European Journal of Cardiovascular Medicine

Snakebite envenomation remains a significant public health concern in many tropical and subtropical regions, particularly in rural areas of developing countries [1]. The World Health Organization estimates that up to 2.7 million people experience venomous snake bites each year, resulting in 81,000 to 138,000 deaths annually [2]. While acute complications such as coagulopathy, neurotoxicity, and acute kidney injury (AKI) are well-documented, endocrine complications, especially those affecting the pituitary gland, are less frequently reported and often overlooked [3]. Acute pituitary insufficiency, hyponatremia resulting from natriuresis, and hypokalemia due to intracellular potassium shift are emergent conditions that can occur following snakebite envenomation [4].

Of particular interest is the potential for chronic hypopituitarism, which may manifest years after the initial envenomation event, presenting a diagnostic challenge for clinicians [5]. The pathophysiology of snake venom-induced hypopituitarism is complex and multifactorial, with proposed mechanisms including direct venom-induced damage to pituitary cells, ischemic necrosis secondary to disseminated intravascular coagulation (DIC), and vascular occlusion by fibrin deposition [6]. The delayed onset of symptoms, which may develop insidiously over months to years, underscores the importance of long-term follow-up and endocrine screening in snakebite survivors, especially those who experienced severe envenomation or complications such as AKI [7]. In this case report, we present a patient who developed chronic hypopituitarism following a Russell's viper bite, with symptoms manifesting gradually over 15 years, aiming to increase awareness among clinicians about this rare but significant complication of snakebite envenomation

A 35-year-old non-alcoholic, non-smoking male from rural Trichy district, India, presented to our endocrinology clinic with complaints of progressive fatigue, weakness, and declining academic performance. The patient's medical history was significant for a Russell's viper snake bite that occurred 15 years prior, at the age of 20. At the time of the snake bite, the patient developed oliguria and acute kidney injury (AKI), necessitating 12 cycles of hemodialysis. He was discharged with a diagnosis of snake bite-induced AKI, with normal creatinine levels and adequate urine output. Prior to the snake bite, the patient reported being healthy with good scholastic performance.

Approximately one year after the snake bite incident, the patient began experiencing gradual onset of easy fatigability, lethargy, and malaise. These symptoms were accompanied by a notable decline in his academic performance. Over time, he observed changes in his physical appearance, including pallor and the development of coarse facial features. The patient also noted a significant reduction in secondary sexual characteristics, with sparse facial, axillary, and pubic hair growth.

On physical examination, the patient was found to be conscious, alert, and cooperative, with a Mini-Mental State Examination (MMSE) score of 30/30. He exhibited moderate pallor without jaundice or cyanosis. His blood pressure was 100/60 mmHg, with a regular pulse of 70 beats per minute. The patient's skin was pale and coarse in texture, and his voice was noticeably hoarse. Thyroid examination revealed no palpable abnormalities. Abdominal examination was unremarkable, with no organomegaly or masses detected. Cardiovascular and respiratory examinations were within normal limits.

Neurological assessment demonstrated intact higher functions, cranial nerves, sensory, and cerebellar functions. However, proximal upper and lower limb muscle weakness was present, and pseudomyotonia was observed in the thenar muscles. No fasciculations were noted. Genitourinary examination revealed a testicular volume of 15 mL, which is below the normal range for his age, and sparse pubic hair.

Laboratory investigations revealed mildly macrocytic anemia (Hemoglobin: 9.2 g/dL, Packed Cell Volume: 29.5%, Mean Corpuscular Volume: 98.2 fL, Corrected Reticulocyte Count: 1.1%). White blood cell and platelet counts were within normal limits. Renal function tests showed normal urea (11 mg/dL) and creatinine (0.9 mg/dL) levels. Urinalysis was unremarkable, with no evidence of proteinuria or hematuria. Serum electrolytes, liver function tests, and glucose levels were all within normal ranges. Serum calcium was 10.1 mg/dL, and ferritin was mildly elevated at 367 ng/mL. Endocrine evaluation revealed a low total T4 level (0.24 ng/dL) with a normal TSH (4.2 μIU/mL), suggesting central hypothyroidism. Further hormonal assays demonstrated markedly low levels of ACTH, cortisol, and growth hormone. Gonadotropins (FSH and LH) were also found to be inappropriately low for the patient's age and sex.

Magnetic Resonance Imaging (MRI) of the pituitary gland revealed an empty sella, consistent with previous pituitary apoplexy. This finding, in conjunction with the clinical presentation and hormonal profile, strongly suggested a diagnosis of delayed hypopituitarism secondary to snake bite-induced pituitary apoplexy.

Based on the diagnosis of panhypopituitarism, the patient was initiated on hormone replacement therapy. This included hydrocortisone (10 mg twice daily, at 8 AM and 6 PM), levothyroxine (100 μg daily), and testosterone enanthate (250 mg intramuscular injection every 4 weeks).

At the three-month follow-up, the patient reported significant improvement in his general well-being, concentration, and physical activity. He had also achieved adequate weight gain. No adverse effects were observed from the hormonal replacement therapy.

This case highlights the potential for delayed endocrine complications following snakebite envenomation, particularly in the context of hemotoxic viper bites. The pathophysiology of snake venom-induced hypopituitarism is complex and not fully elucidated. Several mechanisms have been proposed, including direct venom-induced damage to pituitary cells, ischemic necrosis secondary to disseminated intravascular coagulation (DIC), vascular occlusion by fibrin deposition, and venom-induced systemic inflammatory response contributing to pituitary damage [8].

The delayed presentation of hypopituitarism in this case, occurring approximately one year post-envenomation and progressing over 15 years, underscores the importance of long-term follow-up in snakebite survivors. This temporal pattern is consistent with previous reports, which have documented the onset of hypopituitarism ranging from a few weeks to more than two decades following the initial envenomation event [9,10].

The empty sella observed on MRI in our patient is a common finding in cases of snake venom-induced hypopituitarism, likely resulting from pituitary apoplexy at the time of envenomation. Other reported neuroimaging findings include partially empty sella, pituitary hemorrhage, or occasionally normal pituitary appearance [11]. The clinical presentation of our patient, characterized by fatigue, weakness, and loss of secondary sexual characteristics, is typical of panhypopituitarism. The hormonal profile, showing low levels of thyroid hormones, cortisol, growth hormone, and gonadotropins, further supports this diagnosis. The normal TSH level in the presence of low T4 is indicative of central hypothyroidism, a hallmark of hypopituitarism [11].

The association between snake bite-induced AKI and subsequent hypopituitarism is noteworthy. While AKI is a well-recognized complication of hemotoxic snake bites, its role in precipitating or exacerbating pituitary dysfunction is not fully understood. It is possible that the systemic effects of AKI, including fluid and electrolyte imbalances, oxidative stress, and inflammatory responses, may contribute to pituitary vulnerability [10].

The management of snake venom-induced hypopituitarism follows the general principles of treating panhypopituitarism from other causes. Hormone replacement therapy, as instituted in our patient, aims to address deficiencies in cortisol, thyroid hormone, and sex steroids. The marked improvement in our patient's symptoms and quality of life following hormone replacement underscores the importance of early recognition and appropriate management of this condition [7].

This case report emphasizes the need for heightened awareness of potential endocrine complications, particularly hypopituitarism, in survivors of venomous snake bites. The delayed onset of symptoms highlights the importance of long-term follow-up and endocrine screening in these patients. Future research directions should focus on elucidating the exact mechanisms of snake venom-induced pituitary damage, identifying potential preventive strategies, and determining the incidence and long-term outcomes of hypopituitarism in snakebite survivors.

Acknowledgment:  We acknowledge the collaborative efforts of the healthcare team involved in the diagnosis and management of this challenging case, including endocrinologists, radiologists, and biochemists.

Patient perspective & informed consent.  The patient was very cooperative throughout clinical & laboratory evaluation and treatment. Also, he was very interested in the follow-up reviews when he noticed some marked improvement in his general condition. The patient gave informed consent for this case report publication.

Ethical Approval: ethical committee approval was not required from the committee as per protocol for case reports.

Source of Funding: funding source was self.

Conflict of Interest: there was no conflict of interest.

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