Pathways Case Record: Hypertriglyceridemia-associated Acute Pancreatitis in a Male With Exogenous Estrogen Use

A 26-year-old male (preferred pronouns he/him) desiring a male-to-female transition presented with acute, severe cramping and abdominal pain. His past medical history was significant for depression, remote history of elevated fasting triglycerides (TG) on routine laboratory testing, and a family history of high cholesterol. Before the presentation, he routinely took omega-3 fatty acids, vitamin D, and Pueraria mirifica (a phytoestrogen). He had been taking P. mirifica for two years, but he had recently increased the dose. Physical examination was notable for diffuse abdominal tenderness and gynecomastia with a normal fat distribution. Initial laboratory tests revealed elevated levels of lipase and fasting lipid levels (e.g., total cholesterol, TG). Abdominal CT showed acute necrotizing pancreatitis, resulting in a diagnosis of hypertriglyceridemia (HTG)-induced pancreatitis.

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The patient received conservative treatment with nothing by mouth diet, analgesia, aggressive fluid resuscitation, and insulin infusion, which was titrated throughout his hospitalization. His pancreatitis symptoms resolved within 48 hours, but his TGs remained drastically elevated despite appropriate therapy. The Pathways Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on the mechanisms of acute pancreatitis in the setting of HTG, which was driven by three questions:

1. What causes HTG-induced acute pancreatitis?
2. What role does estrogen play in TG metabolism?
3. Do supraphysiologic estrogen levels have a direct toxic effect on the pancreas?

Background and Diagnosis

HTG refers to circulating TG levels surpassing 175 mg/dL. TGs, the most common type of fat in the body, are composed of a glycerol backbone and three fatty acids, which can be broken down by lipases and processed as a source of energy yielding large quantities of ATP. The primary transporters of TGs in the blood are lipoproteins, such as chylomicrons, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL). Chylomicrons and VLDLs are primarily composed of TGs, while LDL and HSL are mainly comprised of cholesterol and apolipoproteins. Mild-to-moderate HTG results from VLDL accumulation, whereas severe HTG occurs due to the accumulation of both VLDL and chylomicrons. The collection of plasma chylomicrons can occur due to inherited disturbances in lipolysis, leading to inefficient chylomicron metabolism (Front Endocrinol [Lausanne]). Familial chylomicronemia syndrome (FCS) is a rare, monogenic form of HTG resulting from biallelic loss-of-function variants from one of five critical genes associated with breakdown of chylomicrons: LPL, APOC2, APOA5, LMF1, and GHIBP1. Most patients with severe HTG do not have FCS, but rather multifactorial chylomicronemia (MCM), which results from either a rare heterozygous variant in the five genes associated with FCS or an accumulation of common small-effect variants (Arterioscler Thromb Vasc Biol). Acute pancreatitis in patients with FCS or MCM is typically severe and life-threatening.

The most common causes of acute pancreatitis are gallstones blocking the pancreatic duct and alcohol-related damage. Less common causes of pancreatitis include infections, medications, genetic predisposition, pancreatic injury and HTG (N Engl J Med). The mechanism underlying the development of pancreatitis in the setting of HTG remains poorly understood. One hypothesis is that severely elevated TG-rich particles result in physical disruption of capillary blood flow through the pancreas, leading to ischemic damage (United European Gastroenterol J). The absence of similar ischemic injury in highly sensitive organs (e.g., heart and brain) in individuals with HTG makes this less likely in our view. An alternative hypothesis is that the leakage of pancreatic lipase into the pancreatic interstitium elevates TG breakdown products (non-esterified fatty acids) which are toxic to some tissues, including the pancreas. Experimental models have demonstrated promising results for the role of pancreatic lipase in HTG-induced pancreatitis (J Clin Invest). It is possible that elevated plasma TGs led to overexpression of pancreatic lipase, contributing to acute pancreatitis (Gut).

Our patient presented shortly after doubling the dose of his phytoestrogen supplement. The composition of the phytoestrogen taken by our patient is not known, and pancreatic toxicity from non-phytoestrogen components of the compound remains a possibility; alternatively, the specific combination of phytoestrogens found in this compound could be responsible for the observed pancreatic toxicity or estrogen-like effects. Our team focused first on the question: what is the role of estrogen in lipid metabolism, specifically the activity of pancreatic lipase? P. mirifica is an herbal supplement structurally and functionally like 17β-estradiol (E2), the predominant endogenous circulating estrogen (Adv Exp Med Biol). Given the similarities between E2 and P. mirifica, we focused on the effects of E2. Estrogens can increase blood levels of TGs, although this is typically a harmless elevation in patients with normal baseline levels (J Clin Lipidol). For example, pregnant women have consistently elevated lipid levels during high estrogen states (i.e., second and third trimester). Still, only a small subset with underlying risk factors develops severe gestational HTG or severe acute pancreatitis (Obstet Med).

Changes in lipid levels following estrogen exposure can be explained by estrogen's effects on the liver. At high concentrations, estrogen has been shown to enhance lipogenesis and synthesis of Apo-B100, a critical component for VLDL production. Estrogen also suppresses hepatic lipase, which regulates and hydrolyzes VLDL and HDL (Obstet Med, J Lipid Res). Additionally, LDL receptor levels are upregulated by supraphysiologic estrogen levels while adipose lipoprotein lipase is suppressed (J Clin Lipidol, J Lipid Res). Interestingly, transdermal estradiol preparations do not increase VLDL production, suggesting that high first-pass hepatic metabolism of oral estradiol supplements triggers a cascade ultimately leading to HTG. While this suggests that estrogen can increase TG levels which can lead to pancreatitis, reports of estrogen-related pancreatitis in postmenopausal women with normal lipids suggest an additional direct mechanism of estrogen toxicity in the pancreas (Menopause).

Pancreatic acinar cells, the functional unit of the exocrine pancreas, have large amounts of estradiol binding proteins, demonstrating that they are primed to respond to estrogen. In experimental models, chronic estradiol treatment of ovariectomized rats was associated with increased total cellular amylase, suggesting an estrogen-dependent effect on the production of exocrine enzymes (Life Sci). Furthermore, estrogen may also increase the calcium-dependent release of pancreatic lipase vacuoles by upregulating G-protein coupled estrogen receptors (GPER) in acinar cells. Based on current knowledge and our patient's presentation, the Pathways team hypothesized that exogenous estrogen increased pancreatic lipase through signaling of GPER in acinar cells resulting in a leak of pancreatic lipase, local inflammation, and subsequently, pancreatitis.

Summary and Future Steps

In the process of a male-to-female transition using over-the-counter phytoestrogens, our patient presented with acute pancreatitis and early evidence of pancreatic necrosis in the setting of severe, refractory HTG. The combination of genetic susceptibility for HTG and ingestion of oral phytoestrogen may have initiated a cascade, ultimately resulting in pancreatitis in our patient. We recommend a LipidSeq panel to determine if any variants associated with HTG are present in our patient. We further recommend investigation into the role of estrogen in HTG using experimental models to determine:

1. Do elevated plasma TGs promote pancreatic lipase expression?
2. Does estrogen directly stimulate pancreatic lipase production and/or release from pancreatic acinar cells?
3. Does the combination of HTG and estrogen amplify the risk of acute pancreatitis?

Taken together, the information from these experiments would elucidate mechanisms and define the relationship between TGs, exogenous estrogens, diet and pancreatitis risk. These findings could benefit our patient and other patients treated with exogenous estrogen supplementation.

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