Pancreas Function & Chemical Pathology

Pancreas Function & Chemical Pathology

• The pancreas is an elongated, flattened pyramidal organ, primarily located behind the stomach.
• Its tail points towards the spleen, and the head is nestled within the duodenal loop.
• It is a soft gland, susceptible to trauma, positioned behind the peritoneum (the membrane lining the abdominal cavity).

Exocrine Secretions

• Exocrine secretions are drained through ductules that merge into a single pancreatic duct.
• In most individuals, this duct joins the common bile duct at the Ampulla of Vater.

Pancreatic Islets

• Pancreatic islets (Islets of Langerhans) account for about 1% of the pancreatic mass.
• These islets produce endocrine hormones.
• The pancreas contains approximately one million islets.
• The exocrine acinar cells make up over 98% of the pancreatic mass.

Endocrine Physiology

• Pancreatic endocrine secretions from the islets of Langerhans include various hormones, including:
  • Glucagon
  • Insulin
  • Somatostatin
  • Pancreatic polypeptide

Normal Pancreatic Exocrine Secretion

• The pancreas produces at least 22 digestive enzymes, 15 of which are proteases.
• These enzymes aid in the breakdown of proteins, lipids, and complex carbohydrates (dietary energy sources).
• The functional units of the exocrine pancreas are acini, which store digestive enzymes in inactive forms (zymogens) within zymogen granules.

Proenzyme Forms of Proteolytic Enzymes

• Proenzyme forms of proteolytic enzymes prevent autodigestion of the zymogen granules, acinar cells, and the pancreas itself.
• The pancreas also releases protease inhibitors to neutralize potentially misactivated enzymes.
• Congenital deficiencies in trypsinogen inhibitors can predispose individuals to acute pancreatitis.

Enterokinase's Role

• Enterokinase, a brush border enzyme in the duodenum, converts trypsinogen to trypsin.
• Free trypsin then activates other pancreatic proenzymes.

Normal Pancreatic Fluid Secretion

• A healthy adult secretes approximately 2-3 liters of pancreatic juice daily.
• This fluid contains bicarbonate ions (ranging from 120-300 mmol/day).
• Pancreatic juice also contains digestive enzymes.

Pancreatic Juice Composition

• Pancreatic juice includes enzymes with amylase and lipase activity, reaching levels of 500,000 to 1 million U/L.
• Plasma enzyme activities are significantly lower, approximately 1:10,000 of these values.
• Damage to the pancreas can result in elevated levels of these enzymes in the blood.

Control of Exocrine Pancreatic Secretion

• The secretion of pancreatic juice is governed by both neural and hormonal mechanisms.
• Upper gastrointestinal (GI) tract hormones like cholecystokinin (CCK), secretin, and gastrin influence pancreatic juice secretion.
• Ingestion of substances like alcohol or distension of the duodenum stimulate the release of these hormones.

Pathological Conditions

• Pancreatic disease categories include:
  • Islet disorders (e.g., diabetes, glucagon excess)
  • Exocrine insufficiency
  • Inflammatory disorders (e.g., acute and chronic pancreatitis)
  • Neoplastic disorders (e.g., adenocarcinomas, islet cell tumors)

Endocrine Pancreatic Disorders

• Diabetes mellitus is the primary endocrine disorder, characterized by either insufficient insulin secretion or insulin resistance.
• Pancreatic islet cell tumors can lead to excessive hormone production.
• Different islet cell tumors can cause unique clinical syndromes,

Exocrine Pancreatic Disorders

• Acute pancreatitis is an inflammatory disorder related to the activation of pancreatic enzymes, potentially leading to tissue destruction.
• Causes of acute pancreatitis often include alcohol abuse and biliary tract obstruction (often gallstones).

Inflammatory or Necrotic Pancreatic Injury

• Severe acute pancreatitis constitutes a life-threatening medical emergency.
• Lab tests like ALT are often used for diagnosis when gallstones are suspected as a cause of the pancreatitis.

Acute Pancreatitis - Causes

• The most common causes of acute pancreatitis are alcohol abuse and biliary obstruction by gallstones, accounting for approximately 75% of cases.

Acute Pancreatitis - Diagnosis

• Elevated levels of serum amylase and lipase are often observed in acute pancreatitis; however, they are not always reliable predictors of disease severity.
• CRP can be useful in assessing prognosis

Ranson's Criteria for Acute Pancreatitis

• Ranson's criteria help predict the prognosis of acute pancreatitis and assign a mortality risk score; there are several variables measured at initial presentation and 48 hrs after admission.

Chronic Pancreatitis

• Chronic pancreatitis is often a consequence of recurrent acute pancreatitis, but it is not an everyday occurrence.
• In some cases, extensive tissue destruction within the gland causes diabetes
• During acute flare-ups, serum amylase and lipase activities increase.

Cystic Fibrosis

• Cystic fibrosis is a genetically inherited autosomal recessive disease.
• Mutations within the chloride transport genes cause cystic fibrosis, leading to nonfunctional CFTR proteins.
• This results in thicker, lower volume mucus and secretions, blocking pancreatic ducts..
• Newborn screening relies on elevated serum immunoreactive trypsin (IRT).

Pancreatic Insufficiency

• Reduced/lost pancreatic exocrine function, a long-term issue, can lead to severe gastrointestinal problems such as diarrhea, constipation, malabsorption, weight loss, and cachexia.

Common Causes of Pancreatic Insufficiency

• In children: Cystic fibrosis
• In adults: Chronic pancreatitis

Pancreatic Neoplasms

• Adenocarcinoma, arising from ductal epithelial cells, is a common and typically dangerous form of pancreatic cancer.
• Islet cell tumors constitute a smaller fraction (~1%) of pancreatic neoplasms, often detected by their hormone production.

Insulinoma

• An insulinoma is an insulin-producing tumor that typically results in hypoglycemia.
• It is a rare type of pancreatic islet cell tumor.

Glucagonoma

• A glucagonoma produces glucagon, often causing hyperglycemia, weight loss, and a skin rash.

Exocrine Pancreatic Tests

• The best sample for assessing pancreas function is duodenal fluid, containing bicarbonate and pancreatic enzymes (e.g., amylase, lipase, chymotrypsin).

Tests on Feces

• Assessment of fat and certain enzymes in stool is less sensitive for mild to moderate pancreatic disorders. The levels of enzymes become abnormal only once around 85-90% of the acinar tissue is lost

Indirect Tests of Pancreatic Function

• Indirect tests, like N-benzoyl-tyrosyl-para-aminobenzoic acid (NBT-PABA), are used to assess pancreatic function.
• Pancreatic enzyme levels in the blood serve as markers of cellular damage in the pancreas.
• Amylase and lipase measurements are common indirect methods used in these assessments.

Changes in Analytes with Disease

• Increased serum amylase, lipase levels, and immunoreactive trypsin are typically observed in pancreatitis.

Amylase and Lipase

• Amylase and lipase measurements, though helpful in diagnosing pancreatitis, may not always predict the disease's severity.
• Lipase is a more specific marker for diagnosing pancreatitis compared to amylase, and the guidelines often favor using a single enzyme measurement (either one) to validate pancreatitis.

Cancer Markers

• CA19-9 is the frequently used pancreatic cancer marker, though it isn't specific to pancreatic cancer and can be elevated in benign conditions (i.e., bile duct issues).

Endocrine Tumor Markers

• Approximately 20% of islet cell tumors are biochemically silent and do not secrete active hormones.
• These tumors often still secrete other hormones (e.g., insulin, glucagon, gastrin) that need to be considered during diagnosis.

Insulin

• Insulin levels are often reported as a ratio to glucose
• A ratio of above 0.3 suggests inappropriate insulin production, potentially indicative of an insulinoma, and usually is associated with increased C-peptide levels

Glucagon

• Glucagonoma identification relies on plasma glucagon measurement.
• A glucagon level greater than 1000 pg/mL is typically indicative of a glucagonoma but can also be elevated in several other conditions like severe renal issues, starvation, and pancreatitis.