How do triglycerides cause pancreatitis

The patient was initially managed with intravenous boluses of normal saline followed by continuous insulin infusion. Diabetic Ketoacidosis DKA was ruled out due to a past medical history of diabetes.

Her clinical course was complicated by acute respiratory distress syndrome requiring intubation and mechanical ventilation. During the course, she improved symptomatically and was extubated. She was started on nasogastric feeding initially and subsequently switched to oral diet as tolerated.

Emerging literature implicates HTG as an independent indicator of poor prognosis in acute pancreatitis AP. Acute pancreatitis is the leading gastrointestinal cause of hospitalization in the United States [ 1 ].

The two most common causes of acute pancreatitis are gallstones and alcohol [ 2 ]. Hypertriglyceridemia is the third most common cause of acute pancreatitis and accounts for 1 to 4 percent of total cases [ 3 ]. Although hypertriglyceridemia is an established risk factor for acute pancreatitis, the precise relationship between acute pancreatitis and triglyceride levels remains unclear. In acute pancreatitis, there appears to be a process of triglyceride conversion into toxic free fatty acids FFA by pancreatic lipases resulting into lipotoxicity [ 6 , 7 ].

The severity of acute pancreatitis in patients with HTG is dependent on both the inflammatory response caused by acute pancreatitis and the injury caused by lipotoxicity from triglyceride hydrolysis. Secondary causes were also considered, as other conditions can elevate triglycerides and can culminate in HTG induced acute pancreatitis [ 8 ]. In our patient, a workup of secondary causes of hypertriglyceridemia was unremarkable apart from a past medical history of diabetes.

A morbidly obese year-old female with a history of hypertension, dyslipidemia, and diabetes mellitus presented with severe abdominal pain. She had an episode of acute pancreatitis one year ago. She complained of right upper quadrant pain radiating to the back over 6-hour duration alongside six episodes of vomitus.

A review of systems was only notable for a headache and dizziness. She reported no family history of dyslipidemia or acute pancreatitis.

She denied tobacco, alcohol, or illicit substance use. There was no history of gallstones, appendectomy, new medications, procedures including ERCP , or any complications related to her diabetes. The patient was alert and orientated but was in moderate distress. The abdomen was obese and soft and with tenderness in the epigastric region. Her body mass index BMI was Other systemic signs of elevated triglycerides including xanthelasma, corneal arcus, and tendon xanthoma were absent.

Initial laboratory investigations showed an elevated white cell count of Liver function tests showed total bilirubin 0. Initial arterial blood gas ABG analysis showed pH 7. Computed tomography CT of the abdomen showed diffuse enlargement of the pancreas consistent with pancreatitis Figure 1.

There was no evidence of gallstones or biliary sludge which was also confirmed by an ultrasound abdomen. Other competing etiologies including alcohol, autoimmune pancreatitis, abdominal trauma, pancreatic divisum, sphincter of Oddi dysfunction SOD , viral infection, drugs, and toxins were all ruled out, making the most likely diagnosis hypertriglyceridemia-induced AP HTG AP.

The patient was treated with boluses of intravenous IV normal saline and supportive care. On the second day of admission, the patient developed hypotension and had persistent tachycardia. She likely developed acute respiratory distress syndrome ARDS from complications of acute pancreatitis. Fluid overload was ruled out with a sonogram of the inferior vena cava diameter of 1. The patient was subsequently transferred to the intensive care unit for hypovolemic shock and respiratory distress requiring intubation and mechanical ventilation.

ABG analysis showed pH of 7. Following the patients decline into shock, an ABG indicated an acidic pH of 6. Lactic acid level was 3. Repeat abdominal contrast-enhanced CT on the third day showed marked pancreatic and peripancreatic infiltration consistent with AP and no signs of necrosis. She was also started on a liquid diet via nasogastric tube from day 5.

After nine days in the ICU, the patient was successfully extubated and was switched to oral diet on day 11, which was gradually advanced as tolerated. She was downgraded to the floor on the same day and discharged on day The patient required nasal oxygen to maintain saturation as she was recovering from ARDS.

Acute pancreatitis has several etiologies, but alcohol and gallstones make up the majority of the cases [ 9 ]. The exact mechanism of acute pancreatitis AP remains unclear and has been hypothesized as an imbalance between proinflammatory and anti-inflammatory cytokines [ 10 ]. Thus, any sizable ICU will encounter this disorder regularly and must have expertise in dealing with it. However, hypertriglyceridemic pancreatitis is uncommon enough that almost no high-quality evidence exists regarding it.

Case reports and recommendations in the literature abound, yet contradict one another. Practice varies widely from being extremely aggressive e. Most patients will improve with only supportive care , so it's easy for different authors to obtain case series of patients who appear to respond to their preferred therapy. To date, only a single prospective RCT has been performed to rigorously test any of these therapies and — spoiler alert — the more conservative treatment arm had superior outcomes.

The treatment strategy described below attempts to cut a middle ground through this literature, with a strategy which is reasonably aggressive yet fairly noninvasive. In the absence of definitive evidence, this is only one of many reasonable therapeutic approaches. Without any specific therapy, triglyceride levels tend to fall over time likely related to fluid resuscitation and reduced oral fat intake. This natural fall has been well documented over decades; for example, in this study from Insulin infusion would be expected to accelerate the fall in triglyceride levels e.

However, a recent retrospective study compared the rate of triglyceride clearance among patients treated with insulin versus patients who didn't receive insulin. No difference was detected, as shown below. Why didn't insulin accelerate triglyceride clearance to any measurable extent? It seems that the primary driver of the drop in triglyceride levels over time may be reduced oral fat intake and gentle fluid resuscitation. Insulin administration may not add much to these treatments.

This drop in triglyceride levels with conservative therapy only has been replicated by another recent study as well.

It's extremely important to realize that triglyceride levels will fall on their own, without any fancy intervention. Many case reports have demonstrated that triglyceride levels fall with various interventions e. However, these reductions in triglyceride levels may simply reflect the natural history of the disease. The above model of hypertriglyceridemic pancreatitis hasn't been rigorously proven, but seems consistent with observed evidence.

This model has implications for the treatment of hypertriglyceridemic pancreatitis — specifically, that treatments should focus largely on reducing the free fatty acid levels not necessarily reducing the triglyceride level. When viewed through this lens, treatment implications include the following:. Diagnosing hypertriglyceridemic pancreatitis isn't quite as simple as merely measuring a triglyceride level.

If such a person were to develop a gallstone obstructing their pancreatic duct, they would have pancreatitis and hypertriglyceridemia — but the hypertriglyceridemia wouldn't really be the cause of their pancreatitis. Want to Download the Episode? We are the EMCrit Project , a team of independent medical bloggers and podcasters joined together by our common love of cutting-edge care, iconoclastic ramblings, and FOAM. Triglycerides are a form of fat which is trafficked around the body stuffed together within small particles e.

Triglycerides are also the main form of fat stored within adipose tissue. Triglycerides within chylomicrons or VLDL particles seem to be relatively inert. Triglycerides may be metabolized into glycerol plus free fatty acids. Free fatty acids are more water-soluble, so they can dissolve in the blood directly. Free fatty acids appear to be more toxic than triglycerides more on this below.

Inadequate insulin activity leads to lipolysis of triglycerides in adipose cells, releasing free fatty acids into circulation. Some of these free fatty acids are converted by the liver back into triglycerides which circulate in the bloodstream in the form of Very Low Density Lipoproteins VLDL.

Inadequate insulin activity leads to an accumulation of triglycerides in circulation e. When insulin's effects are severely deficient, this physiology may also lead to ketoacid production as free fatty acids are metabolized into ketoacids.

This explains the following clinical phenomena: Patients presenting with diabetic ketoacidosis may have elevated levels of triglycerides. In some cases, insulin deficiency may simultaneously trigger diabetic ketoacidosis and hypertriglyceridemic pancreatitis. The exact mechanism causing pancreatitis isn't entirely clear.

Two possible explainations are as follows: 1 Toxicity due to elevated triglyceride levels?? However, many patients live for years with extremely high triglyceride levels and do not develop pancreatitis, so hypertriglyceridemia alone doesn't seem to be particularly toxic.

It's debatable whether triglycerides are toxic at all, with some authors stating that they lack inherent toxicity. Free fatty acids can stimulate inflammation and form conglomerates that act as a detergent to damage cell membranes. As discussed above, this doesn't appear to be true. Rather than hypertriglyceridemia, it's probably the elevation of free fatty acid levels which causes pancreatitis.

Thus, we remain fixated on the triglyceride level — although this level probably serves as a surrogate measurement of free fatty acid levels which may be the true culprit. Hypocalcemia might be an indirect measurement of elevated fatty acid levels, because the fatty acids can bind to calcium. This natural fall has been well documented over decades; for example, in this study from Insulin infusion would be expected to accelerate the fall in triglyceride levels e.

When viewed through this lens, treatment implications include the following: insulin therapy A biochemical understanding of fatty acid metabolism suggests that insulin should be the front-line therapy for hypertriglyceridemic pancreatitis. Insulin administration is the fastest way to shut off fatty acid production and reduce free fatty acid levels. Analogous to diabetic ketoacidosis, insulin administration has the ability to drop free fatty acid levels within hours.

However, this doesn't make sense, given that insulin doesn't appear to substantially affect triglyceride levels see above. A more sensible approach may be to simply continue an insulin infusion until the patient is making a sustained clinical recovery. Estrogen therapy has also been found to induce pancreatitis in women with type V hyperlipoproteinemia [20].

Type IV hyperlipoproteinemiais an autosomal dominant condition characterized by an increased production of VLDL and generally require another factor such as diabetes or alcohol in order to induce pancreatitis [9,21].

Therefore, this condition should generally be considered in the presence of contributing factors. Non-insulin dependent diabetes mellitus is a well-known cause of hypertriglyceridemia and is the most common cause of hypertriglyceride-induced pancreatitis [1]. There are several mechanisms that may explain this phenomenon. One described thoroughly in literature that may play the largest role in hypertriglyceridemia in insulin resistant patients is the loss of the inhibitory effect of insulin on VLDL apolipoprotein B production by hepatocytes [22].

In addition, Lipoprotein lipase is regulated by insulin levels through gene expression, synthesis and secretion. All of these factors may be impaired in insulin-resistant patients [23]. While hypertriglyceridemia is the most common lipid abnormality in these patients, most well controlled diabetics have triglyceride levels that are within the normal range [24].

However, abrupt elevations in serum triglyceride levels can occur and may result in pancreatitis [24]. Like triglyceride induced pancreatitis, patients with diabetic ketoacidosis DKA may also present with markedly elevated serum triglycerides and acute abdominal pain making it more difficult to differentiate the two entities [16,25].

Deficiency of insulin promotes lipolysis in adipose tissue followed by release of free fatty acids which will eventually be converted to very low density lipoproteins, which, coupled with the inhibition of lipoprotein lipase in peripheral tissues, results in hypertriglyceridemia [26].

Nair et al. DKA patients with pancreatitis had higher glucose levels with higher anion gap acidosis compared to the patients without pancreatitis.

Serum triglyceride levels improved with resolution of ketosis but not with acidosis or anion gap [16]. The degree of hypertriglyceridemia however, did not correlate with the severity of ketoacidosis [25]. Alcohol, when taken with a meal high in saturated fat, can increase postprandial triglyceride level significantly.

On the other hand, excessive alcohol intake can cause hypertriglyceridemia even in a fasting state because it promotes the synthesis of large VLDL particles in the liver. Furthermore, alcohol increases the synthesis of large VLDL particles in the liver, which is the main source of triglycerides in the hypertriglyceridemia associated with chronic excessive alcohol intake.

In case of chronic consumption, lipoprotein lipase activity seems to adapt itself. In an animal study comparing the triglyceride levels after acute and chronic ingestion of alcohol, it was shown that the increase in triglyceride levels were less pronounced in rats subjected to chronic alcohol intake in a non-fasting state, confirming that chronic alcohol intake stimulates the production of extrahepatic lipoprotein lipase in response to the increased triglyceride concentration.

In some cases, acute alcohol intake may cause significantly elevated triglyceride levels with an increased risk of pancreatitis, especially patients with metabolic syndrome[26].

Medications such as estrogen, estradiol, glucocorticoids, thiazide diuretics, beta blockers, sertraline, protease inhibitors, valproate and related drugs, and isotretinoin can cause severe hypertriglyceridemia and the chylomicronemia syndrome in patients with inherited lipid metabolic syndromes Table 2 [27].

These drugs reduce lipoprotein lipase and hepatic triglyceride lipase activity [28]. Oddly, fenofibrates, which decrease triglyceride levels, causes an increased risk of pancreatitis among patients with type 2 DM[29].

Table 2. Causes of Sever Hypertriglyceridemia that maybe associated with pancreatitis [41]. Table 2 shows a list of genetic and acquired cause of severe hypertriglyceridemia that maybe associated with pancreatitis. This was adopted from a scientific statement by the American Heart Association on triglycerides and cardiovascular disease [30]. Initial treatment of hypertriglyceride-induced pancreatitis is no different from treating other causes of pancreatitis bowel rest, aggressive intravenous hydration, pain control and anti-emetics.

A recent study shows that goal-directed hemodynamic management guided by functional hemodynamic parameters such as stroke volume variation, compared to CVP-guided therapy, led to a significantly improved survival, tissue oxygenation, and microcirculatory perfusion, as well as less histopathologic damage in porcine model of severe acute pancreatitis[31]. There are still no randomized studies that compare the efficacy of the different treatment regimens used in the management of this disease.

Insulin may be considered the first choice with or without heparin in patients with concomitant hyperglycemia, but appears to be slower in action compared with apheresis, which decreases serum triglycerides and decrease symptoms in a very short period of time [34].

Intravenous insulin and heparin administration should be considered in patients with concomitant hyperglycemia[32]. Insulin activate lipoprotein lipase which degrade chylomicrons into glycerol and free fatty acids resulting in rapid reduction of triglyceride levels [35,36]. Subcutaneous regular insulin dosed at 0. Intravenous insulin is more efficacious than subcutaneous insulin for treating hypertriglyceride-induced pancreatitis.

While insulin has been shown to be effective when used as monotherapy [37], intravenous heparin does not. Heparin stimulates the release of endothelial lipoprotein lipase and causing an initial rise of the circulating enzyme but is immediately followed by its degradation in the liver resulting in its further depletion and recurrence of hypertriglyceridemia [38]. That is why heparin is recommended only as an adjunct treatment to insulin.

A single bolus of low molecular weight heparin Dalteparin was found to deplete lipoprotein lipase similarly to unfractionated heparin [39]. Apheresis is capable of rapidly lowering markedly elevated triglyceride levels, clear prancreatic enzymes, and provides symptom relief from pancreatitis within 2. Several studies have shown that apheresis can significantly decrease serum triglycerides and cause both clinical and laboratory improvement when conservative treatment with diet and pharmaceutical drugs fail.

All these studies also stress the importance of performing apheresis as soon as possible to maximize therapeutic benefit. Its limiting factor is, however, its availability and very high cost. Prevention of initial and recurrent pancreatitis from hypertriglyceridemia should be emphasized. However, drug treatment with fenofibrates or niacin of asymptomatic persons with high triglyceride levels, particularly those less than Lastly, Pancreatic enzyme therapy has been shown to alleviate abdominal symptoms [49].

Risk factors for hypertriglyceridemia such as insulin resistance and alcoholism should be assessed in this setting as these are correctible factors that can be treated to avoid future bouts of pancreatitis in patients with occult hereditary lipid metabolism disorders. Epidemiologic reports have shown the glycemic index of foods has a direct correlation to triglyceride levels [50]. In conclusion, we provide an evidence based algorithm to summarize the approach to the etiology of hypertriglyceride-induced pancreatitis.

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