Timely Application of Plasma Exchange to Correct Acute Pancreatitis Related to Serum Triglyceride Levels: A Report of 6 Cases and a Literature Review

Introduction

HTG is a prevalent lipid metabolism disorder with a complex etiology. High serum triglyceride levels can result from genetic factors, diet, exercise habits, smoking, obesity, and medications [1]. HTG is a rare but confirmed cause of AP. The risk of AP at triglyceride (TG) levels above 11.3 mmol/L (1000 mg/dL) has been found to be approximately 5%, and the risk rises to 10–20% at levels above 22.58 mmol/L [2,3]. AP is a critical clinical condition that typically affects the pancreas, peripancreatic tissues, and distant organs, and the clinical presentation may range from self-limited mild pancreatitis to very severe disease that can progress to death, with serious complications including dehydration, metabolic imbalance, hypotension, and sepsis [4]. AP can be triggered by a variety of factors, including biliary tract disease, alcohol abuse, and lipid metabolism disorders [4]. Recent studies have shown that serum TG levels play an important role in the development and progression of AP, and that elevated serum TG levels to a certain threshold can directly induce HTG-AP, with the incidence of AP increasing with increasing TG levels [5–7]. However, mild to moderate TG elevation occurs in 30% of patients with acute pancreatitis, so other causes should be ruled out before diagnosing HTG-AP.

TPE is a therapeutic intervention involving the removal, return, or exchange of plasma or components in vitro, and the basic mechanism is achieved by centrifugation or filtration using a semi-permeable membrane [8]. The American Society for Apheresis (ASFA) classification has 4 categories. In Category 1, plasma exchange is the preferred treatment of diseases, such as some autoimmune diseases, thrombotic thrombocytopenic purpura (TTP), and myasthenia gravis. In Category 2, plasma exchange is used as a second-line treatment for options other than standard treatment, such as certain neurological diseases and hematological diseases. In Category 3, there is little evidence for the efficacy of plasma exchange, and the treatment must be individualized, such as for some metabolic diseases. In Category 4, there is evidence that plasma exchange is ineffective or harmful, but may be considered for use after approval by the Ethics Committee [8,9]. TPE may be associated with several complications, including but not limited to hypocalcemia or hypomagnesemia, hypothermia, transfusion reactions, fluid and electrolyte imbalances, bleeding and thrombosis, and allergic reactions [8]. TPE can rapidly reduce the level of triglycerides in the plasma and alleviate pathological damage by removing plasma containing pathological substances and replacing it with an equal volume of replacement fluid [10].

There is little difference in initial treatment for other causes of AP, including fluid resuscitation, pain relief, and nutritional support. If necessary, HTG may be treated with insulin or hemofiltration. Here, we report 6 cases of extremely severe HTG-AP with TG levels >30 moml/L, including 2 cases with TG levels >100 mmol/L, all associated with hypertriglyceridemia with a rapid response to TPE in the intensive care unit. After treatment, the patients had different conditions, and the cases are discussed. These patients received TPE in the intensive care unit (ICU). The outcomes and clinical course of these cases are presented to provide insights into the management and treatment efficacy of TPE for severe HTG-AP.

Case Reports

Six patients diagnosed with HTG-induced AP were hospitalized in the Affiliated Hospital of Shandong University of Traditional Chinese Medicine in 2020 and received TPE combined with continuous veno-venous hemofiltration (CVVH). At the time of admission, all patients had obvious symptoms of abdominal pain. Laboratory tests and abdominal computed tomography (CT) scans (Figures 1–6) were performed, and all signs and test results were consistent with the diagnosis of HTG and AP. The characteristics of all patients are shown in Table 1.

The average age was 43.3 years, with 1 female and 5 males. The mean length of hospital stay was 11.3 days. All patients had 1 or more diseases in their past medical history, as shown in Table 2. Four of these patients had had hyperlipidemia before, and 1 of them (Case 5 in the table) had been treated within 2 months. One patient was diagnosed with diabetes before hospitalization (Case 5) and was initially diagnosed with ketoacidosis. Two patients had hypertension before hospitalization and had been taking medication to control their blood pressure within the normal range (Cases 3 and 4). Two of the patients drank alcohol (Cases 1 and 6); both developed abdominal cramps within 6 hours after drinking, and we believe that the cause was alcohol-related. Case 4 developed an allergic reaction during TPE.

Case 1: A 51-year-old man underwent TPE 2 hours after admission, and when the plasma exchange level reached 1400 ml, he developed head and face rash, itching, throat blockage, edema of both eyes, increased heart rate, and decreased blood pressure. He was immediately given anti-allergy treatment with loratadine, methylprednisolone, calcium gluconate injection, and ipecac hydrochloride injection. After 15 minutes, his blood pressure dropped to 70/59 mmHg, and his heart rate was 132 beats/min. He was conscious, his whole body had a widespread papuloid rash, and the itching was aggravated. After 40 minutes, his symptoms improved, the body rash area was reduced, there was no throat blockage, vital signs were stable, blood pressure was 112/68 mmHg, heart rate was 121 beats per minute, and SPO2 was 92%. Subsequently, he was treated with insulin and heparin for HTG-AP, and was discharged on the 9th day, with improved symptoms. The patient developed an allergic reaction during the treatment of TPE and we promptly stopped treatment, but after the exchange of 1400 ml of plasma, the TG level decreased significantly.

Case 2 was a 48-year-old woman who had had type 2 diabetes for more than 10 years. She usually took dapagliflozin, acarbose, vensupine, metformin, and other drug treatments, and her fasting blood sugar was controlled at 8–9 mmol/L. She told us that she had been admitted to our ward 3 months ago due to acute pancreatitis caused by hyperlipidemia. After admission, she was listless and took deep breaths. The blood gas analysis showed pH 7.08, K 4.31mmol/L, and blood ketones 3.3mmol/L. She was diagnosed with diabetic ketoacidosis. After receiving 2000 ml TPE, the TG level dropped to 44.5mmol/L and she subsequently underwent CVVH. After 2 days of treatment, the abdominal pain symptoms did not subside and she requested to be discharged voluntarily.

Case 3 was a 34-year-old man with a history of pancreatitis, who presented with severe epigastric pain that had persisted for 1 day. On arrival, the vital signs were within normal range; blood pressure was 128/96 mmHg, temperature was 36.6°C, and heart rate was 100 beats per minute. Upon examination, there was tenderness in the upper abdomen. Laboratory results and a CT scan revealed a diagnosis of HTG-AP. He was placed on a fasting regimen and received acipimox dispersible tablets, levofloxacin hydrochloride, mepivacaine, and octreotide acetate injection, after which there was some relief of abdominal pain. After receiving 2030 ml of TPE, the TG level decreased to 8.8 mmol/L. He subsequently underwent CVVH treatment. Five days into the treatment, the abdominal pain was significantly reduced, and he was discharged.

Case 4 was a 32-year-old man with a history of hypertension, who had received treatment at another hospital for persistent severe abdominal pain. Despite receiving antimicrobial and analgesic therapy, the abdominal pain did not subside. He was then transferred to our hospital. On arrival, the vital signs were blood pressure 145/110 mmHg, temperature 36.9°C, and heart rate 106 beats per minute. Upon examination, there was tenderness in the abdomen. Laboratory results and a CT scan led to a diagnosis of HTG-AP. After 2 alternating treatments of TPE and CVVH, the TG level decreased to 8.53 mmol/L, and the abdominal pain symptoms were significantly reduced. He was discharged after 12 days of treatment.

Case 5 was a 37-year-old man with no significant medical or surgical history, who presented with severe epigastric pain and nausea and vomiting for 5 hours. On arrival, the vital signs were within the normal range, except for his blood pressure, which was 159/97 mmHg, and his temperature was 36.8°C, with a heart rate of 85 beats per minute. On examination, there was tenderness in the upper abdomen. Laboratory results and CT scan revealed a diagnosis of HTG-AP. After receiving 2000 ml TPE, the TG level decreased to 5.79 mmol/L. The patient subsequently underwent CVVH treatment. Six days into the treatment, the abdominal pain symptoms were alleviated, and he was transferred to a general ward.

Case 6 was a 45-year-old man who had presented to another hospital with severe epigastric pain that had persisted for 11 hours after drinking alcohol, and was diagnosed with HTG-AP. He was then transferred to our hospital. The vital signs were within normal range: his blood pressure was 129/77 mmHg, his temperature was 36.5°C, and his heart rate was 74 beats per minute. Upon examination, there was tenderness in the upper abdomen. Laboratory results and a CT scan confirmed the diagnosis. After pain relief, antimicrobial therapy, and fluid resuscitation, the patient was treated with 2 alternating rounds of 2000 ml TPE and CVVH, which significantly alleviated his abdominal pain symptoms. He was discharged after 11 days of treatment.

Standard treatment for acute pancreatitis, including fluid resuscitation and pain management, was given to all 6 patients, and they all were treated with insulin, heparin, and antibiotics, and TPE was performed promptly. After 1 TPE treatment, the TG level of all 6 patients decreased significantly (Table 2), the symptoms of abdominal pain were reduced in 5 patients (Cases 1, 2, 3, 4, and 6), and 1 patient was automatically discharged due to complications.

Discussion

THE PATHOGENESIS OF HTG-AP:

The pathogenesis of HTG-AP is multifactorial, which may be related to the accumulation of free fatty acid (FFA), hyperviscosity, activation of inflammatory response, and specific genes. Animal model experiments found that pancreatic lipase metabolized excessive TG to FFA, resulting in pancreatic injury and ischemia [2,3]. In addition, perfusion of the pancreas with unsaturated TG in vitro resulted in a significant increase in serum FA, and the pancreas developed edema and hemorrhage [3]. High concentrations of FAA can trigger an inflammatory response, release calcium ions, and cause acinar necrosis [2,3]. It has also been suggested that excessive TG in the pancreatic capillaries leads to high blood viscosity. The increase in blood viscosity in HTG patients reduces tissue microcirculation [11,12] and leads to ischemia of the pancreas and surrounding organs. Hyperviscosity causes pancreatic ischemia, which leads to cellular acidosis. Acidosis may increase the possibility of cathepsin B activating trypsinogen [13], thereby triggering or aggravating the inflammatory response. Finally, Chang et al [14] found that 26.1% of HTG-AP patients had mutation of the cystic fibrosis transmembrane conductance regulator gene, but this was found in only 1.3% of patients without HTG-AP, suggesting that the occurrence of HTG-AP may be related to genetic components. HTG-AP may be caused by a complex interaction between multiple factors and has different contributing factors in various patients. Further research is needed to elucidate the pathogenesis of HTG-AP.

THE DIAGNOSIS AND CLINICAL CHARACTERISTICS OF HTG-AP:

There is no authoritative definition of HTG-AP, but it usually requires a diagnosis of AP and the presence of high-risk pre-disposing factors for HTG.

Diagnosis of AP requires 2 of the following 3 criteria:acute onset pain in the upper abdomen (usually radiating to the back) characteristic of AP;elevation of serum lipase or amylase more than 3 times the upper limit of normal;radiographic manifestations of acute pancreatitis [15].

Several studies have attempted to establish an appropriate threshold for TG levels that may lead to AP [16]. However, there is no clear evidence that HTG-AP occurs above certain threshold serum TG levels. Typically, TG levels >1000 mg/dL are associated with AP. Even at lower TG levels (<1000 mg/dL), the presence of other risk factors can trigger AP.

In the clinic, HTG-AP can sometimes be suspected by finding abdominal pain during physical examination. It is important to note that a small number of patients present with a serum amylase level within the normal range, because significantly elevated triglyceride levels may cause low serum amylase and lipase [17]. Therefore, a CT scan of the pancreas is required.

The causes of HTG fall into 2 categories: primary (hereditary) and secondary disorders of lipoprotein metabolism. Secondary hypertriglyceridemia is often seen after poorly controlled diabetes, pregnancy, and hypothyroidism, or after medication or alcohol use. In this report, all 6 patients had secondary lipoprotein metabolism disorders. Because genetic testing is not commonly used for diagnosis, our patients are not tested for the relevant genetic defects and we could only learn about the patient’s genetic status by asking for a family history.

Secondary causes alone may not raise the risk of AP. However, the interaction of several secondary causes or a combination of primary and secondary causes may lead to severe HTG levels. In our case series, potential risk factors such as alcoholism were observed in 2 patients and diabetic ketoacidosis in 1 patient.

We had 2 patients potentially associated with alcohol consumption (Cases 1 and 6), and HTG-related alcohol use mainly stimulates fat intake, thereby accelerating the secretion of chylomicrons in the small intestine. After these chylomicrons are secreted, they are carried into the liver, resulting in an in-flux of large amounts of free fatty acids, which in turn secrete VLDL. The increase in VLDL and medium-density lipoprotein (IDL) leads to increased competition for LDL, resulting in an increase in triglycerides [18]. However, no studies have proven whether alcohol consumption exacerbates the underlying dyslipidemia or whether it directly causes HTG-AP [19], but in a retrospective study of 8000 patients elevated serum triglyceride levels were closely associated with higher daily alcohol consumption [20]. In Case 5, diabetes may have had a predominant role in the pathogenesis, leading to elevated levels of triglycerides, VLDL, and chylomicrons, thereby triggering HTG-AP [21]. In type 1 diabetes, decreased insulin production results in significantly reduced lipoprotein lipase activity, causing HTG. The hyperinsulinemia and insulin resistance in patients with type 2 diabetes can expedite triglyceride production and reduce plasma triglyceride clearance [22]. In this case, the patient was later diagnosed with diabetic ketoacidosis, and we believe that diabetic ketoacidosis (DKA) may be a risk factor for HTG-AP, but it is not known whether HTGAP triggers DKA. It has been found that HTG-AP can lead to β cell dysfunction, resulting in transient insulin deficiency and increased insulin resistance due to inflammation, which may lead to DKA [23]. Therefore, we believe that this patient had HTG-AP caused by DKA.

COMPARISON WITH THE OTHER STUDIES:

In comparison with cases from other studies, our patients generally had higher triglyceride (TG) levels, with the highest reaching over 133 mmol/L. In terms of treatment, we alternated between therapeutic plasma exchange (TPE) and continuous veno-venous hemofiltration (CVVH), with most patients experiencing rapid symptomatic relief within 24 hours [10].

We also conducted a literature search and searched PubMed for the keywords “(hypertriglyceridemia or hyperlipidemia) and pancreatitis” and found 15 case reports (Table 3). In Table 3, the patients in studies 1–4 were children under 18 years old [24–27], and HTG-AP occurred. Among them, the patients in study 4 received TPE, but the TG level was lower than in other reports. TPE can also be used to treat young patients with HTG-AP; the TG levels of the patients in study 3 were similar to that of the cases we reported, but insulin was used and TPE was not used. Genetic analysis should be performed for young patients with genetic defects. TPE was used in the patients in reports 4–15 [28–38]. In addition, we should also pay attention to the occurrence of other complications. In study 5, the patient suffered brain stem infarction due to fat embolism. In patients with severe acute pancreatitis, chylomicrons, and very-low-density lipoprotein (VLDL) are released from necrotic omental fat into the circulatory system, C-reactive protein is elevated, and chylomicrons and VLDL are agglutinated in the blood, ultimately leading to vascular occlusion [39]. In contrast to the literature, in our cases, there were no very young patients, but we also paid attention to the risk of developing HTG-AP in children. Therefore, we should focus on the genetic defects when we encounter pediatric patients. Some studies have reported that gene defects can decrease lipase activity, thus inhibiting the clearance of triglyceride and affecting the level of triglyceride. Other genetic mutations may also lead to reduced liver clearance of VLDL and chylomicron residues [3]. Complications of allergic reactions and ketoacidosis also occurred in our patients.

TPE AND CVVH IN THE TREATMENT OF HTG-AP:

HTG-AP patients are a special population with high TG levels, and early and rapid lipid reduction is the key to their treatment. TPE rapidly removes TG and chylomicrons from circulation, removing stimulants and stopping further inflammation and damage to the pancreas. TP has been reported to dramatically and quickly reduce lipid levels and inflammatory factors, but conservative treatment usually takes several days to achieve the same reduction in TG levels, and in most patients TG levels can be reduced by 50–80% with a single course of TPE [9,40]. Chen et al [41] reported the biochemical and clinical trajectories of the observation cohort of 181 HTG-AP patients treated conservatively (n=135) or TPE (n=46), showing that TP resulted in a short-term rapid decrease in plasma TG levels. Another recent large retrospective study, which included 111 patients treated with TPE, found that patients receiving early TPE (within 36 hours) had better outcomes and shorter recovery times than those receiving late TPE (>36 hours) for HTG-AP [42].

TPE is associated with potential complications, such as the risk of infection or allergic reactions (Case 4), and its utilization is currently limited. Premedication regimens of ephedrine, prednisone, and diphenhydramine have been found to be effective in reducing allergic reactions [43].

At the same time, we also administer CVVH to patients, which is another controversial treatment for HTG. It can clear amylase and urea nitrogen from the blood, reduce plasma levels of inflammatory factors, including interleukin-6 (IL-1), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α), and reduce systemic inflammatory responses [44]. Results from our 6 cases suggest that early use of CVVH can be effective in reducing HTG-AP morbidity and mortality. It is also an alternative treatment for severe acute pancreatitis in the ICU. However, the mechanism of CVVH as a treatment for AP is not well understood. In conclusion, this case report suggests that CVVH is effective in the treatment of HTG-AP. However, the controversy over the use of CVVH still requires more precise basic research and more case studies to elucidate the role of CVVH in the treatment of HTG-AP.

We conclude that severe HTG is relatively rare and serious, and it can very easily cause AP. In the treatment of HTG-AP, TPE can be used within a few hours of its occurrence, which can effectively reduce TG levels, and it can be used regularly in patients with milder conditions. However, further studies are needed to determine if TG levels can guide physicians in use of TPE in patients with HTG-AP, and most currently rely only on clinical experience.

STUDY LIMITATIONS AND PROSPECTS:

HTG-AP is rare, and we present the cases of only 6 patients in this a single-center retrospective report, which only reflects the situation of our hospital. Therefore, this study has some limitations, such as a small sample size and geographical limitations. Prospective studies enrolling a larger number of HTGAP patients are needed to promote the development of therapeutic strategies.

Conclusions

TPE can treat severe hypertriglyceridemia and was clearly suitable for the patients in the current study. These patients had severely elevated triglyceride levels causing acute pancreatitis, but their other organs were normal. As expected, the triglyceride level decreased significantly after admission to the ICU for therapeutic plasma exchange, and most patients had less abdominal pain. A high level of triglycerides requires alertness to the risk of acute pancreatitis. It is essential to diagnose dyslipidemia in the initial stage of the disease. For severe hypertriglyceridemia, therapeutic plasma exchange should be performed as early as possible to reduce triglyceride levels and correct the cause. Patients who respond poorly to conventional lipid-lowering therapy, have familial dyslipidemia, or have recurrent hyperlipidemia may have a genetic defect and require genetic testing and treatment. Prospective studies are needed to determine the threshold for selecting therapeutic plasma exchange for hypertriglyceridemic pancreatitis based on triglyceride levels.