Acute Necrotizing Pancreatitis Secondary to Acute Intermittent Porphyria: A Rare Clinical Association.

A 23-year-old man presented with a 3-day history of fever, loose stools, abdominal pain, and shortness of breath. His family history was significant for porphyria spanning 2 generations. He denied alcohol use, smoking, or chronic medication intake. On admission (day 1), he was afebrile with blood pressure 130/70 mm Hg, heart rate 120/min, respiratory rate 30/min, and oxygen saturation of 90% on room air. Examination revealed bilateral lung crepitations and epigastric region tenderness. Arterial blood gas analysis showed type I respiratory failure, while chest radiograph and abdominal ultrasound were unremarkable. He was initiated on noninvasive ventilation and fentanyl infusion for pain control. On day 2, he developed confusion and visual hallucinations; brain computed tomography (CT) was normal. Laboratory evaluation showed hemoglobin 13 g/dL, total leukocyte counts of 13.6 × 10 9 /L, platelets 210 × 10 9 /L, procalcitonin 1.14 ng/mL, hyponatremia (Na + 129 mmol/L), serum amylase 31 U/L and serum lipase 43 U/L. Given the strong family history and neurovisceral symptoms, a qualitative urine porphobilinogen (PBG) test was performed and was positive, confirming AIP (Figure 1 ). Empirical antibiotics were started for suspected gastrointestinal infection, and an intravenous (IV) high-carbohydrate diet (300 g/day glucose) was initiated due to delayed availability of heme analogs. Qualitative urine porphobilinogen test: step 1—equal volumes of urine and the Ehrlich reagent were mixed, producing a pink color indicative of porphobilinogen or urobilinogen. step 2—Chloroform was then added; the pink color did not extract into the lower layer (red arrow), confirming the presence of porphobilinogen. His symptoms improved gradually, and he was weaned off respiratory support by day 9. On day 12, he experienced recurrence of severe epigastric pain radiating to the back. Repeat testing revealed markedly elevated serum amylase 914 U/L and lipase 194 U/L levels. CT imaging demonstrated a bulky pancreas with peripancreatic fat stranding, consistent with acute pancreatitis (Figure 2 ). Liver function test showed aspartate aminotransferase (AST)—53 U/L, alanine aminotransferase (ALT)—46 U/L, alkaline phosphatase—58 IU/L, serum triglyceride level—111 mg/dL, total calcium level of 8.2 mg/dL, and ionized calcium of 4.65 mg/dL (Figure 3 ). There was no history of steroids, opiates, antiepileptic, antimicrobial, and other medication use which are known to cause pancreatitis. Polymerase chain reaction test was negative for hepatitis (A, B and C), HIV, cytomegalovirus, adenovirus, Coxsackie virus, and Leptospirosis. Magnetic resonance cholangiopancreatography (MRCP) abdomen showed normal biliary and pancreatic ducts. He was treated with intravenous fluids, analgesics, and nutritional support. Contrast enhanced computed tomography abdomen: (A) Day 12, bulky and heterogenous pancreas (red arrow) with peripancreatic fat stranding. (B) Day 19, necrotizing pancreatitis with heterogenous collection of 19 × 7.7 cm replacing pancreatic parenchyma (red arrow) and extending into the lesser sac and left anterior pararenal space. (C) Day 48, heterogenous pancreatic parenchyma with 12 × 4 cm collection replacing pancreas extended to pararenal and perisplenic region with pararenal percutaneous drain in situ (red arrow). Timeline of patient symptoms, investigation, and management. Details of CT scan is mentioned in Figure 2 . AIP, acute intermittent porphyria; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; NIV, noninvasive ventilation; PCD, percutaneous drain; USG, ultrasonography. On day 19, he developed fever and anorexia; contrast enhanced CT showed necrotizing pancreatitis with a 19 × 7.7 cm collection extending into the lesser sac and left anterior pararenal space (Figure 2 ). Transgastric catheter and a percutaneous drain (PCD) with tip in paracolic region were placed, which drained necrotic content. By day 30, PCD were upsized for fever and intrapancreatic collection; by day 48, the enlarging walled-off collection extended to pararenal and perisplenic region, requiring further PCD upsizing (Figure 2 ). Persistent drainage from transgastric catheter prompted endoscopic retrograde cholangiopancreatography on day 60, which showed a pancreatic duct leak near the head region. Following internalization of the transgastric drain, the fistula gradually resolved. Exome sequencing performed on the proband using DNA isolated from peripheral blood samples identified a known pathogenic heterozygous frameshift mutation, c.815delA in exon 12 of the HMBS gene, resulting in protein truncation and loss of function. He was discharged on day 70 with advice for high-carbohydrate intake and avoidance of porphyria triggers. At 2-month follow-up, there was no residual collections in CT scan, and transgastric catheter was removed. At 6 months, there were no residual symptoms related to porphyria and pancreatitis.

Acute pancreatitis is an inflammatory disease of the pancreas with diverse etiologies. Although gall stones and alcohol use are most common, other causes include hypertriglyceridemia, drug toxicity, infections, autoimmune disorders and complications postendoscopic retrograde cholangiopancreatography. 1 Acute intermittent porphyria (AIP), a rare metabolic disorder caused by partial deficiency of the Hydroxymethylbilane synthase (HMBS) enzyme in the heme biosynthetic pathway, typically presents with neurovisceral crisis during acute attacks. 2 Although abdominal pain is a hallmark feature, the involvement of pancreas is rarely described. We report a 23-year-old man who developed acute pancreatitis during an attack of AIP.

AIP is an inherited metabolic disorder caused by a partial deficiency of the HMBS enzyme involved in heme biosynthesis. This enzymatic defect leads to the accumulation of porphyrin precursors such as δ-aminolevulinic acid (ALA) and PBG, resulting in neurovisceral crises. Owing to incomplete gene penetrance, approximately 90% of affected individuals remain asymptomatic. When symptomatic, AIP typically presents in adulthood, with a marked female predominance. 2 , 3 Among previously reported cases, all patients were women, aged 23–39 years. 4 – 10 By contrast, our patient was a 23-year-old man; exome analysis and Sanger sequencing confirmed paternal inheritance of the pathogenic frameshift single-nucleotide deletion, consistent with the autosomal dominant inheritance pattern of AIP. Reported triggers of acute attacks of porphyria include analgesic use, hormonal fluctuations during menstruation, weight loss, and contraceptive use. 4 – 10 In our patient, a recent gastroenteritis episode with fever, diarrhea, and poor intake likely precipitated the attack. AIP typically presents with abdominal pain (85%–95%), peripheral neuropathy related weakness, behavioral disturbances, and features of autonomic dysfunction. Hyponatremia, often due to syndrome of inappropriate antidiuretic hormone secretion, is common and may lead to seizures. Respiratory failure, as observed in our case, is uncommon but potentially life-threatening, resulting from ascending motor neuropathy. 11 Abdominal pain in AIP is typically diffuse, visceral, and disproportionate to physical findings. Autonomic neuropathy often results in gastrointestinal dysmotility, constipation, or pseudo-obstruction; however, abdominal imaging is usually normal. 3 In our patient, persistent abdominal pain without peritoneal signs was an early clue toward a porphyria crisis. In previously reported series, abdominal pain remained the most consistent presenting symptom, with occasional cases showing additional neurological deficits such as limb or facial weakness. 4 Although pancreatic involvement is rare, a few cases of concomitant pancreatitis during attack of AIP have been reported in the literature. In a 29-year-old woman who was diagnosed with AIP, symptoms resolved following high carbohydrate diet. On day 10 of admission, there was recurrence of pain; emergency laparotomy showed edematous pancreas. 5 Abdominal pain in AIP can mask other serious abdominal conditions like pancreatitis and intestinal ischemia. 12 , 13 Therefore, persistence or recurrence of pain following standard therapy for porphyria should prompt evaluation for alternative or coexisting etiologies. A similar association was also reported in a 36-year-old woman in whom abdominal pain and pancreatic enzyme levels normalized within 24 hours. However, a recurrence occurred 40 weeks later, just before menstruation, with positive biochemical markers for both AIP and pancreatitis which further supports a potential pathophysiologic link between the 2 conditions. 6 In addition, atypical presentations have also been described where a 34-year-old woman presented with chronic pain abdomen (2 months) and neurological deficits. 4 Such variable presentations other than classic attack episodes lead to diagnostic delay. Our patient developed biochemical and radiologic evidence of pancreatitis 15 days after the onset of porphyria symptoms. This timeline mirrors previous reports, in which the interval between porphyria onset and pancreatitis ranged from 6 to 12 days. 5 , 7 , 8 As abdominal pain in AIP can mimic that of pancreatitis, serial measurement of pancreatic enzymes is advisable when pain persists despite appropriate therapy. In published cases, imaging findings ranged from normal pancreas to diffuse enlargement, 4 – 6 , 8 – 10 however, our patient developed necrotizing pancreatitis with peripancreatic collections an uncommon but severe presentation. Similarly a 39-year-old woman with AIP and recurrent pancreatitis also developed a pancreatic fistula. 7 The exact mechanism linking AIP and pancreatitis remains unclear. Proposed mechanisms include autonomic neuropathy causing sphincter of Oddi spasm and impaired pancreatic drainage, as well as oxidative injury from accumulated porphyrin precursors such as ALA and PBG. These metabolites may generate free radicals, promoting pancreatic acinar injury. 5 – 9 In our case, the strong temporal association, biochemical confirmation, imaging findings, and exclusion of other known etiologies collectively support a causal relationship between the AIP attack and acute pancreatitis. Management of an acute porphyria attack includes identification of precipitating factors, use of heme analogs and symptomatic control. Heme analogs downregulates ALA synthase expression ameliorating production of porphyrin metabolites. Timely initiation of heme therapy prevents the progression of neuropathy, which is also a mechanism speculated to cause pancreatitis during attack of AIP. 2 , 3 When unavailable, high-carbohydrate intake (300–500 g/day of glucose) may serve as a temporary measure, though its effect is less potent. 14 In our patient, heme therapy was delayed due to availability; therefore, intravenous glucose supplementation and nutritional support were initiated early, leading to gradual recovery. However, caution should be exercised with glucose therapy, as excessive glycemic load may potentiate inflammation and oxidative stress, thereby worsening the clinical course of pancreatitis. 15 Although nutritional balance cannot be fully achieved in this setting, glucose administration remains necessary to suppress porphyrin precursor synthesis and prevent further neurovisceral deterioration until heme therapy becomes available. This case highlights the rare but clinically significant coexistence of acute intermittent porphyria and acute necrotizing pancreatitis. Persistent or recurrent abdominal pain during an AIP attack should prompt early evaluation for pancreatitis to prevent diagnostic delay and complications. Awareness of this unusual association is essential for timely diagnosis, rational management, and avoidance of therapeutic pitfalls in patients with porphyria crises.

Author contributions: Literature review, wrote and revised the manuscript: S. Wali. Literature review, provided images and revised the manuscript: G. Pandey, S. Gutte, Srinivasan VM. Critical revision of the article, provided final approval of manuscript: M. Gurjar. Article Guarantor: M. Gurjar. Financial disclosure: None to report. Informed consent was obtained for this case report.