Acute Pancreatitis as a Therapeutic Complication in Case of Paroxysmal Nocturnal Hemoglobinuria

A 32-year-old female patient, resident of Pune, Maharashtra, India, presented to our tertiary care hospital in December 2020 with a chief complaint of passing red-colored urine for 4 days [ Figure 1 ]. The patient was a homemaker with no significant occupational exposures or family history of hematological disorders. Hemoglobinuria (multiple urine specimens showing visible discoloration) The patient reported that the red-colored urine was most prominent in the morning upon waking and decreased in intensity as the day progressed. Notably, the hemoglobinuria was not associated with abdominal pain initially. She had experienced multiple similar episodes over the preceding year and had a significant history of multiple blood transfusions and jaundice. On initial presentation, vital signs were stable with blood pressure of 110/70 mmHg, pulse rate of 88 beats per minute, and temperature of 98.6°F. Physical examination revealed significant pallor and mild icterus, consistent with chronic hemolytic anemia. The patient was not in acute anemic distress and showed no evidence of organomegaly on abdominal examination. Cardiovascular and respiratory system examinations were unremarkable. Lymph node examination did not reveal any significant lymphadenopathy. Initial laboratory investigations revealed pancytopenia with hemoglobin of 8.0 g/dl, total leukocyte count of 2400 cells/mm 3 , and platelet count of 93,000 cells/mm 3 . Biochemical analysis showed indirect hyperbilirubinemia with total bilirubin of 4.6 mg/dl and direct bilirubin of 1.1 mg/dl. Liver enzymes were elevated with serum glutamic-oxaloacetic transaminase of 428 U/L and serum glutamate-pyruvate transaminase of 256 U/L, while alkaline phosphatase remained normal at 70 U/L. Renal function was initially normal with urea of 31 mg/dl and creatinine of 1.1 mg/dl. Urinalysis demonstrated abundant red blood cells and trace proteinuria, consistent with hemoglobinuria. The patient tested positive for antinuclear antibodies. Hemoglobin electrophoresis showed a normal pattern, ruling out hemoglobinopathies. Bone marrow studies revealed a compensatory response to anemia without evidence of dysplastic changes or infiltrative disease. Although the Ham’s serum test was negative, flow cytometry analysis confirmed the presence of PNH clones, establishing the diagnosis of PNH. Following confirmation of the PNH diagnosis, the patient was initiated on capsule danazol 200 mg twice daily and tablet deflazacort 30 mg once daily. The corticosteroid dose was gradually tapered to 6 mg once daily over the course of 1 year. The patient initially showed clinical improvement with reduced frequency of hemoglobinuric episodes and stabilization of hemoglobin levels. However, approximately 6 months after initiation of therapy, the patient developed acute kidney injury secondary to pigment nephropathy, with creatinine levels rising significantly. This was managed conservatively with adequate hydration, and renal function subsequently improved. During this period, the patient also developed androgenic side effects from danazol therapy, including amenorrhea for 1 year and hirsutism [ Figure 2 ]. Hirsutism In September 2021, nearly 10 months after initial treatment, the patient was readmitted with severe complications. She presented with intense epigastric abdominal pain, multiple episodes of vomiting, and recurrent hematuria. Laboratory investigations revealed worsening anemia with hemoglobin of 5.4 g/dl, though platelet count had improved to 120,000 cells/mm 3 . Most significantly, the patient had developed severe acute kidney injury with urea of 139 mg/dl rising to 196 mg/dl and creatinine of 15.9 mg/dl escalating to 17.7 mg/dl over 3 days. Serum potassium was elevated at 5.7 mEq/L. Initially, the abdominal pain was attributed to uremia secondary to acute kidney injury, and the patient underwent urgent hemodialysis due to oliguria and metabolic complications. However, the abdominal pain persisted despite dialysis, and the patient developed bilious vomiting. Further evaluation revealed markedly elevated pancreatic enzymes with serum amylase of 3370 U/L and lipase of 12,478 U/L, confirming the diagnosis of acute pancreatitis. Ultrasonography of the abdomen demonstrated a bulky head of the pancreas with heterogeneous echotexture, consistent with acute pancreatitis [ Figure 3 ]. Bilateral raised cortical echogenicity indicated underlying medical renal disease. Importantly, no gallstones or pancreatic duct obstruction were identified, ruling out biliary causes of pancreatitis. Ultrasonography (abdomen and pelvis) suggestive of a bulky head of pancreas with heterogeneous echotexture, bilateral raised cortical echogenicity suggestive of medical renal disease The patient was managed conservatively for acute pancreatitis with nil per oral intake, nasogastric decompression [ Figure 4 ], intravenous meropenem 500 mg twice daily, subcutaneous octreotide 100 mcg three times daily, intravenous pantoprazole 40 mg once daily, and intravenous ondansetron 4 mg three times daily. Danazol was immediately discontinued due to acute kidney injury, and deflazacort was tapered and stopped. Pancreatic enzyme supplementation was initiated with pancreatin 10,000 IU with meals. Bilious Ryles tube secretion The patient’s clinical course was complicated but gradually improved with conservative management. The acute pancreatitis resolved over several weeks, and renal function slowly recovered with supportive care and dialysis. This case represented a rare but serious therapeutic complication of PNH treatment, highlighting the importance of vigilant monitoring during therapy with danazol and corticosteroids in resource-limited settings where newer complement inhibitors may not be readily available.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematopoietic stem cell disorder caused by somatic mutations in the phosphatidylinositol glycan class A gene, resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored proteins on blood cell surfaces.[ 1 ] This deficiency renders red blood cells susceptible to complement-mediated intravascular hemolysis, leading to the characteristic clinical triad of hemolytic anemia, thrombotic complications, and bone marrow failure.[ 2 ] The condition predominantly affects adults with a median age of diagnosis around 42 years and carries significant morbidity and mortality, with thrombotic events being the leading cause of death in approximately 50% of patients.[ 3 ] The introduction of complement inhibitors, particularly eculizumab (a terminal complement inhibitor targeting C5 protein), has revolutionized PNH management since its approval in 2007.[ 4 ] Eculizumab effectively reduces intravascular hemolysis, decreases transfusion requirements, and significantly improves quality of life in PNH patients.[ 5 ] Long-term studies have demonstrated sustained efficacy with a substantial reduction in thrombotic events from 7.37 to 1.07 events per 100 patient-years, representing an 85% relative risk reduction.[ 6 ] Despite these remarkable therapeutic advances, complement inhibitors are not without complications, and their safety profile continues to evolve as clinical experience expands. Acute pancreatitis represents one of the most common gastrointestinal causes of hospitalization globally, with an increasing incidence ranging from 13 to 45 per 100,000 persons annually.[ 7 ] The epidemiology of acute pancreatitis varies significantly across geographic regions and racial groups, with African population demonstrating unique disease characteristics.[ 8 ] Studies from South Africa have challenged the previously held notion that acute pancreatitis has a benign course in African population, revealing substantial morbidity rates of 32.3% and mortality rates of 8.1%, comparable to western population.[ 9 ] In African settings, alcohol emerges as the predominant etiological factor in up to 83% of cases, followed by biliary disease and idiopathic causes.[ 10 ] The pathophysiology of acute pancreatitis involves activation of pancreatic enzymes leading to autodigestive destruction of the pancreas and systemic activation of protease cascades, including the complement system. Complement activation plays a crucial role in the inflammatory cascade of acute pancreatitis, with evidence suggesting that complement inhibition may interfere with disease progression and prevent multiorgan failure.[ 11 ] This mechanistic overlap between complement-mediated processes in both PNH and acute pancreatitis raises important questions about potential therapeutic complications. While eculizumab has demonstrated an excellent safety profile in clinical trials, with headache, nasopharyngitis, and nausea being the most common adverse events, the relationship between complement inhibition and acute pancreatitis remains poorly understood.[ 12 ] The intersection of PNH treatment and acute pancreatitis represents an emerging clinical scenario that warrants careful documentation and analysis. Given the rarity of PNH (approximately 6 per million people diagnosed annually) and the specific therapeutic interventions involved, comprehensive case reporting becomes essential for understanding potential treatment-related complications and optimizing patient care.[ 3 ] This case report aims to describe the development of acute pancreatitis as a potential therapeutic complication in a patient with PNH, contributing to the limited literature on this complex clinical scenario and providing insights for healthcare practitioners managing similar cases in African healthcare settings.

This case demonstrates that drug-induced acute pancreatitis represents a serious potential complication of PNH treatment with danazol and corticosteroids, requiring immediate discontinuation of offending agents and supportive management. In resource-limited African healthcare settings where complement inhibitors remain largely inaccessible, healthcare providers must maintain heightened awareness of the pancreatic toxicity associated with traditional PNH therapies. The complex interplay between PNH-related complications, such as pigment nephropathy, and treatment-related adverse events necessitates careful risk–benefit assessment and comprehensive monitoring protocols. This case underscores the urgent need for improved access to safer, targeted therapies like eculizumab in African healthcare systems while emphasizing the importance of case reporting to enhance understanding of rare disease complications and optimize patient care in challenging clinical environments. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. There are no conflicts of interest.

This case represents a rare but significant complication of PNH treatment, where the patient developed acute pancreatitis following therapy with danazol and deflazacort. Our findings align with previously reported cases of drug-induced pancreatitis, highlighting the importance of vigilant monitoring during PNH management, particularly in resource-limited settings where newer complement inhibitors may not be readily available. Danazol-induced pancreatitis, while uncommon, has been documented in various clinical contexts. Chevalier et al . reported the first case of danazol-induced pancreatitis and hepatitis in a patient receiving 400 mg daily for systemic lupus erythematosus, demonstrating that both conditions were drug-induced.[ 11 ] Similarly, Balasch et al . described acute pancreatitis associated with danazol treatment for endometriosis, further establishing the drug’s potential pancreatic toxicity.[ 12 ] A comprehensive systematic review by Wolfe et al . identified danazol among medications with potential associations with acute pancreatitis, though the evidence was classified as limited due to sparse reporting.[ 13 ] More recently, a case of danazol-induced pancreatitis was reported in a patient with telomere biology disorders, where the patient experienced recurrent episodes that resolved after discontinuation of the drug.[ 14 ] These reports collectively support the causal relationship between danazol and acute pancreatitis, consistent with our patient’s clinical course. The mechanism of danazol-induced pancreatitis remains unclear, though several hypotheses have been proposed. Danazol, a synthetic androgen with antigonadotropic properties, may cause pancreatitis through altered lipid metabolism, as evidenced by our patient’s development of hypertriglyceridemia during treatment.[ 15 ] The drug’s hepatotoxic potential may also contribute to pancreatic inflammation through metabolic derangements. In our case, the patient developed both hepatic enzyme elevation and pancreatitis, mirroring the pattern described by Chevalier et al .[ 11 ] The latency period in our patient (approximately 10 months) falls within the variable range reported in the literature, where drug-induced pancreatitis can occur from days to months after initiation.[ 13 ] Corticosteroid-induced pancreatitis represents another important consideration in our case. The patient was receiving deflazacort, a corticosteroid with potentially fewer side effects than prednisolone, yet still capable of causing pancreatic inflammation. Sadr-Azodi et al . conducted a large population-based case–control study demonstrating a significant association between oral glucocorticoid use and acute pancreatitis, with an adjusted odds ratio of 1.52.[ 16 ] The mechanism of steroid-induced pancreatitis may involve increased pancreatic secretion viscosity, leading to ductal obstruction, or alterations in calcium and lipid metabolism.[ 17 ] Recent studies have shown that corticosteroids can increase the risk of acute pancreatitis in susceptible individuals, though the exact pathophysiology remains under investigation.[ 18 ] Our patient’s clinical improvement following corticosteroid discontinuation supports this association. The concurrent use of danazol and corticosteroids in our patient creates a challenging scenario for determining causality. Both drugs have been independently associated with pancreatitis, and their combined use may have had a synergistic effect. This is particularly relevant given that patients with PNH often require multidrug regimens for optimal management. The rarity of PNH limits large-scale studies on treatment complications, making case reports like ours essential for understanding drug safety profiles in this population. Our patient’s development of acute kidney injury secondary to pigment nephropathy represents a well-recognized complication of PNH, occurring in up to 65% of patients due to chronic hemoglobinuria and hemosiderosis.[ 19 ] The progression to dialysis-requiring kidney failure complicated the management of acute pancreatitis, as danazol was appropriately withheld due to renal dysfunction. This highlights the complex interplay between PNH complications and treatment-related adverse events, emphasizing the need for careful risk-benefit assessment in therapeutic decision-making. The androgenic side effects observed in our patient, including hirsutism and amenorrhea, are well-documented consequences of danazol therapy and occurred at the relatively low dose of 200 mg twice daily. These effects, while distressing for the patient, typically resolve after drug discontinuation, though complete reversal may take months to years.[ 20 ] The occurrence of these side effects serves as an important clinical marker for drug compliance and systemic exposure, potentially correlating with the risk of more serious complications like pancreatitis. In the context of African healthcare settings, this case underscores the challenges of managing rare hematological disorders with limited therapeutic options. While eculizumab and other complement inhibitors have revolutionized PNH treatment in developed countries, their availability and cost remain prohibitive in many African healthcare systems. Consequently, older agents such as danazol and corticosteroids continue to play important roles in PNH management despite their associated risks. This necessitates enhanced monitoring protocols and awareness of potential complications among healthcare providers managing these patients. The diagnostic approach in our case followed established guidelines for drug-induced pancreatitis, including exclusion of other common causes and temporal relationship with drug exposure. The absence of gallstones on imaging, normal triglyceride levels at the time of pancreatitis onset, and a negative alcohol history supported a drug-induced etiology. The elevated pancreatic enzymes (amylase: 3370 U/L and lipase: 12,478 U/L) and characteristic imaging findings confirmed the diagnosis of acute pancreatitis according to current diagnostic criteria.[ 21 ] This case contributes to the limited literature on PNH treatment complications and emphasizes the importance of comprehensive monitoring during therapy. Healthcare providers managing PNH patients should maintain high clinical suspicion for drug-induced pancreatitis, particularly when using agents with known pancreatic toxicity. Regular monitoring of pancreatic enzymes may be warranted in high-risk patients, though the optimal frequency and duration of such monitoring remain to be established.