Nils Ewald

Severe hypertriglyceridemia and pancreatitis: presentation and management

Purpose of review Hypertriglyceridemia (HTG) is a well recognized cause of acute pancreatitis accounting for approximately up to 10% of all cases and even up to 50% of all cases in pregnancy. Both primary and secondary disorders of lipoprotein metabolism may be associated with hypertriglyceridemic pancreatitis (HTGP). The purpose of this review is to provide an overview of the current studies on presentation and management of HTGP. Recent findings/conclusion Hydrolysis of triglycerides by pancreatic lipase and formation of free fatty acids that induce inflammatory changes are postulated to account for the development of HTGP, yet the exact pathophysiology remains unclear. The clinical features of patients with HTGP are generally not different from patients with acute pancreatitis of other causes, and there is some evidence that HTGP is associated with a higher severity or a higher complication rate. There is no clear evidence as to which HTG patients will develop pancreatitis. Several studies have evaluated the effect of apheresis, the benefit of insulin and/or heparin treatment and the use of different antihyperlipidemic agents in HTGP. Dietary modifications resemble the key features in the long-term management of HTG. Whether HTG may cause chronic pancreatitis in the long-term follow-up remains controversial.

Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c)

Diabetes mellitus secondary to pancreatic diseases is a condition seldom thought of in clinical practice. Yet, a high percentage of exocrine pancreatic insufficiency has been reported for the general population and especially for diabetic subjects. Thus, we investigated the prevalence of diabetes mellitus due to pancreatic diseases.

Current knowledge of hypertriglyceridemic pancreatitis

Severe hypertriglyceridemia (HTG) is a well established and the most common cause of acute pancreatitis (AP) after alcohol and gall stone disease. It is alleged to account for up to 10% of all pancreatitis episodes. Studies suggest that in patients with triglyceride (TG) levels>1000 mg/dL (>11.3 mmol/L), hypertriglyceridemia-induced acute pancreatitis (HTGP-AP) occurs in approximately 15-20% of all subjects referred to Lipid Clinics. Until now, there is no clear evidence which patients with severe HTG will develop pancreatitis and which will not. Underlying pathophysiological concepts include hydrolysis of TG by pancreatic lipase and excessive formation of free fatty acids with inflammatory changes and capillary injury. Additionally hyperviscosity and ischemia may play a decisive role. The clinical features of HTG-AP patients are supposed to be no different from patients with AP of other etiologies. Yet, there are well-conducted studies suggesting that HTG-AP is associated with a higher severity and complication rate. Therapeutic measurements in HTG-AP include dietary modifications, different antihyperlipidemic agents, insulin and/or heparin treatment. The beneficial use of plasmapheresis is repeatedly reported and suggested in many studies. Yet, due to the lack of randomized and controlled trials, it is currently unknown if plasmapheresis may improve morbidity and mortality in the clinical setting of HTG-AP. Since there are no commonly accepted clinical guidelines in the management of HTG-AP, there is a definite need for an international, multicenter approach to this important subject.

Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes?

Pancreatic exocrine insufficiency is a frequently observed phenomenon in type 1 and type 2 diabetes mellitus. Alterations of exocrine pancreatic morphology can also be found frequently in diabetic patients. Several hypotheses try to explain these findings, including lack of insulin as a trophic factor for exocrine tissue, changes in secretion and/or action of other islet hormones, and autoimmunity against common endocrine and exocrine antigens. Another explanation might be that diabetes mellitus could also be a consequence of underlying pancreatic diseases (e.g., chronic pancreatitis). Another pathophysiological concept proposes the functional and morphological alterations as a consequence of diabetic neuropathy. This paper discusses the currently available studies on this subject and tries to provide an overview of the current concepts of exocrine pancreatic insufficiency in diabetes mellitus.

Diagnosis and treatment of diabetes mellitus in chronic pancreatitis

Diabetes secondary to pancreatic diseases is commonly referred to as pancreatogenic diabetes or type 3c diabetes mellitus. It is a clinically relevant condition with a prevalence of 5%-10% among all diabetic subjects in Western populations. In nearly 80% of all type 3c diabetes mellitus cases, chronic pancreatitis seems to be the underlying disease. The prevalence and clinical importance of diabetes secondary to chronic pancreatitis has certainly been underestimated and underappreciated so far. In contrast to the management of type 1 or type 2 diabetes mellitus, the endocrinopathy in type 3c is very complex. The course of the disease is complicated by additional present comorbidities such as maldigestion and concomitant qualitative malnutrition. General awareness that patients with known and/or clinically overt chronic pancreatitis will develop type 3c diabetes mellitus (up to 90% of all cases) is rather good. However, in a patient first presenting with diabetes mellitus, chronic pancreatitis as a potential causative condition is seldom considered. Thus many patients are misdiagnosed. The failure to correctly diagnose type 3 diabetes mellitus leads to a failure to implement an appropriate medical therapy. In patients with type 3c diabetes mellitus treating exocrine pancreatic insufficiency, preventing or treating a lack of fat-soluble vitamins (especially vitamin D) and restoring impaired fat hydrolysis and incretin secretion are key-features of medical therapy.

Diabetes mellitus secondary to pancreatic diseases (Type 3c) — Are we neglecting an important disease?

Type 3c diabetes mellitus (T3cDM) is a clinically relevant condition with a prevalence of 5-10% among all diabetic subjects in Western populations. Its prevalence and clinical importance have been underestimated and underappreciated so far. In contrast to the management of type 1 or type 2 diabetes, the endocrinopathy in T3cDM is very complex and complicated by additional present comorbidities such as maldigestion and concommitant qualitative malnutrition. The failure to correctly diagnose T3cDM leads to failure to implement an appropriate medical therapy of these patients. Physicians should screen for important and easily reversable pathological conditions such as exocrine insufficiency, lack of fat-soluble vitamins (especially vitamin D) and impairment of fat hydrolysis and incretin secretion which are found very commonly in T3cDM. Since most patients with T3cDM suffer from chronic pancreatitis, physicians must additionally be aware of the elevated risk of pancreatic cancer in this subset of patients.

Treatment options for severe hypertriglyceridemia (SHTG): the role of apheresis

Hypertriglyceridemia is associated with a number of severe diseases such as acute pancreatitis and coronary artery disease. In severe hypertriglyceridemia (SHTG, triglycerides > 1,000 mg/dL), rapid lowering of plasma triglycerides (TG) has to be achieved. Treatment regimes include nutritional intervention, the use of antihyperlipidemic drugs, and therapeutic apheresis. Apheretic treatment is indicated in medical emergencies such as hypertriglyceridemic pancreatitis. Reviewing the current literature, plasmapheresis appears to be a safe and useful therapeutic tool in patients suffering from SHTG. Apheretic treatment is able to remove the causative agent for pancreatic inflammation. Data suggests that the use of apheresis should be performed as early as possible in order to achieve best results. The use of plasmapheresis, however, is limited due to the rather high costs and the limited availability of the procedure.

Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-centre trial.

Recently, high prevalence of exocrine dysfunction in diabetic populations has been reported. Patients with fecal elastase 1 concentration (FEC) <100 µg/g have also been demonstrated to suffer from steatorrhea in about 60% of cases, indicating the need of pancreatic enzyme replacement therapy. Until now, there have only been a few reports on the use of enzyme replacement therapy in diabetic patients with exocrine pancreatic insufficiency. This investigation was designed to evaluate the impact of enzyme‐replacement therapy on glucose metabolism and diabetes treatment in a prospective study of insulin‐treated patients with diabetes mellitus.

Severe Hypertriglyceridemia: An indication for apheresis?

OBJECTIVE Severe hypertriglyceridemia is associated with a number of severe complications such as acute pancreatitis. Rapid lowering of excessively elevated triglyceride (TG) levels is therefore a primary medical goal in these patients. According to previous reports, immediate apheretic treatment might be an interesting option in order to rapidly lower excessively elevated TG levels. METHODS A review of the current available literature was therefore conducted in order to provide an overview of the present data on apheretic treatment for patients with severe hypertriglyceridemia. RESULTS A single session of plasmapheresis proofs capable of lowering TG levels by up to 70%, producing clear clinical and laboratory improval. The best clinical benefit concerning reduction in morbitity and mortality can be achieved when apheresis is used as early as possible. Even repetitive use of apheresis is reported. There is controversy on technical details, such as different apheresis techniques (plasma exchange versus double-membrane filtration), slightly favoring plasma exchange. CONCLUSIONS In patients with severe hypertriglyceridemia plasmapheresis seems to be a safe and useful tool in rapidly lowering excessively elevated TG levels. Apheresis can be used to rapidly decrease triglyceride levels, and thus remove the causative agent for continuing damage. The indications are medical emergencies such as hypertriglyceridemic pancreatitis with excessively elevated TG levels (TG > 1000 mg/dl). If indicated, it should be used as early as possible.

Tumor M2 pyruvate kinase: a tumor marker and its clinical application in gastrointestinal malignancy

Proliferating cells, in particular tumor cells, express a dimeric isoenzyme of pyruvate kinase, termed Tumor M2 pyruvate kinase. In the last few years, much attention has been paid to this novel tumor marker that can be determined in EDTA–plasma and in the feces. It has been used in diagnosis and surveillance of a variety of malignant diseases. As compared with the established tumor markers, Tumor M2-PK in EDTA–plasma proves to have at least equal sensitivity in pancreatic, gastric, esophageal, colorectal and cholangiocellular cancer. In combination with established tumor markers, EDTA–plasma M2-PK is a useful tool in diagnosis and surveillance of gastrointestinal tumors. In colorectal cancer, M2-PK in EDTA–plasma even proves superiority as compared with CEA. Fecal Tumor M2-PK testing resembles a good noninvasive screening parameter for colorectal cancer with a reported sensitivity of 68.8–91.0% and a specificity of 71.9–100%. It is superior to fecal occult blood testing in colorectal cancer screening. Since it is effective, easy to handle and bears rather low costs, fecal Tumor M2-PK testing is recommended for large-scale CRC screening.