United States

Calciphylaxis is a disorder causing ischemic skin necrosis, typically associated with end-stage renal disease (ESRD) or those receiving dialysis. Occurrence is rare in those without ESRD, and treatment options are limited. This case report describes a patient with calciphylaxis without ESRD or history of dialysis. Treatment with sodium thiosulfate, a first line option, had to be stopped due to metabolic derangements, limiting the healing process. Diagnosis and treatment of this rare disorder is important to prevent further complications that may result.

AMA Research Challenge 2024 

Non-Chronic Kidney Disease-Induced Calciphylaxis: A Rare Case Report

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Title: Pembrolizumab-Induced Epidermotropic CD8+ Dermatitis in a Patient with Multiple Squamous Cell Carcinomas

Background:
Pembrolizumab, a programmed death-1 (PD-1) inhibitor, has been increasingly associated with dermatologic immune-related adverse events (irAEs), varying from benign rashes to severe conditions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. While the literature describes various dermatologic manifestations like lichenoid dermatitis and granuloma annulare as pembrolizumab side effects, we report a distinctive case of pembrolizumab-induced epidermotropic CD8+ dermatitis in a patient with a history of multiple squamous cell carcinomas (SCCs) and a keratin-positive malignant spindle cell neoplasm. This case adds to the evolving spectrum of pembrolizumab's dermatologic irAEs, underscoring the need for vigilance in patients receiving immune checkpoint inhibitors (ICIs).

A 69-year-old female with a history of multiple SCCs treated across various anatomical sites presented with complaints of a widespread rash. The patient reports that the rash had persisted for 20-30 years but had notably worsened following the initiation of pembrolizumab treatment two years prior. Pembrolizumab was administered as part of her treatment regimen for a keratin-positive malignant spindle cell neoplasm of the right proximal femur. She described the rash as intensely pruritic, worsening during winter months, with mild improvement during summer.

Methods:
Compiled through a retrospective review of medical records with patient consent. Diagnostic assessments were conducted using standard histological and immunohistochemical techniques, supplemented by PCR for T-cell receptor gene rearrangements to evaluate T-cell clonality.

Results
On skin examination, extensive coalescing, ill-defined erythematous patches with associated xerosis were observed. A biopsy of an eczematous lesion on the left lower back was performed to further investigate the rash's etiology. Histopathological analysis revealed hyperkeratosis, parakeratosis, and infiltration of epidermotropic lymphocytes within the epidermis. The infiltrate was predominantly composed of CD8+ T cells. Further molecular studies were negative for clonal T-cell receptor rearrangements.

Conclusion
Given the lack of T-cell clonality and the CD8+ cell-rich infiltrate, a diagnosis of pembrolizumab-induced epidermotropic CD8+ dermatitis was favored over other dermatologic conditions such as mycosis fungoides. The chronicity and the pre-existing nature of the rash, coupled with the exacerbation post-pembrolizumab therapy, underscore its drug-induced origin, distinct from typical dermatologic irAEs reported with ICIs. This case is particularly unique due to the uncommon histopathological feature of epidermotropism of CD8+ T cells, divergent from the more common CD4+ presentations seen in other cases of pembrolizumab-induced dermatitis.

The patient continued with pembrolizumab therapy for her underlying malignancy and her rash was managed with triamcinolone 0.1% topical ointment.This case adds to the literature on pembrolizumab-induced skin reactions, emphasizing the nuanced understanding needed for diagnosis and treatment, particularly in the context of a pre-existing dermatologic condition exacerbated by ICI therapy.

Pembrolizumab-Induced Epidermotropic CD8+ Dermatitis in a Patient with Multiple Squamous Cell Carcinomas

Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic inflammatory disorder of the hair follicle that presents in apocrine gland-bearing areas of the body. It is characterized by nodules, abscesses, fistulae, scars, and sinus tracts in the perineal and perianal regions. The most commonly affected region is the axilla but can also present in the perineal/perianal site in 30-50% of cases. HS cannot be cured, but clinical management can control the disease. HS prevalence is unclear, estimates range from 0.00033% to 4.10% in the US population. Squamous cell carcinoma (SCC) is the second most common non-melanoma skin cancer, and accounts for 20% of skin cancer causes. SCC has been documented to be a rare complication of HS lesions. Early detection of SCC in HS patients is important for timely clinical management and treatment. The University of Southern California (USC) Institutional Review Board approved this study. Using de-identified electronic medical records on TriNetX from USC, we used ICM-10- CM codes to identify HS patients who developed skin cancer (basal cell carcinoma, squamous cell carcinoma, melanoma in situ, and malignant melanoma) from 1 day to present day post-HS diagnosis. Kaplan Meier analysis was conducted to compare survival probabilities of HS patients who developed the different skin cancers. Preliminary results show that out of 990 HS patients at USC, 20 patients develop some form of skin cancer in the HS regions (2.02%). SCC was the most common form of skin cancer arising in HS regions. The survival probability was lowest among HS patients who developed SCC (97.08%), compared to BCC (99.35%), melanoma in situ (99.41%), and malignant melanoma (99.60%). Clinicians should be aware of SCC as a complication of HS and be diligent in screening for SCC in management. SCC in HS patients is a rare, but serious complication and delays in diagnosis may lead to worse outcomes.

Squamous Cell Carcinoma in Hidradenitis Suppurativa Patients

Background: 
Scleroderma-associated digital ulcers (SSc-DUs) are seen in up to 50% of patients with scleroderma (SSc) and may precede complications including osteomyelitis and gangrene. The current literature regarding the risk factors for gangrene in SSc is scarce, as the presentation is becoming increasingly rare.
Risk factors for gangrene in unselected patients with SSc include previous digital ulcers (DUs), previous digital gangrene, and the diffuse-cutaneous subtype of SSc (dcSSc)3, which affects the visceral organs and the skin to a higher degree than the limited-cutaneous subtype of SSc (lcSSc). 
Traditional cardiovascular risk factors for peripheral arterial disease (PAD) (smoking, hypertension, dyslipidemia, diabetes mellitus, previous acute cardiovascular events) have not been consistently associated with gangrene in SSc.

Case Presentation: 
An 81-year-old female with Raynaud’s phenomenon, sick sinus syndrome status post pacemaker implantation, and well-controlled non-insulin-dependent diabetes mellitus presented to the emergency department complaining of two weeks of left foot pain.
She endorsed swelling and redness of the foot and ankle after having sustained minor trauma directly over a distal ulcer on the first digit of the affected foot. She denied prior digital ulcerations as well as a history of smoking, alcohol, and drug use. 
Laboratory analysis, including a complete blood count and a complete metabolic panel were within normal limits. Notably, the erythrocyte sedimentation rate and C-reactive protein suggested acute on chronic inflammation at 106 (normal range: 0-30 mm/hr) and 7.9 (0.1-0.9 mg/dL), respectively. Serology confirmed lcSSc with a positive anti-centromere antibody. Wound cultures obtained from purulent drainage grew Pseudomonas. Magnetic resonance imaging was contraindicated, given pacemaker incompatibility. Computed tomography and arterial ultrasonography of the extremity demonstrated no significant abnormalities. 
She was treated with six weeks of intravenous cefepime, given concerns of osteomyelitis. Soon after starting treatment, soft tissue edema subsided, and gangrenous changes were noted across the fifth digit of the left foot. Unfortunately, treatment further included digital amputation of the gangrenous digit.

Discussion: 
The currently available literature suggests that the development of gangrene would not be expected in the digital ulcers of the presented patient, given the absence of prior ulcerations and classically more aggressive subtype of SSc. The lack of established risk factors for both SSc-DU-associated gangrene and PAD in this patient suggests that SSc itself may have a unique disease course in the setting of trauma. A history of trauma may be a key element in helping clinicians categorize patients to determine which patients are likely to have increased disease burden and, therefore, benefit from more complex management. 

Conclusion: 
Due to the heterogeneity and small sample sizes in the currently available cohort studies on the topic, patients with SSc of all subtypes should be educated on the risk of complications that may follow injuries of ulcerated digits. Close follow-up and treatment after injuries may prevent digital amputation.

Patients should be educated on the risk of complications after injuries of ulcerated digits and be recommended close follow-up if these occur.

Trauma Leading to Gangrene in Digital Ulcers Affecting the Limited Cutaneous Subtype of Scleroderma

Background

Takotsubo Cardiomyopathy (TTC), or broken heart
syndrome, was first described in Japan in 1990. It is a
stress-induced cardiomyopathy in which the heart
resembles a Japanese “octopus pot”, or takotsubo.
TTC is characterized by the weakening of the left
ventricle, resulting in ballooning of the heart and left
ventricular apical akinesis, causing symptoms that
mimic acute coronary syndrome (ACS). Patients may
present with myocardial infarction (MI) - like
symptoms, show ST-segment elevation on
electrocardiogram (ECG), and have elevation in
ischemic cardiac enzymes. However, no coronary
artery blockage will be seen. Onset usually follows a
significant stressor, such as the death of a loved one,
coining the term “broken heart syndrome”. It is
hypothesized to be caused by the stunning of the
myocardium via catecholamine release. Treatment
involves ruling out ACS and MI, supportive care, and
follow up with a cardiologist to ensure resolution of
the syndrome. In the rare (<5%) case that a left
ventricular thrombus forms, systemic anticoagulation
is required.

Case Presentation

We present a case of a patient with a history
significant for chronic kidney disease and
hypertension presenting to the emergency
department with one-day history of unchanged acute
onset dyspnea and hypotension. She remarked that
she was “incredibly stressed'' recently. Labs were
significant for leukocytosis, increased troponins, and
lactic acidosis. Her ECG showed T-wave inversions in
the inferior and anterolateral leads.
Echocardiography was significant for findings
suggestive of TTC with an ejection fraction (EF) of 25-
30%. The patient was transferred to the intensive
care unit for cardiogenic shock. Following supportive
treatments, she was optimized based on her TTC,
and was discharged with cardiology follow up.
Currently, she is on goal-directed medical therapy,
wears a life-vest, and continues to have left
ventricular akinesis with an EF of 25-30%.

Discussion

Acute treatments are supportive, but vary based on
level of left ventricular outflow tract obstruction.
Traditional heart failure with reduced ejection
fraction (HFrEF) treatments have limited efficacy for
TTC-induced HFrEF. Some data indicates that TTC is
often underdiagnosed, and the true rate may be
closer to 5.7%. While most cases recover within 2
weeks, there is a significant recurrence rate of up to
4% per year. A consideration for prevention of
recurrence is screening and addressing mental health
comorbidities. It is important to note, that TTC is less
commonly also referred to as “Happy Heart
Syndrome,” so clinicians should be cognizant of TTC
patients presenting with positive symptoms.

A Heart-breaking Case of Takotsubo Presenting to a Community Emergency Department

Background:
We report two cases of seizure-like activity after accidental pediatric cannabis ingestion. As states continue to alter laws regarding sale and formulation of cannabis products, pediatric ingestion of these products remains a dynamic public health concern. Expansion of marijuana legalization has been paralleled by increasing availability of edible THC products, including ones that may be mistaken by children for snack foods like cookies and gummies. Diagnosis of cannabis intoxication in children has proven a difficult and costly endeavor. Many caregivers are reluctant to admit that a child could have been exposed to marijuana due to stigmas and fear of liability. On the other hand, physicians may fail to consider cannabis in children due to nonspecific symptoms (drowsiness, tremors, palpitations, numbness) and fear of a missed, more serious diagnosis. 

Case Presentation:
The first patient is an 8-year-old male who presented with focal shaking and abnormal behavior that progressed to generalized full body shaking. He reported muscle pain as well as auditory and visual hallucinations, a constellation of symptoms that have not been reported in the setting of pediatric cannabis ingestion. Presenting vitals were stable and bloodwork and head CT were negative, resulting in discharge home. Urine drug testing was positive for cannabinoids with a THC of 504 ng/mL. 
The second patient, a 2-year-old female, presented with agitation and neck and limb stiffening followed by multiple episodes of rhythmic truncal flexion without extremity shaking. Her vital signs were stable with normal blood work, blood cultures, urinalysis, viral testing, x-rays and head CT. Her urine drug testing was positive for cannabinoids with a THC level of 820 ng/mL. 

Discussion:
Both patients’ presentations led to extensive, expensive workups, placing patients at risk of harm. The only necessary interventions for either patient were intravenous normal saline, social services, and observation. Public health efforts must be taken to decrease pediatric exposures to cannabis, including, but not limited to, regulations on snack-food-like packaging. Additionally, more timely identification of cannabis intoxication through history and drug screening may decrease invasive and costly testing in pediatric populations. One such recommendation incudes delaying all testing other than urine drug screening in children who are stable and have bilaterally reactive pupils. Rapid, more specific urine toxin immunoassay may also facilitate more efficient diagnosis. Physician education regarding atypical case presentation, such as those addressed in this case report, may aid in more streamlined diagnosis as well as decreased cost and patient risk.


Accidental Pediatric Cannabis Ingestion Causing Seizure-Like Activity: Case Reports to Inform Diagnosis

Background
Atraumatic hemothorax presents a diagnostic challenge due to its rarity and the wide, diverse range of potential etiologies. We present a case of massive hemothorax without a clear cause, aiming to highlight the complexities of this pathology and the critical considerations necessary for accurate diagnosis.

Case Presentation
A 20-year-old male with a history of spine surgery presented to the ED following two syncopal episodes and a one-day history of nausea, vomiting, and right-sided back pain. The patient began practicing Jiujitsu two days prior but denies any significant injuries. Upon EMS arrival, systolic blood pressure was 90 mm Hg and the patient remained hypotensive after receiving two units of crystalloids. Chest X-ray revealed a large right-sided pleural effusion and thoracentesis with subsequent tube thoracostomy evacuated three liters of blood. The patient was transferred for higher level of care, and was transfused with four units of packed red blood cells, one unit of fresh frozen plasma, and a bolus of tranexamic acid. A FAST exam was negative. An additional 700-800 mL of sanguineous blood was evacuated upon a second thoracostomy with chest tubes left in place. CT angiography of the chest, abdomen, and chest did not reveal active contrast extravasation or traumatic injury of the aorta. Over the following five days, the patient’s symptoms and hemothorax resolved, chest tubes were removed, and the patient was discharged. There are no records of patient readmission.

Discussion
Massive hemothoraces, defined by blood drainage exceeding 1,000 mL after closed thoracostomy, are typically associated with high-impact traumas such as blunt or penetrating chest injuries. We present an unusual case with minimal evident trauma. Although our patient denied significant injury, it is possible that a minor incident may have been overlooked. We suspect our patient’s hemothorax was due to intercostal artery damage if he did suffer some type of injury. Regardless, minor injury alone would still not typically explain this massive hemothorax and therefore, must also consider the possibility of a massive, non-traumatic hemothorax due to coagulopathy, vascular malformations, connective tissue diseases, or autoimmune diseases. Given the unclear history, a broad differential diagnosis is crucial. This case underscores the importance of gathering a detailed history during the patient encounter and maintaining a high degree of suspicion for hemothorax in cases of refractory hypotension, even in the absence of a clear trauma history.

Into the Unknown: Exploring a Case of Massive Atraumatic Hemothorax with Enigmatic Origins

Authors: Amelia Klamen B.S., Wouter Ritsema B.S., Ankit Hanmandlu M.D., Ayman Salem M.D., Sahalia Rashid M.D.

Introduction: 
Acute aortic dissection (AAD) is a highly lethal phenomena with a mortality rate of 50% within 48 hours. Timely diagnosis and management of AAD is crucial, yet often is delayed by ambiguous symptomatology. Patients commonly present with extreme chest pain, dyspnea, and abdominal pain, but clinical presentation can also include focal neurological defects, altered mentation, and syncope.

Case Description:
A 56 year old man with a history of hypertension, asthma, polysubstance use, insecure housing, and seizure disorder presented to the emergency department with abdominal pain. His initial workup, including basic labs, lactic acid, and chest x-ray, was unremarkable. He received fluids, Droperidol and was discharged. Three days later, the patient returned with chest pain, shortness of breath, abdominal pain, generalized fatigue, and a new productive cough. Furthermore, he mentioned a severe (10/10) shooting pain his chest to his scrotum, across his shoulders and diffusely throughout his abdomen after smoking heroin three days prior. 

In the emergency department, the patient was afebrile and hemodynamically stable. Laboratory findings demonstrated elevated lactic acid and troponins. Upon examination, he was found to have a bounding S1 and S2 with a holosystolic murmur at the left upper sternal border, and a visible and inferolaterally displaced point of maximal impulse. These findings prompted a transthoracic echocardiogram which showed pericardial effusion and a dissection flap. An emergent CT-Angiogram showed an Type A aortic dissection spanning from the ascending aorta to just proximal of the renal arteries. The patient subsequently underwent emergent surgical aortic dissection repair.

Discussion: 
Aortic dissection is commonly misdiagnosed, with 1/3rd of aortic dissection patients receiving an incorrect initial diagnosis. The case underscores the need for clinicians to consider AAD in patients presenting with acute chest pain, dyspnea, abdominal pain and scrotal pain, even in the absence of classic distress. Furthermore, the association between substance use, particularly heroin, and AAD warrants further investigation. Awareness of atypical presentations and a comprehensive diagnostic approach are crucial for timely identification and intervention in AAD cases. 

Conclusion: 
This case report emphasizes the diagnostic challenges associated with atypical presentations of AAD. Clinicians should maintain a high level of suspicion, especially in patients with diverse symptomatology and risk factors. Further research is needed to explore the relationship between substance use, such as heroin, and the development of AAD. Timely recognition and intervention are pivotal for improving outcomes in this life-threatening condition. 

References:
Levy D, Goyal A, Grigorova Y, et al. Aortic Dissection. [Updated 2023 Apr 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan.
Lovatt S, Wong CW, Schwarz K, et al. Misdiagnosis of aortic dissection: A systematic review of the literature. Am J Emerg Med. 2022;53:16-22.

Pain from Chest to Scrotum: An Initial Presentation of Aortic Dissection

Background:
Pembrolizumab is a monoclonal antibody that blocks the immune inhibitory effects of the programmed cell death protein-1 (PD-1) resulting in the enhanced effects of T cells which are beneficial in multiple conditions including malignancies but consequently could have serious autoimmune complications. 

Objectives:
We aim to highlight the mechanism of Pembrolizumab-induced autoimmune conditions and focus on identifying susceptible patients while emphasizing the essential role of physicians in informed patient decision-making regarding whether to continue the medication once the autoimmune condition resolves.

Case Presentation:
A 69-year-old male presenting with progressive lethargy for 1 week associated with fatigue, shortness of breath, and excessive thirst without complaints of nausea or vomiting, abdominal pain, weight loss, polyuria, lightheadedness, or focal neurologic deficits.

Past Medical History of Graves’ Disease status post total thyroidectomy now on Levothyroxine, Stage IV Non-Small Cell Lung Carcinoma of the right upper lobe with metastasis to the bones and adrenals, treated with a combination of Carboplatin, Paclitaxel, and Pembrolizumab. No prior personal or family history of diabetes mellitus.

In the emergency department, Vital signs Temp 36.7, BP 150/90, RR 30s, HR 120s. On physical examination, the patient was lethargic but arousable without focal neurologic deficits and appeared cachectic with dry skin and oral mucosa with noticeable rapid shallow breathing. Diagnostic tests showed serum Glucose 829, Beta-hydroxybutyrate 11.5, urinalysis ++ketones, ABG pH 6.9, Bicarbonate 23, Anion Gap 20, lactate 3.50, Creatinine 2.2 from baseline of 0.86, K 7.7, EKG with peaked T waves with no QRS widening or PR prolongation, other tests including Head CT and Chest X-ray imaging studies were normal. 

The patient was immediately given intravenous fluids and bicarbonate, was started on insulin drip, 
hyperkalemia was temporized with calcium gluconate, and adjunctively given albuterol nebulization with close monitoring of blood glucose and electrolytes. Endocrinology was consulted, and tested for C peptide level (0.22 ng/mL) and Anti-GAD-65 (<5 IU/mL) which were both low. Oncology was also consulted for which they recommended stopping Pembrolizumab for now.

Throughout his hospital stay, his symptoms and blood glucose improved and his Anion Gap normalized, later tolerated oral diet, was successfully transitioned to subcutaneous basal-bolus insulin, and was eventually discharged with strict outpatient endocrinology and oncology follow-up. 

Discussions/Conclusion:
The primary function of the programmed cell death protein-1 (PD-1) is to down-regulate the immune system preventing damage to self-antigen. Pembrolizumab is a monoclonal antibody that blocks the binding of the PDL1 ligand to its receptor causing enhanced T cell response resulting in better tumor killing with consequent increased risk of adverse autoimmune effects such as hyper and hypothyroidism, colitis, nephritis, with type 1 diabetes accounting for only 0.1% of the patients. 

Pembrolizumab added to a standard chemotherapy regimen has shown longer overall and progression-free survival than chemotherapy alone and this is likely the reason why Pembrolizumab-induced autoimmune conditions have been increasing for the past couple of years. 

The predisposing factors for the development of Pembrolizumab-induced type 1 diabetes (T1DM) is not well known. However, previous studies support that patients with a history of autoimmune diseases are more susceptible to develop this complication which was consistent with our patient’s prior history of Graves’ disease.  Pembrolizumab-induced T1DM can present with classic symptoms of diabetes but on rare occasions, it can initially present with diabetic ketoacidosis as evident in our patient. Unlike the classic T1DM where at least one autoantibody is present in 98% of patients, Pembrolizumab-induced diabetes had lower levels which was evident in our patient.

In one meta-analysis, the onset of Pembrolizumab-induced diabetes varied and ranged from one cycle to as long as 19 cycles and most studies showed that continuation of Pembrolizumab after initial treatment of diabetes ketoacidosis was still possible with initiation of basal-bolus insulin regimen since stopping Pembrolizumab in the setting of advanced malignancies, where only a few treatment options are available, is not always possible, and the overall prognosis of malignancies treated with Pembrulizumab did not seem to change even if they develop endocrinopathies. Hence, an informed decision by the patient with a transparent and collaborative effort between healthcare providers is of utmost importance, zeroing in on the risks and benefits of continued treatment.  

A Case of Pembrolizumab-Induced Diabetic Ketoacidosis in a Patient with Non-Small Cell Lung Carcinoma: Understanding the Basics of What We Should Know

Background: Diabetes insipidus, now called arginine vasopressin deficiency, is an uncommon endocrine disorder characterized by abnormality in antidiuretic hormone (ADH). It is either due to insufficiency in ADH or decreased peripheral response to normal levels of ADH. It commonly manifest as polyuria and polydipsia. There have been very few cases reported in medical literature highlighting the correlation between untreated common variable immunodeficiency (CVID) and arginine vasopressin deficiency (AVPD). Here we present a case of AVP-D in patient with established but untreated CVID

Case description: A male in his mid-fifties presented with altered mental status and was found to have sepsis secondary to community acquired pneumonia. Additionally, he complained of significant thirst and large amounts urine output which has been ongoing for four months but was not adequately addressed. His urine output was noted to be 7.2 Liters in 24 hours with an inappropriately low urine osmolality in the setting of hypernatremia as documented below. This raised the suspicion for ADH imbalance which led us to pursue water deprivation test.
It revealed minimal change in urine output and osmolality. This further led us to perform a desmopressin challenge test. We administered 4 mcg of desmopressin (DDAVP) subcutaneously which resulted in an appropriate decrease in urine output in addition to increase in urine osmolality (A Delta of 40 mOsm/kg representing >50% increase in urine osmolality). This was consistent with central AVPD. He was started on DDAVP and immunoglobulin replacement therapy.

Discussion: CVID is a hereditary hypogammaglobulinemia with reported 20% of patients with concomitant autoimmune endocrine disorders. Untreated CVID leads to the involvement of multiple organ systems, as was the case with our patient who had features of CVID enteropathy, CVID granulomatous Interstitial lung disease, and now ADH imbalance emphasizing the condition's diverse manifestation. This correlation is poorly understood but is hypothesized to be linked to lymphocytic neurohypophysitis. Hence more in-depth research needs to be done into ADH imbalance in patients with CVID particularly if untreated. This case underscores the necessity of maintaining a high suspicion for AVP-D in patients with CVID to prevent debilitating yet reversible complications. Early recognition and appropriate replacement therapy are essential in improving patient outcomes and quality of life.


Arginine Vasopressin Deficiency in Patient with Untreated Common Variable Immunodeficiency - An Uncommon Manifestation

Background: Tirzepatide is a dual incretin (GLP-1 and GIP) receptor agonist approved for Type 2 Diabetes Mellitus (T2DM) and chronic weight management with significant cardiovascular and renal benefits. Gastrointestinal discomfort is the most commonly reported adverse effect with this drug, with uncommon occurence of acute kidney injury, gall bladder disease and pancreatitis. We present 2 cases to report the occurrence of diabetic ketoacidosis (DKA) in T2DM patients and its noteworthy temporal association with Tirzepatide, the first clinical encounter of its kind. The purpose of this case report is to document a potential adverse outcome associated with this drug that mandates further research.

Case presentation: 
Case 1- A 35 year old,female, BMI-36.92, with T2DM since 4 years, presented with severe nausea, vomiting and abdominal pain one week following increase in the dose of Tirzepatide. The patient had a prior episode of DKA which led to hospitalization within a week of her first Tirzepatide injection 2 months back. Initial investigation upon admission was consistent with euglycemic DKA- pH-7.31, HCO3-9.9, blood glucose-178, beta-hydroxybutyrate-13.5, anion gap-31, C-peptide-3.6 and GAD antibody <5.

Case 2- A 46 year old male, BMI-31.93, with T2DM since 23 years, presented with severe nausea and vomiting that developed after he took his dose of Tirzepatide the previous day. He had been on this drug for about 6 months and reported persistent GI discomfort that he associates with this medication. Initial investigation was consistent with the diagnosis of DKA-blood glucose-507, betahydroxybutyrate -7.7, pH -7.44, HCO3-16.6, anion gap-24, C-peptide-2.8 and GAD antibody <5.

Other possible triggers for DKA including infection, trauma, alcohol use and withdrawal were ruled out in both the cases through history and labs. Both the patients were hospitalized and managed with DKA protocol in the ICU.

Discussion:
The aforementioned cases illustrate a rare but notable risk of DKA with either hyperglycemia and euglycemia in patients on Tirzepatide. This has not been observed previously. One plausible explanation is that significant reduction in calorie intake due to Tirzepatide can potentially trigger starvation ketoacidosis. Another concern is the potential for Tirzepatide to unmask ketosis-prone diabetes in individuals who are not phenotypically T1DM characterized by absolute insulin deficiency. This case report emphasizes the importance of recognizing this rare complication in patients prescribed this increasingly used drug.


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