional drug monitoring in comprehensively elucidating the safety characteristics of marketed drugs.

Taken together, tiopronin-induced salivary gland enlargement is likely multifactorial, involving immune modulation, autonomic imbalance, salivary biochemical alterations, and individual susceptibility factors. While these mechanisms remain hypothetical, they are consistent with the wide range of drug-induced sialadenopathies and provide a foundation for future pharmacovigilance and mechanistic studies.

3.3. Clinical implications and pharmacovigilance lessons

Clinically, the implications are far-reaching. Awareness of this possible adverse reaction can prevent unnecessary imaging, invasive procedures, and empiric antibiotic or corticosteroid therapy. Notably, multiple susceptible groups face higher risks of tiopronin-related parotid enlargement. As mentioned above, patients with decompensated cirrhosis accompanied by hypoalbuminemia and electrolyte disturbances carry elevated risks, as do elderly individuals with impaired hepatic and renal clearance. Additionally, patients with malnutrition-associated hypoalbuminemia, a prior history of autoimmune diseases or salivary gland disorders, or concurrent use of other thiol agents have further increased odds of developing this adverse reaction. Clinicians should perform intensified close monitoring in the early stage after drug administration in all aforementioned susceptible populations to enable early detection and prompt drug withdrawal. For patients receiving tiopronin, especially in the long-term management of cystinuria, baseline records of salivary gland status and patient education on early symptom reporting could enable timely intervention. This is especially important because drug-induced parotid swelling may recur upon reexposure, as has been demonstrated in cases involving other medications, and recurrent episodes may risk chronic sialadenitis or ductal fibrosis.

From a pharmacovigilance standpoint, this case merits reporting to national adverse event registries. We have duly submitted this rare adverse drug reaction to China’s National Adverse Drug Reaction Monitoring System. Single case reports such as this one, though anecdotal, often represent the early signal in the detection of rare drug-related events. If similar cases are identified in post-marketing surveillance, a class warning for thiol-containing drugs may be justified. Moreover, molecular docking or in vitro studies could be undertaken to investigate whether the sulfhydryl moiety interacts specifically with salivary gland epithelium or vascular components, providing a mechanistic explanation for this adverse effect.

4. Conclusion

We report a case of reversible bilateral parotid gland swelling associated with tiopronin therapy in a patient with alcoholic cirrhosis. This rare but benign reaction underscores the need for clinician awareness of drug-induced sialadenopathy. Prompt identification and cessation of tiopronin can lead to rapid recovery and avoidance of unnecessary diagnostic and therapeutic interventions. Further investigation is warranted to elucidate the mechanism and confirm whether this represents a class effect among thiol-containing agents.

Acknowledgments

We thank all of the authors who contributed to this article.

Author contributions

Writing – original draft: Shunshun Jiang, Ge Chen, Lingling Kong

Writing – review & editing: Shunshun Jiang, Ge Chen, Lingling Kong, Hong Zhao