Acute pancreatitis (AP) is an inflammatory process affecting the pancreas. It is characterized by severe epigastric pain, 3X upper limit of normal increase serum amylase and lipase, and radiological evidence of pancreatic oedema or necrosis [1] . In 2019, its global age-standardized incidence rate was 34.8/100,000 [2] . The mortality of acute pancreas ranges from 3% in patients with mild edematous pancreatitis to as high as 20% in patients with pancreatic necrosis [3] . The most common causes of acute pancreatitis are gallstones (20% - 70%) followed by alcohol use (30%) [4] . Other notable causes are metabolic (hypercalcemia, hypertriglyceridemia), drug-induced, autoimmune, post-endoscopic retrograde cholangiopancreatography, trauma, infectious, congenital or genetic, and idiopathic. The rate of occurrence of each etiology of acute pancreatitis varies across geographic regions and socioeconomic strata [4] . Hypertriglyceridemic acute pancreatitis (HTAP) accounts for 9% of AP and is the second etiology of AP in Chinese women after cholelithiasis [5] . High-index of suspicion is indicated in early diagnosis and skilled management (treatment and prevention) is essential in prevention of long-term sequelae. In this case report, we present a late presentation of HTAP in an adult patient and outline a non-invasive new innovation in its management and disease prevention.

A 57-year-old man presented with recurrent epigastric pain for months that was worse a few days prior to admission. The pain was dull ache in character, lasted for hours, radiated to the back and worse on lying down. It was associated with nausea and vomiting that did not relieve the pain. Attacks mostly develop after fatty meals. The patient did not have a past history of other significant medical illness, surgery, allergy, or chronic intake of medications or alcohol. Family history was significant for hyperlipidemia. On his initial physical examination, he was drowsy, exhausted and in distress of epigastric pain that had required narcotics to relieve. His body weight was 116 kg, blood pressure was 90/50 mm Hg and was afebrile. Systemic examination did not show abnormality except for severe epigastric tenderness. Abnormal clinical data and laboratory investigations are summarized in Table 1 . He had normal peripheral leucocytic and platelet counts. Hemoglobin was normal. Serum sugar, electrolytes and liver functions were normal. Serum urea and creatinine were elevated at 14 mmol/L and 240 umol/L, respectively. He had metabolic acidosis with high lactate levels. Serum amylase and lipase were elevated at 776 IU/L (N: 26 - 100) and 1691 IU/L (N: 13 - 60), respectively. Lipid profile showed high serum cholesterol at 9 mmol/L (N: < 5.2), LDL-cholesterol at 7 mmol/L (N: < 3), VLDL at 7 mmol/L (N: < 0.78), and triglycerides at 18 mmol/L (N: < 1.7). Lipoprotein electrophoresis showed absent chylomicrons, 21% alpha lipoproteins (HDL), 21% pre-beta lipoproteins ((VLDL) and 58% beta lipoproteins (LDL). Urine routine and microscopy were normal. Abdomenal and pelvic ultrasound showed enlarged and edematous pancreas. Computerized tomography of abdomen revealed bulky pancreatic head and uncinate process with hazy outline, fat stranding with peripancreatic and pelvic free fluid and multiple subcentrimetric regional lymph nodes ( Figure 1 ). It showed normal enhancement without pseudocyst formation or tumors. Grading of such pancreatitis (modified severity index) was at 4. Hence, diagnosis of hyperlipidemic pancreatitis was established which was associated with severe intravascular volume compromise due to external fluid loss and translocation of fluid into pancreatic bed. He was treated with saline and bicarbonate infusions to restore intravascular volume as well as intravenous proton pump inhibitors. In the first few days, he was kept without oral feed and received Evolocumab 140 mg subcutaneously every week. The patient improved, clinically, within 3 days, and low fat diet was started with Simvastatin 40 mg daily as well as fenofibrate 145 mg daily ( Table 1 ). By 2 weeks his clinical as well as his laboratory abnormalities had normalized and hence Evolocumab was held. He was instructed to avoid fatty meals, comply with statin and fibrate therapy and reduce his weight. After 2 years of follow-up the patient: a) remained stable without recurrence of clinical pancreatitis or high amylase/lipase, b) lipid profile remained normal, c) did not have malabsorption features with normal hemoglobin A1c, d) was able to reduce his weight to 87 kg, and e) had normal pancreatic architectures by repeat CT of abdomen ( Figure 2 ).

HTAP is a “two-hit phenomenon”. It develops when stars align viz. genetic hypertriglyceridemia and triggers (acquired surges). Our patient had severe type IIb genetic disorder (familial combined hyperlipidemia) according to Fredrickson’s classification of hyperlipidemia since, a) did not have hyperchylomicronemia (type I), b) isolated hypercholesterolemia (type IIa) or hypertriglyceridemia (type IV), c) presented at an adult age and lacked growth retardation, malabsorption, neurological and neuromuscular manifestations (type III), d) lacked eruptive xanthomata and hepatomegaly (type V) [6] . Type IIb is a common hyperlipidemic disorder with a prevalence of 1 in 40 and with an autosomal dominant inheritance as in our patient with a strong family history of hyperlipidemia [7] . In general, the list of triggers of HTAP includes uncontrolled diabetes mellitus, morbid obesity, therapeutic keto-genic or high-carbohydrate diets, hypothyroidism, cigarette smoking, alcohol consumption, pregnancy, obstructive liver diseases, renal diseases, drugs (anabolic steroids, corticosteroids, bile acid-binding resins, anticonvulsants, oral contraceptives, anti-retroviral therapy, Isotretinoin and Depo-Provera), autoimmune diseases, and solid-organ transplants [8] . In our patient, the most plausible trigger was his fatty meals. Omitting fatty meals and weight reduction were cornerstones in his long-term disease prevention. In HTAP, a sudden rise of HTG, due to secondary cause/s, triggers the disorder. Such phenomenon should not be confused with the mild to moderate hyperlipidemia (4% - 20%) associated with other AP [9] . HTAP is increased in patients with plasma triglyceride (TG) levels > 1000 mg/dl (11.3 mmol/l) compared with patients with plasma TG levels ≤ 1000 mg/dl. Excess TGs are hydrolyzed by lipase enzymes excreted by pancreatic acinar cells to produce free fatty acids (FFAs). High levels of FFAs: a) have direct cytotoxic effect on acinar and vascular endothelial cells, and b) trigger inflammatory cascade of pancreatitis [10] . Moreover, activation of pancreatic proteolytic enzymes within acinar tissues, may progress to systemic inflammation [11] . In the management of HTAP, it should be noted that the risk of acute pancreatitis increases progressively with serum triglyceride levels over 500 mg/dL (5.6 mmol/L), with the risk increasing markedly with levels over 1000 mg/dL (11.3 mmol/L) [12] . Hence, aggressive measures, to lower TG below this level, are indicated in the acute phase and its prevention. Though early support is not different from that of other causes, a) rapid correction of triggers and b) rapid lowering of TG are indicated. The first measure indicates: a) nil by mouth to avoid fatty meals and rest the pancreas, b) insulin infusion to correct hyperglycemia, reverse the stress-associated release of fatty acids from adipocytes by inhibiting hormone-sensitive lipase in adipocytes, and c) plasmapheresis in multi-organ failure and systemic acidosis by rapid lowering of TG and chylomicrons (50% - 80%) and inflammatory cytokines [13] . Theoretically, heparin anticoagulation reduces the thrombotic mechanism of HTAP and stimulates lipoprotein lipase which lowers triglyceride levels by converting them to free fatty acids [14] . However, its effect is transient with a high risk of rebound HT and bleeding in the pancreatic bed in the setting of acute pancreatitis. Hemofiltration is another controversial therapy in the management of HTG. It removes amylase and urea nitrogen from the blood, and also reduces the level of cytokines in the plasma, downregulating systemic inflammatory response [15] . In refractory cases of HTG, newer pharmacologic treatments for the targeted treatment of hypertriglyceridemia are under investigation and may be promising for patients with very high TG levels at risk for acute pancreatitis. The most promising of these are ANGPTL3 inhibitors, ApoC-III inhibitors, and Pemafibrate [16] . Lastly, it should be noted that hypercholesterolemia is a major risk factor for atherosclerosis yet it has not been shown to cause AP [17] .

In type IIb-HTAP, a) triggers can be controlled by nil-by-mouth with weekly Evolocumab-therapy and b) long-term prevention can be achieved by weight reduction and Fenofibrate alone. The approach is safe, practical and effective.

Prof/Kamel El-Reshaid conceived the study, participated in its design, and drafted the manuscript. Dr. Abass Hakim participated in the study design and tabulated the data. Dr. Reji Philip Athyal participated in manuscript preparation regarding radiological issues. All authors read and approved the final manuscript.

The data provided in the current review are available from the references.