The Endocrine System
Basic Concept Of endocrines
The development, structure and functions of the human body are governed and maintained by 2 mutually interlinked systems the endocrine system and the nervous system; a third system combining features of both these systems is appropriately called the neuroendocrine system.
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Neuroendocrine System:
This system forms a link between endocrine glands and the nervous system. The cells of this system elaborate polypeptide hormones; owing to these biochemical properties, it has also been called an APUD cell system (an acronym for Amine Precursor Uptake and Decarboxylation properties).
Read And Learn More: Systemic Pathology Notes
However, though having common biochemical properties, the cells of this system are widely distributed in the body in different anatomic areas; hence it is called a dispersed neuroendocrine system. Cells comprising this system are as under:
- Neuroendocrine cells are present in the gastric and intestinal mucosa and elaborate peptide hormones.
- Neuroganglia cells lie in the ganglia cells in the sympathetic chain and elaborate amines.
- The adrenal medulla elaborates on epinephrine and norepinephrine.
- Parafollicular C cells of the thyroid secrete calcitonin.
- Islets of Langerhans in the pancreas (included in both endocrine and neuroendocrine systems) secrete insulin.
- Isolated cells in the left atrium of the heart secrete atrial natriuretic (salt-losing) peptide hormone.
In addition to the above, other non-endocrine secretions include neurotransmitter substances such as acetylcholine and dopamine released from neural synapses, and erythropoietin and vitamin D3 elaborated from the kidney.
Endocrine System:
- Anatomically, the endocrine system consists of 6 distinct organs: pituitary, adrenals, thyroid, parathyroids, gonads, and pancreatic islets; the last one is included in the neuroendocrine system also).
- Understanding the pathology of these endocrine organs requires the knowledge of the overall framework of hormone secretions, their actions and broad principles of feedback mechanisms.
- Broadly speaking, human hormones are divided into 5 major classes which are further grouped under two headings depending upon their site of interactions on the target cell receptors (whether cell membrane or nuclear receptor):
Group 1: Those interacting with cell-surface membrane receptors:
- 1. Amino acid derivatives: thyroid hormone, catecholamines.
- 2. Small neuropeptides: gonadotropin-releasing hormone (GnRH), thyrotropin-releasing hormone (TRH), somatostatin, and vasopressin.
Group 2: Those interacting with intracellular nuclear receptors:
- 3. Large proteins: insulin, luteinising hormone (LH), parathormone hormone.
- 4. Steroid hormones: cortisol, estrogen.
- 5. Vitamin derivatives: retinol (vitamin A) and vitamin D.
The synthesis of these hormones and their precursors takes place through a prescribed genetic pathway that involves: transcription → mRNA → protein synthesis → post-translational protein processing → intracellular sorting/membrane integration → secretion.
The major functions of hormones are as under:
- Growth and differentiation of cells: by pituitary hormones, thyroid, parathyroid, and steroid hormones.
- Maintenance of homeostasis: by the thyroid (by regulating BMR), parathormone, mineralocorticoids, vasopressin, and insulin.
- Reproduction: sexual development and activity, pregnancy, foetal development, menopause etc.
A basic feature of all endocrine glands is the existence of both negative and positive feedback control system that stimulates or regulates hormone production in a way that levels remain within the normal range (abbreviated as S or R respectively with the corresponding hormone example TSH-TRH pathway, GnRH-LH/FSH pathway etc).
This system is commonly termed the hypothalamic-pituitary hormone axis for different hormones schematically illustrated. The stimulatory or regulatory action by endocrine hormonal secretions may follow paracrine or autocrine pathways:
- Paracrine regulation means that the stimulatory/regulatory factors are released by one type of cell but act on another adjacent cell of the system.
- Autocrine regulation refers to the action of the factor on the same cell that produced it.
With this brief overview of the principles of the physiology of hormones, we now turn to the study of diseases of the endocrine organs. In general, pathologic conditions affecting endocrine glands with resultant hormonal abnormalities may have the following causes:
Hyperfunction: This results from an excess of hormone-secreting tissues hyperplasia, tumours (adenoma, carcinoma), ectopic hormone production, excessive stimulation from inflammation (often autoimmune), infections, iatrogenic (drugs-induced, hormonal administration).
Hypofunction: Deficiency of hormones occurs from the destruction of hormone-forming tissues from inflammation (often autoimmune), infections, iatrogenic (for example surgical removal, radiation damage), developmental defects (exampleTurner’s syndrome, hypoplasia), enzyme deficiency, haemorrhage and infarction (example;Sheehan’s syndrome), nutritional deficiency (example iodine deficiency).
Hormone resistance: There may be adequate or excessive production of a hormone but there is peripheral resistance, often from inherited mutations in receptors (for example defects in membrane receptors, nuclear receptors or receptors for signal transduction).
Basic Concept of Endocrines:
- The neuroendocrine system forms a link between endocrine glands and the nervous system. The cells comprising this system lie at different places in the body, hence called the dispersed neuroendocrine system.
- These include neuroendocrine cells in the gastric and intestinal mucosa, neuro ganglia cells, adrenal medulla, parafollicular C cells of the thyroid, islets of Langerhans and isolated cells in the left atrium.
- Anatomically, the endocrine system consists of 6 distinct organs: pituitary, adrenals, thyroid, parathyroids, gonads, and pancreatic islets.
- A basic feature of all endocrine glands is the existence of both negative and positive feedback control system that stimulates or regulates hormone production in a way that levels remain within the normal range.
- Various causes of diseases in endocrine organs result in dysfunctions that may be hyperfunction, hypofunction or peripheral hormonal resistance.
Benign Tumours:
Follicular Adenoma:
- A follicular adenoma is the most common benign thyroid tumour occurring more frequently in adult women. Clinically, it appears as a solitary nodule which can be found in approximately 1% of the population.
- Besides the follicular adenoma, other conditions which may produce clinically apparent solitary nodules in the thyroid are a dominant nodule of nodular goitre and thyroid carcinoma. It is thus important to distinguish adenomas from these two conditions.
- Though most adenomas cause no clinical problem and behave as a ‘cold nodule’, rarely they may produce mild hyperthyroidism and appear as a ‘hot nodule’ in RAIU studies. Adenoma, however, rarely ever becomes malignant.
Morphologic Features Grossly, the follicular adenoma is characterised by four features so as to distinguish it from a nodule of nodular goitre:
- solitary nodule,
- complete encapsulation,
- clearly distinct architecture inside and outside the capsule, and
- compression of the thyroid parenchyma outside the capsule.
Usually, an adenoma is small (up to 3 cm in diameter) and spherical. On the cut section, the adenoma is grey-white to red-brown, less colloidal than the surrounding thyroid parenchyma and may have degenerative changes such as fibrous scarring, focal calcification, haemorrhages and cyst formation.
Histologically, the tumour shows complete fibrous encapsulation. The tumour cells are benign
follicular epithelial cells lining follicles of various sizes. The following 5 types of growth patterns
are distinguished, though more than one pattern may be present in a single tumour:
- A classic follicular adenoma is composed of small follicles most often containing little or no
colloid and separated by abundant loose stroma (earlier called a foetal adenoma). - Normofollicular (simple) adenoma has closely packed follicles like that of a normal thyroid
gland. - Macrofollicular (colloid) adenoma contains large follicles of varying size and are distended with colloid.
- Solid (embryonal) adenoma resembles embryonal thyroid and consists of a closely packed solid or trabecular pattern of epithelial cells with an occasional small abortive follicle.
- Hürthle cell (oxyphilic) adenoma is an uncommon variant composed of solid trabeculae of large cells having abundant granular oxyphilic cytoplasm and vesicular nuclei. The tumour cells do not form follicles and contain little stroma.
Hyalinising Trabecular Tumour:
Hyalinising trabecular tumour is a rare follicular-derived benign tumour with a trabecular pattern
of growth and marked hyalinisation. It was previously considered as a variant of papillary thyroid cancer.
Grossly, it occurs as solitary or multiple nodules which are circumscribed or encapsulated.
Microscopically, the main features are:
- The classic trabecular growth pattern of elongated or polygonal cells.
- Intra- and intertrabecular hyaline material.
- Cellular features show prominent nuclear grooving and cytoplasmic inclusions, causing confusion with papillary thyroid cancer.
Genetic studies, however, show that these tumours do not have RAS or BRAF mutations which are common in papillary thyroid cancer.
Borderline Tumours
Encapsulated Follicular Patterned Tumours:
This is a group of encapsulated, follicular-patterned, borderline tumours added recently to the classification of thyroid tumours. These tumours are placed between follicular adenoma and follicular carcinoma or follicular variant of papillary carcinoma. It includes three entities with fairly descriptive nomenclature:
1. Follicular tumour of uncertain malignant potential: It is an encapsulated or well-circumscribed tumour, composed of well-differentiated follicular cells but a questionable capsular or vascular invasion.
The tumour lacks any papillary architecture or nuclear features of papillary thyroid carcinoma. This tumour is placed as indeterminate between follicular adenoma and follicular carcinoma.
2. Well-differentiated thyroid tumour of uncertain malignant potential: This tumour has some features similar to the preceding entity (encapsulation or circumscription, well-differentiated follicular cells, no capsular or vascular invasion) but, in addition, has some features of papillary carcinoma in having some papillae (<1%) and nuclear features but not fully agreeing with a diagnosis of papillary thyroid carcinoma.
3. Non-invasive follicular thyroid neoplasm with papillary nuclear features: This entity was previously called a non-invasive encapsulated follicular variant of papillary thyroid carcinoma. This tumour has features of encapsulation or circumscription, follicular growth pattern, papillae >1%, and nuclear features of papillary thyroid carcinoma.
However, it lacks psammoma bodies and shows genetic changes of RAS mutation rather than BRAF mutation seen commonly in papillary thyroid cancer.
These tumours comprise <10% of thyroid neoplasms; they are indolent and slow-growing and have an excellent prognosis.
Thyroid Cancer:
Approximately 95% of all primary thyroid cancers are carcinomas. Primary lymphomas of the thyroid comprise less than 5% of thyroid cancers and the majority of them possibly evolve from autoimmune (lymphocytic) thyroiditis.
Sarcomas of the thyroid are extremely rare. About 20% of patients dying of metastasising malignancy have metastatic deposits in the thyroid gland, most commonly from malignant melanoma, renal cell carcinoma and bronchogenic carcinoma.
As is the case with most other thyroid lesions, the majority of thyroid cancers too have female
preponderance and are twice more common in women. The most important thyroid carcinomas are papillary, follicular, medullary and anaplastic carcinoma. Each of these four morphologic types has distinctly different clinical behaviour and variable prevalence; their contrasting features are summed up.
Etiology And Pathogenesis: Most important environmental factor implicated in the aetiology of thyroid cancer is external radiation, and to some extent, there is a role of TSH receptors and iodine excess.
Pathogenesis of thyroid cancer is explained on a combination of these environmental etiologic factors and distinct genetic alterations in different microscopic types as under
1. External radiation: Single most important environmental etiologic factor associated with increased risk of developing thyroid carcinoma after many years of exposure to external radiation of high dose. Evidence in support includes a high incidence of thyroid cancer in individuals irradiated an early age for enlarged thymus and for skin disorders, in Japanese atomic bomb survivors, and in individuals living in the vicinity of nuclear accident sites. In particular, exposure to radiation to children and young adults has been found to be associated with a higher incidence of development of papillary carcinoma later.
2. Iodine excess and TSH: In regions where endemic goitre is widespread, the addition of iodine to diet has resulted in an increase in the incidence of papillary cancer. Many well-differentiated thyroid cancers express TSH receptors and thus respond to T4 suppression of TSH.
3. Genetic basis: Familial clustering of thyroid cancer has been observed, especially in medullary carcinoma. Molecular studies reveal that thyroid carcinoma is a multistep process involving genetic alterations but distinct mutations are seen in different histologic types:
- Papillary thyroid carcinoma: Activation of the signalling pathway due to certain mutations is seen in 70% of papillary thyroid cancers. These mutations are as under:
- RET gene rearrangement (located on chromosome 10q) is seen in about 20-40% of cases of papillary thyroid carcinoma. This mutation brings the tyrosine kinase receptor under the target of other tumour-promoters such as radiation exposure in papillary carcinoma.
- TRK1 (tyrosine kinase receptor-1 located on chromosome 1q) gene rearrangement is seen in 5-10% of cases.
- BRAF (a MEK kinase gene) point mutation is commonly seen in papillary thyroid carcinoma (particularly in classic and tall cell variants). Its presence is also an adverse molecular prognostic factor.
- PTEN (phosphatase and tensin homologue) point mutation.
- TERT (telomerase reverse transcriptase) promoter mutations are also seen in some variants
and are associated with poor prognosis.
- Follicular thyroid carcinoma: Common mutations in these cases are:
- The RAS family of oncogenes (includes HRAS, NRAS and KRAS) have a point mutation in about
50% of cases of follicular thyroid carcinoma. - Fusion-translocation between 2 genes—PAX-8 (paired domain transcription factor) and PPAR γ-1 (gene coding for peroxisome proliferator-activator receptor γ-1), has also been described in a proportion of cases of follicular thyroid neoplasms, both adenoma and carcinoma.
- TERT promoter mutations are also noted in this tumour and are associated with aggressive tumour behaviour.
- The RAS family of oncogenes (includes HRAS, NRAS and KRAS) have a point mutation in about
- Medullary thyroid carcinoma: Medullary thyroid carcinoma arises from parafollicular C-cells in the thyroid.
- RET-protooncogene point mutation is seen in both familial (MEN2) as a well as sporadic cases of medullary thyroid carcinoma.
- Anaplastic thyroid carcinoma: This tumour either arises from further dedifferentiation of differentiated papillary, or from follicular thyroid carcinoma, and therefore most of the mutations seen in these thyroid cancers are also seen in anaplastic thyroid cancer. Besides, additional mutations in this tumour are:
- p53 tumour suppressor gene having inactivating point mutation.
- p21 overexpression.
- The CTNNB1 gene coding for β-catenin pathway having point mutation.
- LOH (loss of heterozygosity) by deletion of tumour suppressor genes.
Papillary Thyroid Carcinoma:
- Papillary carcinoma is the most common type of thyroid carcinoma, comprising 80-90% of cases. It can occur at all ages including children and young adults but the incidence is higher with advancing age. The tumour is found about three times more frequently in females than in males.
- Papillary carcinoma is typically a slow-growing malignant tumour, most often presenting as an asymptomatic solitary nodule. Involvement of the regional lymph nodes is common but distant metastases to organs are rare.
- Some cases first come to attention by spreading to regional lymph nodes and causing cervical lymphadenopathy. ‘Lateral aberrant thyroid’ is the term used for the occurrence of thyroid tissue in the lateral cervical lymph node, which in most patients represents a well-differentiated metastasis of an occult papillary carcinoma of the thyroid.
Morphologic Features Grossly, papillary carcinoma may range from microscopic foci to nodules up to 10 cm in diameter and is generally poorly delineated. The cut surface of the tumour is greyish-white, hard and scar-like. Sometimes the tumour is transformed into a cyst, into which numerous papillae project and is termed papillary cystadenocarcinoma.
Histologically, the following features are present:
- Papillary pattern Papillae composed of a fibrovascular stalk and covered by a single layer of tumour cells is the predominant feature. Papillae are often accompanied by follicles.
- Tumour cells The tumour cells have characteristic nuclear features due to dispersed nuclear chromatin imparting it ground glass or optically clear appearance and clear or oxyphilic cytoplasm. These tumour cells, besides covering the papillae, may form follicles and solid sheets.
- Invasion The tumour cells invade the capsule and intrathyroid lymphatics but invasion of blood vessels is rare.
- Psammoma bodies Half of the papillary carcinomas show typical small, concentric, calcified spherules called psammoma bodies in the stroma.
Papillary thyroid carcinoma is graded as a well-differentiated cancer and its prognosis is good: the 10-year survival rate is 80-95%, irrespective of whether the tumour is pure papillary or mixed papillary-follicular carcinoma.
Follicular Thyroid Carcinoma:
Follicular carcinoma is the other common type of thyroid cancer, next only to papillary carcinoma and comprises 5-10% of all thyroid carcinomas. It is more common in middle and old age and has preponderance in females (female-male ratio 2.5:1). In contrast to papillary carcinoma, follicular carcinoma has a positive correlation with endemic goitre but the role of external radiation in its aetiology is unclear.
Follicular carcinoma presents clinically either as a solitary nodule or as an irregular, firm and nodular thyroid enlargement. The tumour is slow-growing but more rapid than papillary carcinoma. In contrast to papillary carcinoma, regional lymph node metastases are rare but distant metastases by the haematogenous route are common, especially to the lungs and bones, and sometimes this may be the presenting feature.
MORPHOLOGIC FEATURES Grossly, follicular carcinoma may be either in the form of a solitary adenoma-like circumscribed nodule or as an obvious cancerous irregular thyroid enlargement. The cut surface of the tumour is grey-white with areas of haemorrhages, necrosis and cyst formation and may extend to involve adjacent structures.
Microscopically, the features are as under
1. Follicular pattern: Follicular carcinoma, like follicular adenoma, is composed of follicles of various sizes and may show the trabecular or solid pattern. The tumour cells have hyperchromatic nuclei and the cytoplasm resembles that of normal follicular cells. However, variants like clear cell type and signet ring cell type of follicular carcinoma may occur. The tumour differs from papillary carcinoma in lacking: papillae, ground-glass nuclei of tumour cells and psammoma bodies.
2. Vascular invasion and direct extension: Vascular invasion and direct extension to involve the adjacent structures (e.g. into the capsule) are significant features but lymphatic invasion is rare. In terms of extent of invasion, follicular thyroid carcinoma has been divided into three subtypes:
- Minimally invasive
- Encapsulated angioinvasive
- Widely invasive
Follicular thyroid carcinoma is also well-differentiated cancer; its prognosis is good; however, poor prognostic features are age of patient >50 years, tumour size >4 cm, distant metastases, and presence of significant vascular invasion. Overall prognosis is between that of papillary and anaplastic carcinoma: 10-year survival rate is 50-70%.
Hürthle Cell Carcinoma:
This tumour was previously considered as a variant of follicular thyroid carcinoma but has now been separately classified due to a different genetic profile than other thyroid carcinomas. Morphologically, Hürthle cell carcinoma is composed of oncocytic cells having granular cytoplasm with large nuclei containing prominent nucleoli, and having capsular and vascular invasion.
The prognosis of cases with Hürthle cell carcinoma is worse than follicular thyroid carcinoma.
Medullary Thyroid Carcinoma:
Medullary carcinoma is a less frequent type derived from parafollicular or C-cells present in the thyroid and comprises approximately 5% of thyroid carcinomas. It is equally common in men and women. There are 3 distinctive features which distinguish medullary carcinoma from other thyroid carcinomas. These are its familial occurrence, secretion of calcitonin and other peptides, and amyloid stroma.
1. Familial occurrence: Most cases of medullary carcinoma occur sporadically, but about 10% have a genetic background with a point mutation in RET-protooncogene located on chromosome 10q.
The familial form of medullary carcinoma has an association with pheochromocytoma and parathyroid adenoma (multiple endocrine neoplasia, MEN 2 A), or with pheochromocytoma and multiple mucosal neuromas (MEN 2 B).
The sporadic cases occur in the middle and old age (5th-6th decades) and are generally unilateral, while the familial cases are found at younger ages (2nd-3rd decades) and are usually bilateral and multicentric.
2. Secretion of calcitonin and other peptides: Like normal C-cells, tumour cells of medullary
carcinoma secrete calcitonin, the hypocalcaemic hormone. In addition, the tumour may also elaborate prostaglandins, histaminase, somatostatin, vasoactive intestinal peptide (VIP) and ACTH. These hormone elaborations are responsible for a number of clinical syndromes such as carcinoid syndrome, Cushing’s syndrome and diarrhoea.
3. Amyloid stroma: Most medullary carcinomas have amyloid deposits in the stroma which stains positively with usual amyloid stains such as Congo red. The amyloid deposits are believed to represent stored calcitonin derived from neoplastic C-cells in the form of prohormone.
Most cases of medullary carcinoma present as solitary thyroid nodules but sometimes an enlarged cervical lymph node may be the first manifestation.
Morphologic Features Grossly, the tumour may either appear as a unilateral solitary nodule (sporadic form), or have bilateral and multicentric involvement (familial form).
However, sporadic neoplasms also eventually spread to the contralateral lobe. The cut surface of the tumour in both forms shows well-defined tumour areas which are firm to hard, and grey-white to yellow-brown with areas of haemorrhages and necrosis.
Histologically, the features are as under:
- Tumour cells: Like other neuroendocrine tumours (for example carcinoid, islet cell tumour, paraganglioma etc.), medullary carcinoma of the thyroid too has a well-defined organoid pattern, forming nests of tumour cells separated by fibrovascular septa.
- Sometimes, the tumour cells may be arranged in sheets, ribbons pseudopapillary or small follicles. The tumour cells are uniform and have the structural and functional characteristics of C-cells. Less often, the neoplastic cells are spindle-shaped.
- Amyloid stroma The tumour cells are separated by amyloid stroma derived from altered calcitonin which can be demonstrated by immunostain for calcitonin.
- The staining properties of amyloid are similar to that seen in systemic amyloidosis and may have areas of irregular calcification but without regular laminations seen in psammoma bodies.
- C-cell hyperplasia Familial cases generally have C-cell hyperplasia as a precursor lesion but not in sporadic cases.
Most medullary carcinomas are slow-growing. Regional lymph node metastases may occur but distant organ metastases are infrequent. The prognosis is better in the familial form than in the sporadic form: the overall 10-year survival rate is 60-70%.
Anaplastic Thyroid Carcinoma:
- Anaplastic carcinoma of the thyroid comprises less than 5% of all thyroid cancers and is one of the most malignant tumours in humans. The tumour is predominantly found in old age (7th-8th decades) and is slightly more common in females than in males (female-male ratio 1.5:1).
- The tumour is widely aggressive and rapidly growing. The features at presentation are usually those of extensive invasion of adjacent soft tissue, trachea and oesophagus.
- These features include dyspnoea, dysphagia and hoarseness, in association with a rapidly-growing tumour in the neck. The tumour metastasises both to regional lymph nodes and to distant organs such as the lungs.
Morphologic Features Grossly, the tumour is generally large and irregular, often invading the adjacent strap muscles of the neck and other structures in the vicinity of the thyroid. The cut surface of the tumour is white and firm with areas of necrosis and haemorrhages.
Histologically, the tumour is too poorly-differentiated to be placed in any other histologic type of thyroid cancer but usually shows a component of either papillary or follicular carcinoma in better-differentiated areas. The tumour is generally composed of 3 types of cells occurring in varying proportions: small cells, spindle cells and giant cells. When one of these cell types is predominant, the histologic variant of undifferentiated carcinoma is named accordingly:
- Small cell variant is composed of closely packed small cells having hyperchromatic nuclei and numerous mitoses. This variant closely resembles malignant lymphoma.
- The spindle cell variant is composed of spindle cells resembling sarcoma. Some tumours may contain apparent sarcomatous components (for example areas of osteosarcoma, chondrosarcoma or rhabdomyosarcoma).
- The giant cell variant has highly anaplastic giant cells showing numerous atypical mitoses, bizarre and lobed nuclei and some assuming spindle shapes. The prognosis is poor: 5-year survival rate is less than 10% and median survival after the diagnosis is about 2 months.
Diseases of Thyroid Gland:
- The most common benign thyroid neoplasm is a follicular adenoma. It is encapsulated.
- The aetiology of thyroid cancer has a strong role in chronic radiation exposure, iodine excess and genetic changes in different morphologic types.
- Carcinoma of the thyroid has 4 major morphologic types with distinctly different clinical behaviour and variable prevalence.
- Papillary thyroid carcinoma is the most frequent, is well-differentiated cancer and has a good prognosis.
- Follicular thyroid carcinoma has capsular and vascular invasion but is otherwise a well differentiated cancer. Hürthle cell carcinoma has some similarities with follicular cancer but has a worse prognosis.
- Medullary thyroid carcinoma is a tumour from parafollicular or C-cells, that secretes calcitonin and contains amyloid stroma.
- Anaplastic carcinoma is less common and is the most malignant. It may be a small cell, spindle cell and giant cell type.
Endocrine Pancreas
The human pancreas, though anatomically a single organ, histologically and functionally, has 2 distinct parts—the exocrine and endocrine. The exocrine part of the gland and its disorders have already been discussed. The discussion here is focused on the endocrine pancreas and its two main disorders: diabetes mellitus and islet cell tumours.
Normal Structure:
The endocrine pancreas consists of microscopic collections of cells called islets of Langerhans found scattered within the pancreatic lobules, as well as individual endocrine cells found in duct epithelium and among the acini.
The total weight of the endocrine pancreas in the adult, however, does not exceed 1-1.5 gm (total weight of pancreas 60-100 gm). The islet cell tissue is more greatly concentrated in the tail than in the head or body of the pancreas.
Islets possess no ductal system and they drain their secretory products directly into the circulation. Ultrastructurally and immunohistochemically, 4 major and 2 minor types of islet cells are distinguished, each type having its distinct secretory product and function. These are as follows:
Major cell types:
- Beta (β) or B cells comprise about 70% of islet cells and secrete insulin, the defective response or deficient synthesis of which causes diabetes mellitus.
- Alpha (α) or A cells comprise 20% of islet cells and secrete glucagon which induces hyperglycaemia.
- Delta (δ) or D cells comprise 5-10% of islet cells and secrete somatostatin which suppresses both insulin and glucagon release.
- Pancreatic polypeptide (PP) cells or F cells comprise 1-2% of islet cells and secrete pancreatic polypeptide having some gastrointestinal effects.
Minor cell types
- D1 cells elaborate vasoactive intestinal peptide (VIP) which induces glycogenolysis and hyperglycaemia and causes secretory diarrhoea by stimulation of gastrointestinal fluid secretion.
- Enterochromaffin cells synthesise serotonin which pancreatic tumours may induce carcinoid syndrome.
The major disease of the endocrine pancreas is diabetes mellitus; others are uncommon islet cell tumours.
Diabetes Mellitus
Definition And Epidemiology:
Diabetes mellitus (DM) is defined as a heterogeneous metabolic disorder characterised by the common feature of chronic hyperglycaemia with disturbance of carbohydrate, fat and protein metabolism.
- At this point, it is also important to understand another related term, metabolic syndrome (also called syndrome X or insulin resistance syndrome), consisting of a combination of metabolic abnormalities which increase the risk of developing diabetes mellitus and cardiovascular disease.
- Major features of metabolic syndrome are central obesity, hypertriglyceridaemia, low HDL cholesterol, hyperglycaemia and hypertension. DM is a leading cause of morbidity and mortality the world over.
- It is expected to continue as a major health problem owing to its serious complications, especially end-stage renal disease, IHD, gangrene of the lower extremities, and blindness in adults. China, India and the US top the countries with the highest number of diabetic populations.
- In India, its incidence is estimated at 7% of the adult population, largely due to genetic susceptibility combined with changing lifestyle of low-activity and high-calorie diet in the growing Indian middle class. The incidence is somewhat low in Africa.
- But the prevalence of DM is expected to rise in developing countries of Asia and Africa due to urbanisation and associated obesity and increased body weight.
- The rise in prevalence is more for type 2 diabetes than for type 1. As per International Diabetes Federation (IDF) estimates, there are 450 million people with diabetes worldwide in 2017 and this figure is expected to increase to 700 million by the year 2045.
Classification And Etiology:
The older classification dividing DM based on age (juvenile-onset and maturity-onset types) and therapy (insulin-dependent and non-insulin-dependent types) have become obsolete and undergone major revision due to extensive understanding of aetiology and pathogenesis of DM in recent times.
As outlined, currently DM is classified into the following 4 broad groups:
TYPE 1 DM: It constitutes about 10% of cases of DM. It was previously termed as juvenile-onset diabetes (JOD) due to its occurrence in younger ages and was called insulin-dependent DM (IDDM) because it was known that these patients have absolute requirements for insulin replacement as treatment.
However, in the new classification, neither age nor insulin dependence are considered as absolute criteria. Instead, based on underlying aetiology, type 1 DM is further divided into 2 subtypes:
Subtype 1A (immune-mediated) DM: characterised by autoimmune destruction of β-cells which usually leads to insulin deficiency.
Subtype 1B (idiopathic) DM: is characterised by insulin deficiency with a tendency to develop ketosis but these patients are negative for autoimmune markers.
Though type 1 DM occurs commonly in patients under 30 years of age, autoimmune destruction of β-cells can occur at any age. In fact, 5-10% of patients who develop DM above 30 years of age are of type 1A DM and hence the term JOD has become obsolete.
TYPE 2 DM: This type comprises about 80% of cases of DM. It was previously called maturity-onset diabetes (MOD), or non-insulin dependent diabetes mellitus (NIDDM) of obese and nonobese type. Although type 2 DM predominantly affects older individuals, it is now known that it also occurs in obese adolescent children; hence the term MOD for it is inappropriate.
Moreover, many cases of type 2 DM also require insulin therapy to control hyperglycaemia or to prevent ketosis and thus are not truly non-insulin dependent contrary to its older nomenclature. Type 2 DM occurs due to progressive loss of β-cell insulin secretion frequently on the background of insulin resistance.
Gestational DM: About 4% of pregnant women develop DM due to metabolic changes during pregnancy. Gestational DM is defined as diabetes diagnosed in the second or third trimester of pregnancy in a woman who did not have overt diabetes earlier. Although these women revert back to normal glycaemia after delivery, they are prone to develop DM later in their life.
Other Specific Etiologic Types Of Dm: Besides these three main types, about 10% of cases of DM have a known specific etiologic defect listed. Important examples include diseases of the exocrine pancreas (for example cystic fibrosis, pancreatitis), drug and chemical-induced DM (for example glucocorticoid use, treatment of HIV/AIDS, following organ transplantation), and monogenic diabetes syndrome (for example neonatal diabetes and maturity-onset diabetes of the young MODY that has autosomal dominant inheritance, early onset of hyperglycaemia and impaired insulin secretion).
American Diabetes Association (2018) has identified various risk factors for type 2 DM which are listed.
Pathogenesis:
Depending upon aetiology of DM, hyperglycaemia may result from the following:
- Reduced insulin secretion
- Decreased glucose use by the body
- Increased glucose production.
Pathogenesis of two main types of DM and its complications is distinct. In order to understand it properly, it is essential to first recall the physiology of normal insulin synthesis and secretion.
Normal Insulin Metabolism: The major stimulus for both the synthesis and release of insulin is glucose. The steps involved in the biosynthesis, release and actions of insulin are as follows:
Synthesis Insulin is synthesised in the β-cells of pancreatic islets:
- It is initially formed as pre-proinsulin which is a single-chain 86-amino acid precursor polypeptide.
- Subsequent proteolysis removes the amino-terminal signal peptide, forming proinsulin.
- Further cleavage of proinsulin gives rise to A (21 amino acids) and B (30 amino acids)
chains of insulin, linked together by connecting segments called C-peptide, all of which are stored in the secretory granules in the β-cells. As compared to the A and B chains of insulin, C-peptide is less susceptible to degradation in the liver and is therefore used as a marker to distinguish endogenously synthesised and exogenously administered insulin.
For therapeutic purposes, human insulin is now produced by recombinant DNA technology.
Release: Glucose is the key regulator of insulin secretion from β-cells by a series of steps:
- Hyperglycaemia (glucose level more than 70 mg/dl or above 3.9 mmol/L) stimulates transport into β-cells of glucose transporter, GLUT2. Other stimuli influencing insulin release include nutrients in the meal, ketones, amino acids etc.
- An islet transcription factor, glucokinase, causes glucose phosphorylation and thus acts as a step for the controlled release of glucose-regulated insulin secretion
- Metabolism of glucose to glucose-6-phosphate by glycolysis generates ATP.
- The generation of ATP alters the ion channel activity on the membrane. It causes inhibition of the ATP-sensitive K+ channel on the cell membrane and opening up of the calcium channels with the resultant influx of calcium, which stimulates insulin release.
Action: Half of the insulin secreted from β-cells into the portal vein is degraded in the liver while the remaining half enters the systemic circulation for action on the target cells:
- Insulin from circulation binds to its receptor on the target cells. Insulin receptor has intrinsic tyrosine kinase activity.
- This, in turn, activates post-receptor intracellular signalling pathway molecules, insulin receptor substrates (IRS) 1 and 2 proteins, which initiate a sequence of phosphorylation and dephosphorylation reactions.
- These reactions on the target cells are responsible for the main mitogenic and anabolic actions of insulin glycogen synthesis, glucose transport, protein synthesis, and lipogenesis.
- Besides the role of glucose in maintaining equilibrium of insulin release, low insulin level in the fasting state promotes hepatic gluconeogenesis and glycogenolysis, reduced glucose uptake by insulin-sensitive tissues and promotes mobilisation of stored precursors, so as to prevent hypoglycaemia.
Pathogenesis Of Type 1 Dm: A basic phenomenon in type 1 DM is the destruction of β-cell mass, usually leading to absolute insulin deficiency. While type 1B DM remains idiopathic, the pathogenesis of type 1A DM is immune-mediated and has been extensively studied. Currently, the pathogenesis of type 1A DM is explained on the basis of 3 mutually-interlinked mechanisms: genetic susceptibility, autoimmunity, and certain environmental factors.
1. Genetic susceptibility: Type 1A DM involves the inheritance of multiple genes to confer susceptibility to the disorder:
- It has been observed in identical twins that if one twin has type 1A DM, there is about a 50% chance of the second twin developing it, but not all. This means that some additional modifying factors are involved in the development of DM in these cases.
- About half the cases with a genetic predisposition to type 1A DM have the susceptibility gene located in the HLA region of chromosome 6 (MHC class II region), particularly the HLA DR3, HLA DR4 and HLA DQ locus.
2. Autoimmunity: Studies on human and animal models of type 1A DM have shown several immunologic abnormalities:
- Presence of islet cell antibodies against GAD (glutamic acid decarboxylase), insulin etc, though their assay largely remains a research tool due to the tedious method.
- Lymphocytic infiltrate in and around the pancreatic islets is termed insulitis. It chiefly consists of CD8+ T lymphocytes with a variable number of CD4+ T lymphocytes and macrophages.
- Selective destruction of β-cells while other islet cell types (glucagon-producing alpha cells, somatostatin-producing delta cells, or polypeptide-forming PP cells) remain unaffected. This is mediated by T-cell-mediated cytotoxicity or by apoptosis.
- The role of T cell-mediated autoimmunity is further supported by the transfer of type 1A DM from a diseased animal by infusing T lymphocytes into a healthy animal.
- Association of type 1A DM with other autoimmune diseases in about 10-20% of cases such as Graves’ disease, Addison’s disease, Hashimoto’s thyroiditis, and pernicious anaemia.
- Remission of type 1A DM in response to immunosuppressive therapy such as administration of cyclosporin A.
3. Environmental factor: Epidemiologic studies in type 1A DM suggest the involvement of certain environmental factors in its pathogenesis, though the role of none of them has been conclusively proved. In fact, the trigger may precede the occurrence of the disease by several years. It appears that certain viral and dietary proteins share antigenic properties with human cell surface proteins and trigger the immune attack on β-cells by a process of molecular mimicry. These factors include the following:
- Certain viral infections preceding the onset of disease example mumps, measles, coxsackie B virus, cytomegalovirus and infectious mononucleosis.
- Experimental induction of type 1A DM with certain chemicals has been possible example alloxan, streptozotocin and pentamidine.
- Geographic and seasonal variations in its incidence suggest some common environmental factors.
- A possible relationship between early exposure to bovine milk proteins and the occurrence of the autoimmune process in type 1A DM is being studied.
Key Points: Pathogenesis of type 1A DM can be summed up by interlinking the above three factors as under:
- At birth, individuals with genetic susceptibility to this disorder have normal β-cell mass.
- β-cells act as autoantigens and activate CD4+ T lymphocytes, bringing about immune destruction of pancreatic β-cells by autoimmune phenomena which takes months to years. Clinical features of diabetes manifest after more than 80% of β-cell mass has been destroyed.
- The trigger for the autoimmune process appears to be some infectious or environmental factor which specifically targets β-cells.
Pathogenesis Of Type 2 Dm The basic metabolic defect in type 2 DM is either a delayed insulin secretion relative to glucose load (impaired insulin secretion) or the peripheral tissues are unable to respond to insulin (insulin resistance).
Type 2 DM is a heterogeneous disorder with a more complex aetiology and is far more common than type 1, but much less is known about its pathogenesis. A number of factors have been implicated though, but HLA association and autoimmune phenomena are not implicated. These factors are as under:
1. Genetic factors: Genetic component has a stronger basis for type 2 DM than type 1A DM. Although no definite and consistent genes have been identified, multifactorial inheritance is the most important factor in the development of type 2 DM:
- There is approximately an 80% chance of developing diabetes in the other identical twin if one twin has the disease.
- A person with one parent having type 2 DM is at an increased risk of getting diabetes, but if both parents have type 2 DM the risk in the offspring rises to 40%.
2. Constitutional factors: Certain environmental factors such as obesity, hypertension, and level of physical activity play a contributory role and modulate the phenotyping of the disease.
3. Insulin resistance: One of the most prominent metabolic features of type 2 DM is the lack of
responsiveness of peripheral tissues to insulin, especially of the skeletal muscle and liver.
Obesity, in particular, is strongly associated with insulin resistance and hence type 2 DM. The mechanism of hyperglycaemia in these cases is explained as under:
- Resistance to the action of insulin impairs glucose utilisation and hence hyperglycaemia.
- There is increased hepatic synthesis of glucose.
- Hyperglycaemia in obesity is related to high levels of free fatty acids and cytokines (for example TNF-α and adiponectin) that affect peripheral tissue sensitivity to respond to insulin.
The precise underlying molecular defect responsible for insulin resistance in type 2 DM has yet not been fully identified. Currently, it is proposed that insulin resistance may be possibly due to one of the following defects:
- Polymorphism in various post-receptor intracellular signal pathway molecules.
- Elevated free fatty acids seen in obesity may contribute e.g. by impaired glucose utilisation in the skeletal muscle, by increased hepatic synthesis of glucose, and by impaired β-cell function.
- Insulin resistance syndrome is a complex of clinical features occurring from insulin resistance and its resultant metabolic derangements that include hyperglycaemia and compensatory hyperinsulinaemia. The clinical features are in the form of accelerated cardiovascular disease and may occur in both obese as well as non-obese type 2 DM patients.
The features include: mild hypertension (related to endothelial dysfunction) and dyslipidaemia (characterised by reduced HDL level, increased triglycerides and LDL level).
4. Impaired insulin secretion: In type 2 DM, insulin resistance and insulin secretion are interlinked:
- Early in the course of the disease, in response to insulin resistance, there is compensatory increased secretion of insulin (hyperinsulinaemia) in an attempt to maintain normal blood glucose levels.
- Eventually, however, there is the failure of β-cell function to secrete adequate insulin, although there is some secretion of insulin i.e. cases of type 2 DM have mild to moderate deficiency of insulin (which is much less severe than that in type 1 DM) but not its total absence. The exact genetic mechanism for why there is a fall in insulin secretion in these cases is unclear. However, the following possibilities are proposed:
- Islet amyloid polypeptide (amylin) which forms fibrillar protein deposits in pancreatic islets
in long-standing cases of type 2 DM may be responsible for the impaired function of β-cells of islet cells. - The metabolic environment of chronic hyperglycaemia surrounding the islets (glucose toxicity) may paradoxically impair islet cell function.
- Elevated free fatty acid levels (lipotoxicity) in these cases may worsen islet cell function.
- Islet amyloid polypeptide (amylin) which forms fibrillar protein deposits in pancreatic islets
5. Increased hepatic glucose synthesis One of the normal roles played by insulin is to promote hepatic storage of glucose as glycogen and suppress gluconeogenesis. In type 2 DM, as a part of insulin resistance by peripheral tissues, the liver also shows insulin resistance i.e. in spite of hyperinsulinaemia in the early stage of the disease, gluconeogenesis in the liver is not suppressed. This results in increased hepatic synthesis of glucose which contributes to hyperglycaemia in these cases.
Key Points: In essence, hyperglycaemia in type 2 DM is not due to the destruction of β-cells but is instead a failure of β-cells to meet the requirement of insulin in the body. Its pathogenesis can be summed up by interlinking the above factors as under:
- Type 2 DM is a more complex multifactorial disease.
- There is a greater role for genetic defects and heredity.
- Two main mechanisms for hyperglycaemia in type 2 DM—insulin resistance and impaired insulin secretion, are interlinked.
- While obesity plays a role in the pathogenesis of insulin resistance, impaired insulin secretion may be from many constitutional factors.
- Increased hepatic synthesis of glucose in the initial period of the disease contributes to hyperglycaemia.
Morphologic Features In Pancreatic Islets:
Morphologic changes in islets have been demonstrated in both types of diabetes, though the changes are more distinctive in type 1 DM:
1. Insulitis:
In type 1 DM, characteristically, in the early stage, there is lymphocytic infiltrate, mainly by T cells, in the islets which may be accompanied by a few macrophages and polymorphs.
Diabetic infants born to diabetic mothers, however, have eosinophilic infiltrate in the islets. In type 2 DM, there is no significant leucocytic infiltrate in the islets but there is a variable degree of fibrous tissue in the islets.
2. Islet cell mass:
In type 1 DM, as the disease becomes chronic there is progressive depletion of β-cell mass, eventually resulting in total loss of pancreatic β-cells and its hyalinisation. In type 2 DM, β-cell mass is either normal or mildly reduced. Infants of diabetic mothers, however, have hyperplasia and hypertrophy of islets as a compensatory response to maternal hyperglycaemia.
3. Amyloidosis
In type 1 DM, deposits of amyloid around islets are absent.
In type 2 DM, characteristically chronic long-standing cases show deposition of amyloid material, amylin, around the capillaries of the islets causing compression and atrophy of islet tissue.
β-cell degranulation:
In type 1 DM, EM shows degranulation of the remaining β-cells of islets.
In type 2 DM, no such change is observed.
Clinical Features:
It can be appreciated that hyperglycaemia in DM does not cause a single disease but is associated with numerous diseases and symptoms, especially due to complications. Two main types of DM can be distinguished clinically to a limited extent as shown. However, overlapping of clinical features occurs as regards the age of onset, duration of symptoms and family history. Pathophysiology in the evolution of clinical features is schematically shown.
Type 1 DM:
- Patients with type 1 DM usually manifest at an early age, generally below the age of 35.
- The onset of symptoms is often abrupt.
- At presentation, these patients have polyuria, polydipsia and polyphagia.
- The patients are not obese but have generally progressive loss of weight.
- These patients are prone to develop metabolic complications such as ketoacidosis and hypoglycaemic episodes.
Type 2 DM:
- This form of diabetes generally manifests in middle life or beyond, usually above the age of 40.
- The onset of symptoms in type 2 DM is slow and insidious.
- Generally, the patient is asymptomatic when the diagnosis is made on the basis of glucosuria or hyperglycaemia during physical examination, or may present with polyuria and polydipsia.
- The patients are frequently obese and have unexplained weakness and loss of weight.
- Metabolic complications such as ketoacidosis are infrequent.
Pathogenesis Of Complications:
- It is now known that in both type 1 and 2 DM, severity and chronicity of hyperglycaemia forms the main pathogenetic mechanism for ‘microvascular complications’ (for example retinopathy, nephropathy, neuropathy); therefore, control of blood glucose level constitutes the mainstay of treatment for minimising development of these complications.
- Long-standing cases of type 2 DM, however, in addition, frequently develop ‘macrovascular complications’ (for example atherosclerosis, coronary artery disease, peripheral vascular disease, cerebrovascular disease) which are more difficult to explain on the basis of hyperglycaemia alone.
- The following biochemical mechanisms have been proposed to explain the development of complications of diabetes mellitus:
1. Non-enzymatic protein glycosylation: Free amino group of various body proteins bind by a non-enzymatic mechanism to glucose; this process is called glycosylation and is directly proportionate to the severity of hyperglycaemia.
- Various body proteins undergoing chemical alterations in this way include haemoglobin, lens crystalline protein, and basement membrane of body cells. An example is the measurement of a fraction of haemoglobin called glycosylated haemoglobin (HbA1C) as a test for monitoring glycaemic control in a diabetic patient during the preceding 90 to 120 days which is the lifespan of red cells.
- Similarly, there is the accumulation of labile and reversible glycosylation products on collagen and other tissues of the blood vessel wall which subsequently become stable and irreversible by chemical changes and form advanced glycosylation end-products (AGE).
- The AGEs bind to receptors on different cells and produce a variety of biological and chemical changes example thickening of the vascular basement membrane in diabetes.
2. Polyol pathway mechanism: This mechanism is responsible for producing lesions in the aorta, the lens of the eye, kidney and peripheral nerves. These tissues have an enzyme, aldose reductase, that reacts with glucose to form sorbitol and fructose in the cells of the hyperglycaemic patient and increases the flux. Intracellular accumulation of sorbitol and fructose so produced results in the entry of water inside the cell and consequent cellular swelling and cell damage.
Also, intracellular accumulation of sorbitol causes intracellular deficiency of myoinositol which promotes injury to Schwann cells and retinal pericytes. These polyols result in the disturbed processing of normal intermediary metabolites leading to complications of diabetes.
3. Excessive reactive: oxygen species In hyperglycaemia, there is increased production of reactive oxygen species (ROS) from mitochondrial oxidative phosphorylation which may damage various target cells in diabetes.
Complications Of Diabetes:
As a consequence of hyperglycaemia of diabetes, every tissue and organ of the body undergoes biochemical and structural alterations which account for the major complications in diabetics which may be acute metabolic or chronic systemic.
Both types of diabetes mellitus may develop complications which are broadly divided into 2 major groups:
- Acute metabolic complications include diabetic ketoacidosis, hyperosmolar nonketotic coma, and hypoglycaemia.
- Late systemic complications These are atherosclerosis, diabetic microangiopathy, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and infections.
Acute Metabolic Complications: Metabolic complications develop acutely. While ketoacidosis and hypoglycaemic episodes are primarily complications of type 1 DM, hyperosmolar nonketotic coma is chiefly a complication of type 2 DM. Pathways of biochemical mechanisms involved i
1. Diabetic ketoacidosis (DKA): Ketoacidosis is almost exclusively a complication of type 1 DM. It can develop in patients with severe insulin deficiency combined with glucagon excess. Failure to take insulin and exposure to stress are the usual precipitating causes.
- A severe lack of insulin causes lipolysis in the adipose tissues, resulting in the release of free fatty acids into the plasma. These free fatty acids are taken up by the liver where they are oxidised through acetyl coenzyme-A to ketone bodies, principally acetoacetic acid and β-hydroxybutyric acid.
- Such free fatty acid oxidation to ketone bodies is accelerated in the presence of elevated levels of glucagon. Once the rate of ketogenesis exceeds the rate at which the ketone bodies can be utilised by the muscles and other tissues, ketonaemia and ketonuria occur.
- If urinary excretion of ketone bodies is prevented due to dehydration, systemic metabolic ketoacidosis occurs. Clinically, the condition is characterised by anorexia, nausea, vomiting, deep and fast breathing, mental confusion and coma. Most patients of ketoacidosis recover.
2. Hyperosmolar hyperglycaemic nonketotic coma: Hyperosmolar hyperglycaemic nonketotic coma is usually a complication of type 2 DM. It is caused by severe dehydration resulting from sustained hyperglycaemic diuresis. The loss of glucose in the urine is so intense that the patient is unable to drink sufficient water to maintain the urinary fluid loss.
- The usual clinical features of ketoacidosis are absent but prominent central nervous signs are present. Blood sugar is extremely high and plasma osmolality is high. Thrombotic and bleeding complications are frequent due to the high viscosity of blood.
- The mortality rate in a hyperosmolar nonketotic coma is high. The contrasting features of diabetic ketoacidosis and hyperosmolar non-ketotic coma are summarised.
3. Hypoglycaemia: Hypoglycaemic episodes may develop in patients with type 1 DM. It may result from excessive administration of insulin, missing a meal, or due to stress. Hypoglycaemic episodes are harmful as they produce permanent brain damage, or may result in worsening of diabetic control and rebound hyperglycaemia, the so-called Somogyi’s effect.
Late Systemic Complications: A number of systemic complications may develop after a period of 15-20 years in either type of diabetes. Late complications are largely responsible for morbidity and premature mortality in diabetes mellitus. These complications are briefly outlined below and have been discussed in detail in relevant chapters.
1. Atherosclerosis: Diabetes mellitus of both type 1 and type 2 accelerates the development of atherosclerosis. Consequently, atherosclerotic lesions appear earlier than in the general population, are more extensive, and are more often associated with complicated plaques such as ulceration, calcification and thrombosis.
- The cause for this accelerated atherosclerotic process is not known but possible contributory factors are hyperlipidaemia, reduced HDL levels (see metabolic syndrome,), nonenzymatic glycosylation, increased platelet adhesiveness, obesity and associated hypertension in diabetes.
- The possible ill effects of accelerated atherosclerosis in diabetes are early onset of coronary artery disease, silent myocardial infarction, cerebral stroke and gangrene of the toes and feet. Gangrene of the lower extremities is 100 times more common in diabetics than in non-diabetics.
2. Diabetic microangiopathy: Microangiopathy of diabetes is characterised by basement membrane thickening of small blood vessels and capillaries of different organs and tissues such as the skin, skeletal muscle, eye and kidney.
- A similar type of basement membrane-like material is also deposited in nonvascular tissues such as peripheral nerves, renal tubules and Bowman’s capsule.
- The pathogenesis of diabetic microangiopathy as well as of peripheral neuropathy in diabetics is believed to be due to recurrent hyperglycaemia that causes increased glycosylation of haemoglobin and other proteins (for example collagen and basement membrane material) resulting in the thickening of basement membrane.
3. Diabetic nephropathy: Renal involvement is a common complication and a leading cause of death in diabetes. Four types of lesions are described in diabetic nephropathy:
- Diabetic glomerulosclerosis which includes diffuse and nodular lesions of glomerulosclerosis.
- Vascular lesions that include hyaline arteriolosclerosis of afferent and efferent arterioles and atheromas of renal arteries.
- Diabetic pyelonephritis and necrotising renal papillitis.
- Tubular lesions or Armanni-Ebstein lesions.
4. Diabetic neuropathy: Diabetic neuropathy may affect all parts of the nervous system but symmetric peripheral neuropathy is most characteristic. The basic pathologic changes are segmental demyelination, Schwann cell injury and axonal damage.
The pathogenesis of neuropathy is not clear but it may be related to diffuse microangiopathy as already explained or may be due to the accumulation of sorbitol and fructose as a result of hyperglycaemia, leading to deficiency of myoinositol.
5. Diabetic retinopathy: Diabetic retinopathy is a leading cause of blindness. There are 2 types of lesions involving retinal vessels: background and proliferative. Besides retinopathy, diabetes also predisposes the patients to early development of cataracts and glaucoma.
6. Infections: Diabetics have enhanced susceptibility to various infections such as tuberculosis, pneumonia, pyelonephritis, otitis, carbuncles and diabetic ulcers. This could be due to various factors such as impaired leucocyte functions, reduced cellular immunity, poor blood supply due\ to vascular involvement and hyperglycaemia per se.
Diagnosis Of Diabetes:
Hyperglycaemia remains the fundamental basis for the diagnosis of diabetes mellitus. In symptomatic cases, the diagnosis is not a problem and can be confirmed by finding glucosuria and a random plasma glucose concentration above 200 mg/dl.
The severity of clinical symptoms of polyuria and polydipsia is directly related to the degree of hyperglycaemia. In asymptomatic cases, when there is persistently elevated fasting plasma glucose level, diagnosis again poses no difficulty.
The problem arises in asymptomatic patients who have normal fasting glucose levels in the plasma but are suspected to have diabetes on other grounds and are thus subjected to an oral glucose tolerance test (OGTT). If abnormal OGTT values are found, these subjects are said to have ‘chemical diabetes’.
The American Diabetes Association (2018) has recommended fresh guidelines for making a diagnosis of diabetes mellitus and for categorising patients who are at increased risk for diabetes (i.e. prediabetics).
The following investigations are helpful in establishing the diagnosis of diabetes mellitus:
Urine Testing: Urine tests are cheap and convenient but the diagnosis of diabetes cannot be based on urine testing alone since there may be false-positives and false negatives. They can be used in population screening surveys. Urine is tested for the presence of glucose and ketones.
1. Glucosuria: Benedict’s qualitative test detects any reducing substance in the urine and is not specific for glucose. A more sensitive and glucose-specific test is the dipstick method based on an enzyme-coated paper strip which turns purple when dipped in urine containing glucose. The main disadvantage of relying on urinary glucose tests alone is the individual variation in the renal threshold.
Thus, a diabetic patient may have a negative urinary glucose test and a nondiabetic individual with low renal threshold may have a positive urine test. Besides diabetes mellitus, glucosuria may also occur in certain other conditions such as renal glycosuria, alimentary (lag storage) glucosuria, many metabolic disorders, starvation and intracranial lesions (for example cerebral tumour, haemorrhage and head injury). However, two of these conditions—renal glucosuria and alimentary glucosuria, require further elaboration here.
- Renal glucosuria After diabetes, the next most common cause of glucosuria is the reduced renal threshold for glucose. In such cases, although the blood glucose level is below 180 mg/dl (i.e. below normal renal threshold for glucose) glucose still appears regularly and consistently in the urine due to lowered renal threshold.
Renal glucosuria is a benign condition unrelated to diabetes and runs in families and may occur temporarily in pregnancy without symptoms of diabetes.
- Alimentary (lag storage) glucosuria A rapid and transitory rise in blood glucose level above the normal renal threshold may occur in some individuals after a meal. During this period, glucosuria is present.
This type of response to a meal is called a ‘lag storage curve’ or more appropriately ‘alimentary glucosuria’. A characteristic feature is that unusually high blood glucose level returns to normal 2 hours after a meal.
2. Ketonuria: Tests for ketone bodies in the urine are required for assessing the severity of diabetes and not for the diagnosis of diabetes. However, if both glucosuria and ketonuria are present, the diagnosis of diabetes is almost certain. Rothera’s test (nitroprusside reaction) and strip test are conveniently performed for the detection of ketonuria.
Besides uncontrolled diabetes, ketonuria may appear in individuals with prolonged vomiting, fasting state or exercising for long periods.
Single Blood Sugar Estimation: For diagnosis of diabetes, blood sugar determinations are absolutely necessary. The folin-Wu method of measurement of all reducing substances in the blood including glucose is now obsolete.
Currently used are O-toluidine, Somogyi-Nelson and glucose oxidase methods. Whole blood or plasma may be used but whole blood values are 15% lower than plasma values. A grossly elevated single determination of plasma glucose may be sufficient to make the diagnosis of diabetes.
Fasting Glucose Test: Fasting plasma glucose determination is a screening test for DM type 2. Fasting is defined as no caloric intake for at least 8 hours prior to the test. It is recommended that all individuals above 45 years of age must undergo screening fasting glucose test every 3 years, and relatively earlier if the person is overweight or at risk because of the following reasons:
- Many of the cases meeting the current criteria of DM are asymptomatic and do not know that they have the disorder.
- Studies have shown that type 2 DM may be present for about 10 years before symptomatic
disease appears. - About half the cases of type 2 DM have some diabetes-related complication at the time of diagnosis.
- The course of the disease is favourably altered with treatment.
A fasting plasma glucose value above 126 mg/dl (≥7 mmol/L) is certainly indicative of diabetes. In other cases, oral GTT is performed.
Two-Hour Plasma Glucose Test And Oral Glucose Tolerance Test (Ogtt): OGTT is performed principally for patients with borderline fasting plasma glucose value (i.e. between 100-125 mg/dl). The patient who is scheduled for OGTT is instructed to eat a high-carbohydrate diet for at least 3 days prior to the test and come after an overnight fast (for at least 8 hours) on the day of the test.
A fasting blood sugar sample is first drawn. Then 75 gm of glucose dissolved in 300 ml of water is given. Blood and urine specimens are collected at half-hourly intervals for at least 2 hours.
Blood or plasma glucose content is measured and urine is tested for glucosuria to determine the approximate renal threshold for glucose. Venous whole blood concentrations are 15% lower than plasma glucose values.
- Currently accepted criteria for diagnosis of DM (as per American Diabetes Association, 2018) are given.
- The normal cut-off value for fasting blood glucose level is considered 100 mg/dl.
- Cases with fasting blood glucose values in the range of 100-125 mg/dl are considered as impaired fasting glucose tolerance (IGT); these cases are at increased risk of developing diabetes later and therefore kept under observation for repeating the test. During pregnancy, however, a case of IGT is treated as a diabetic.
- Individuals with a fasting value of plasma glucose higher than 126 mg/dl and a 2-hour value after 75 gm oral glucose higher than 200 mg/dl are labelled as diabetics.
- In symptomatic cases, a random blood glucose value above 200 mg/dl is diagnosed as diabetes mellitus.
Glycosylated Haemoglobin (Hba1c): Hba1c or glycosylated haemoglobin is a minor haemoglobin component present in normal persons. Non-enzymatic glycosylation of haemoglobin takes place over 90-120 days, the lifespan of red blood cells, and hence HbA1C determination provides control of blood glucose in the previous 3-4 months.
- Measurement of plasma glucose level suffers from variation due to dietary intake of the previous day. This assay has the advantage over traditional blood glucose tests in that no dietary preparation or fasting is required.
- The normal value of HbA1C is <5.7% while the value of 5.7-6.4% is in the borderline range. Over the years, the main role of the HbA1C test has been for monitoring the long-term glycaemic control in diabetics for the preceding 3-4 months.
- As per 2018-ADA recommendations, HbA1C criteria has now been included for making diagnosis of DM (HbA1C >6.5%) in addition to fasting plasma glucose, 2-hour plasma glucose and OGTT. This test for diagnosis of DM has several advantages:
- It avoids misdiagnosis.
- Picks up missed diagnosis of DM.
- It is more convenient as fasting is not required.
- It has higher preanalytical stability.
- The test does not undergo variation in value if the individual has stress or illness prior to the test.
- Moreover, since the HbA1C assay has a direct relationship between poor control and the development of complications, it is also a good measure of prediction of microvascular complications in diabetics.
- However, it should be borne in mind that HbA1C value varies with the assay method used and is affected by the presence of haemoglobinopathies, anaemia, reticulocytosis, transfusions and uraemia. In such cases, serum fructosamine can be estimated which gives the average value for the previous 15 days.
Other Tests: A few other tests are sometimes performed in specific conditions in diabetics and for research purposes:
- Glycated albumin: This is used to monitor the degree of hyperglycaemia during the previous 1-2 weeks when HbA1C can not be used.
- Extended GTT: The oral GTT is extended to 3-4 hours for the appearance of symptoms of hyperglycaemia. It is a useful test in cases of reactive hypoglycaemia of early diabetes.
- Intravenous GTT: This test is performed in persons who have intestinal malabsorption or in postgastrectomy cases.
- Cortisone-primed GTT: This provocative test is a useful investigative aid in cases of potential diabetics.
- Insulin assay: Plasma insulin can be measured by radioimmunoassay and ELISA technique. Plasma insulin deficiency is crucial for type 1 DM but is not essential for making the diagnosis of DM.
- Proinsulin assay: Proinsulin is included in the immunoassay of insulin; normally it is ≤20% of total insulin.
- C-peptide assay: C-peptide is released in circulation during the conversion of proinsulin to insulin in equimolar quantities to insulin; thus its levels correlate with insulin levels in blood except in islet cell tumours and in obesity. This test is even more sensitive than insulin assay because its levels are not affected by insulin therapy.
- Islet autoantibodies: Glutamic acid decarboxylase and islet cell cytoplasmic antibodies may be used as a marker for type 1 DM.
- Screening for diabetes-associated complications: Besides making the diagnosis of DM based on the defined criteria, screening tests are done for DM-associated complications e.g. microalbuminuria, dyslipidaemia, thyroid dysfunction etc.
Neuroendocrine Tumours (Islet Cell Tumours):
- Pancreatic neuroendocrine tumours, previously known as islet cell tumours, are rare as compared with tumours of the exocrine pancreas. Islet cell tumours are generally small and may be
hormonally inactive or may produce hyperfunction. - They may be benign or malignant, single or multiple. They are named according to their histogeneses such as β-cell tumour (insulinoma), Gcell tumour (gastrinoma), A-cell tumour (glucagonoma) D-cell tumour (somatostatinoma), lipoma (diarrhoeagenic tumour from D1 cells which elaborate VIP), pancreatic polypeptide (PP)-secreting tumour, and carcinoid tumour.
- Their functional nature can be demonstrated by immunohistochemical stains with specific antibodies example to synaptophysin, chromogranin etc. However, except for insulinoma and gastrinoma, all others are extremely rare and require no further comments.
Insulinoma (Β-Cell Tumour):
Insulinomas or beta (β)-cell tumours are the most common islet cell tumours. The neoplastic β- cells secrete insulin into the bloodstream which remains unaffected by normal regulatory mechanisms. This results in characteristic attacks of hypoglycaemia with blood glucose level falling to 50 mg/dl or below, high plasma insulin level (hyperinsulinism) and high insulin glucose ratio.
The central nervous manifestations are conspicuous and are promptly relieved by the intake of glucose. Besides insulinoma, however, there are other causes of hypoglycaemia such as in starvation, partial gastrectomy, diffuse liver disease, hypopituitarism and hypofunction of the adrenal cortex.
Morphologic Features Grossly, insulinoma is usually a solitary and well-encapsulated tumour which may vary in size from 0.5 to 10 cm. Rarely, they are multiple.
Microscopically, the tumour is composed of cords and sheets of well-differentiated β-cells which do not differ from normal cells. Electron microscopy reveals typical crystalline rectangular granules in the neoplastic cells. It is extremely difficult to assess the degree of anaplasia to distinguish benign from malignant β-cell tumours.
Gastrinoma (G-Cell Tumour, Zollinger-Ellison Syndrome):
Zollinger and Ellison described a diagnostic triad consisting of the following:
- Fulminant peptic ulcer disease
- Gastric acid hypersecretion
- Presence of non-β pancreatic islet cell tumour.
Such non-β pancreatic islet cell tumour is the source of gastrin, producing hypergastrinemia and hence named gastrinoma. Definite G cells similar to intestinal and gastric G cells which are normally the source of gastrin in the body, have not been identified in the normal human pancreas but neoplastic cells of certain islet cell tumours have ultrastructural similarities.
Morphologic Features: The majority of gastrinomas occur in the wall of the duodenum. They may be benign or malignant. Gastrinomas are associated with peptic ulcers at usual sites such as the stomach, first and second part of the duodenum, or sometimes at unusual sites such as in the oesophagus and jejunum. About one-third of patients have multiple endocrine neoplasia—multiple adenomas of the islet cells, pituitary, adrenal and parathyroid glands.
Diseases of Endocrine Pancreas:
- Diabetes mellitus is a heterogeneous metabolic disorder characterised by the common feature of chronic hyperglycaemia with disturbance of carbohydrate, fat and protein metabolism. Based on aetiology, DM has classified into type 1 and type 2; other types are gestational DM and DM with known causes (genetic, pancreatic diseases, drugs and chemicals, infections etc).
- Pathogenesis of DM lies in reduced insulin, decreased glucose use by the body, and increased glucose production.
- Type 1 DM occurs commonly in patients under 30 years of age and has autoimmune pathogenesis (autoimmune destruction of β-cells).
- Type 2 DM comprises about 80% of cases of DM and predominantly affects older individuals and is a complex multifactorial disease with a greater role of genetic defect and heredity. It occurs due to progressive loss of β-cell insulin secretion.
- Both types of DM may develop complications. These may be acute metabolic complications (for example diabetic ketoacidosis, hyperosmolar nonketotic coma, and hypoglycaemia) and late systemic complications (for example atherosclerosis, diabetic microangiopathy, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and infections).
- Diagnostic criteria have been developed: fasting plasma glucose value ≥126 mg/dl, 2-hour plasma glucose value after 75 gm oral glucose ≥200 mg/dl, and HbA1C ≥6.5% are labelled as diabetics.
- Pancreatic neuroendocrine tumours (islet cell tumours) are rare; examples are insulinoma and gastrinoma.
Miscellaneous Endocrine Tumours
Multiple Endocrine Neoplasia (Men) Syndromes:
Multiple adenomas and hyperplasias of different endocrine organs are a group of genetic disorders which produce heterogeneous clinical features called multiple endocrine neoplasias (MEN) syndromes. These are MEN type 1 and type 2 and mixed type:
1. MEN type 1 syndrome (Werner’s syndrome): includes adenomas of the parathyroid glands, pancreatic islets and pituitary. The syndrome is inherited as an autosomal dominant trait. There is 50% chance of transmitting the predisposing gene, MEN 1 (or menin) gene, to the child of an affected person. MEN 1 is characterised by the following features:
- Parathyroid Hyperplasia or adenoma; hyperparathyroidism is the most common (90%) clinical manifestation.
- Pancreatic islet cells Hyperplasia or adenoma is seen in 80% of cases; frequently with ZollingerEllison syndrome.
- Pituitary Hyperplasia or adenoma in 65% of cases; manifests as acromegaly or hypopituitarism.
- Adrenal Uncommonly involved by adenoma or pheochromocytoma.
- The thyroid is Less commonly involved by adenoma or hyperplasia.
2. MEN type 2 syndrome (Sipple’s syndrome): is characterised by medullary carcinoma thyroid and pheochromocytoma. The genetic abnormality in these cases is a mutation in RET gene in almost all cases. MEN 2 has two major syndromes:
- MEN type 2A is the combination of medullary carcinoma thyroid, pheochromocytoma and hyperparathyroidism. MEN type 2A has further three subvariants:
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- MEN 2A with familial medullary carcinoma thyroid
- MEN 2A with cutaneous lichen amyloidosis
- MEN 2A with Hirschsprung’s disease.
- MEN type 2B is the combination of medullary carcinoma thyroid, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromatosis, and marfanoid features.
3. Mixed syndromes: include a variety of endocrine neoplastic combinations which are distinct from those in MEN type 1 and type 2. A few examples are as under:
- von Hippel-Lindau syndrome from a mutation in the VHL gene is associated with CNS tumours, renal cell carcinoma, pheochromocytoma and islet cell tumours.
- Type 1 neurofibromatosis from inactivation of neurofibromin protein and activation of RAS gene, is associated with MEN type 1 or type 2 features.
Polyglandular Autoimmune (Pga) Syndromes:
Immunologic syndromes affecting two or more endocrine glands and some non-endocrine immune disturbances produce syndromic presentations termed polyglandular autoimmune (PGA) syndromes. PGA syndromes are of two types:
- PGA type 1 occurring in children is characterised by mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency.
- PGA type 2 (Schmidt syndrome) presents in adults and commonly comprises of adrenal insufficiency, autoimmune thyroiditis, and type 1 diabetes mellitus.
Miscellaneous Endocrine Tumours:
- Multiple adenomas and hyperplasias of different endocrine organs are a group of genetic disorders which produce heterogeneous clinical features called multiple endocrine neoplasias (MEN) syndromes. These are MEN type 1, MEN type 2, and mixed syndromes.
- Polyglandular autoimmune syndromes (PGA) affect two or more endocrine glands and some non-endocrine immune disturbances and has 2 types: PGA type 1 and 2.
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