Multiple Endocrine Neoplasia Syndromes (MEN)

The MEN syndromes are a group of inherited diseases resulting in proliferative lesions (hyperplasias, adenomas, and carcinomas) of multiple endocrine organs. Even in one organ, the tumors are often multifocal. These tumors are usually more aggressive and recur in a higher proportion of cases than similar but sporadic endocrine tumors. 

Multiple Endocrine Neoplasia Type 1 (MEN1) is inherited in an autosomal dominant pattern. The gene (MEN1) is a tumor suppressor gene; thus, inactivation of both alleles of the gene is believed to be the basis of tumorigenesis. Organs commonly involved include the parathyroid, pancreas, and pituitary (the 3 Ps). Parathyroid hyperplasia is the most consistent feature of MEN-1 but endocrine tumors of the pancreas are the leading cause of death because such tumors are usually aggressive and present with metastatic disease.

Zollinger-Ellison syndrome, associated with gastrinomas, and hypoglycemia, related to insulinomas, are common endocrine manifestations. Prolactin-secreting macroadenoma is the most frequent pituitary tumor in MEN-1 patients. 

Multiple Endocrine Neoplasia Type 2 (MEN2)

MEN type 2 is actually two distinct groups of disorders that are unified by the occurrence of activating mutations of the RET protooncogene. Both are inherited in an autosomal dominant pattern. 

MEN 2A

Organs commonly involved include:

Medullary carcinoma of the thyroid develops in virtually all cases, and the tumors usually occur in the first 2 decades of life. The tumors are commonly multifocal, and foci of C-cell hyperplasia can be found in the adjacent thyroid. Adrenal pheochromocytomas develop in 50% of patients; fortunately, no more than 10% are malignant. Parathyroid gland hyperplasia with primary hyperparathyroidism occurs in a third of patients. 

Multiple Endocrine Neoplasia, Type 2B 

Organs commonly involved include the thyroid and adrenal medulla. The spectrum of thyroid and adrenal medullary disease is similar to that in MEN-2A. However, unlike MEN-2A, patients with MEN-2B: 

1. Do not develop primary hyperparathyroidism
2. Develop extraendocrine manifestations: ganglioneuromas of mucosal sites (gastrointestinal tract, lips, tongue) and marfanoid habitus 

Megaloblastic anaemia

Metabolism: B12(cyanocobalamin) is a coenzyme in DNA synthesis and for maintenance of nervous system. Daily requirement 2 micro grams. Absorption in terminal ileum in the presence gastric intrinsic factor. It is stored in liver mainly-

Folic acid (Pteroylglutamic acid) is needed for DNA synthesis.. Daily requirement 100 micro grams. Absorption in duodenum  and jejunum

Causes of deficiency .-

- Nutritional deficiency-
- Malabsorption syndrome.
- Pernicious anaemia (B12).
- Gastrectomy (B12).
- Fish tapeworm infestation (B12).
- Pregnancy and puerperium (Folic acid mainly).
- Myeloproliferative disorders (Folic acid).
- Malignancies (Folic acid).
- Drug induced (Folic-acid)

Features:

(i) Megaloblastic anaemia.
(ii) Glossitis.
(iii) Subacute combined degeneration (in B12deficiency).

Blood picture :

- Macrocytic normochromic anaemia.
- Anisocytosis and poikilocytosis with Howell-Jolly bodies and  basophilic stippling.
- Occasional megalo blasts may be-seen.
- Neutropenia with hypersegmented neutrophills and macropolycytes.
- Thrombocytopenia.
- Increased MVC and MCH with normal or decreased MCHC.

Bone marrow:

- Megaloblasts are seen. They are larger with a more open stippled chromatin. The nuclear maturation lags behind. the cytoplasmic maturation. Maturation arrest is seen (more of early forms).
- Immature cells of granulocyte series are also larger.
 -Giant stab forms (giant metamyelocytes).
 

Rheumatic fever

Before antibiotic therapy, this was the most common cause of valvular disease.
1. Usually preceded by a group A streptococci respiratory infection; for example, strep throat.
2. All three layers of the heart may be affected. The pathologic findings include Aschoff bodies, which are areas of focal necrosis surrounded by a dense inflammatory infiltration.

3. Most commonly affects the mitral valve, resulting in mitral valve stenosis, regurgitation, or both.

Cushing’s syndrome

The symptoms and signs of Cushing’s syndrome are associated with prolonged inappropriate elevation of free corticosteroid levels.

Clinical features

- Central obesity and moon face.
- Plethora and acne.
- Menstrual irregularity.
- Hirsutism and hair thinning.
- Hypertension.
- Diabetes.
- Osteoporosis—may cause collapse of vertebrae, rib fractures.
- Muscle wasting and weakness.
- Atrophy of skin and dermis—paper thin skin with bruising tendency, purple striae.

Aetiopathogenesis — patients with Cushing’s syndrome can be classified into two groups on the basis of whether the aetiology of the condition is ACTH dependent or independent. 

Classification of Cushing's syndrome

ACTH dependent- Iatrogenic (ACTH therapy) Pituitary hypersecretion of ACTH Ectopic ACTH syndrome (benign or malignant non-endocrine tumour)

Non-ACTH dependent - Iatrogenic, e.g. prednisolone Adrenal cortical adenoma , Adrenal cortical carcinoma

ACTH-dependent aetiology:

- Pituitary hypersecretion of ACTH (Cushing’s disease)—bilateral adrenal hyperplasia secondary to excessive secretion of ACTH by a corticotroph adenoma of the pituitary gland.
- Production of ectopic ACTH or corticotrophin- releasing hormone (CRH) by non-endocrine neoplasm, e.g. small cell lung cancer and some carcinoid tumours. In cases of malignant bronchial tumour, the patient rarely survives long enough to develop any physical features of Cushing’s syndrome.

Non-ACTH-dependent aetiology

Iatrogenic steroid therapy—most common cause of Cushing’s syndrome.
Adrenal cortical adenoma—well-circumscribed yellow tumour usually 2–5 cm in diameter.
Extremely common as an incidental finding in up to 30% of all post-mortem examinations. The yellow colour is due to stored lipid (mainly cholesterol) from which the hormones are synthesised. The vast majority have no clinical effects (i.e. they are non-functioning adenomas), with only a small percentage producing Cushing’s syndrome.

Adrenal cortical carcinoma—rare and almost always associated with the overproduction of hormones, usually glucocorticoids and sex steroids. 

Cushing’s syndrome mixed with androgenic effects which are particularly noticeable in women. Tumours are usually large and yellowish white in colour. Local invasion and metastatic spread are common.

Irrespective of the aetiology, the diagnosis is based on clinical features and the demonstration of a raised plasma cortisol level.
The aetiology of the disorder is elucidated through:
- Raised urinary cortisol in the first instance, but further testing is required.
- Low-dose dexamethasone suppression test (suppression of cortisol levels in Cushing’s disease due to suppression of pituitary ACTH secretion, but a lack of suppression suggests ACTH-independent Cushing’s syndrome).
- MRI and CT scan visualisation of pituitary and adrenal glands.
- Analysis of blood ACTH (high = pituitary adenoma or ectopic ACTH source; low = primary adrenal tumour due to feedback suppression).
- Treatment of the underlying cause is essential as untreated Cushing’s syndrome has a 50% 5-year mortality rate.

The therapeutic administration of glucocorticosteroids (e.g. prednisolone) is a common cause of the features of Cushing’s syndrome. 

Osteoporosis
 
is characterized by increased porosity of the skeleton resulting from reduced bone mass. The disorder may be localized to a certain bone (s), as in disuse osteoporosis of a limb, or generalized involving the entire skeleton. Generalized osteoporosis may be primary, or secondary

Primary generalized osteoporosis
• Postmenopausal
• Senile
Secondary generalized osteoporosis

A. Endocrine disorders
• Hyperparathyroidism
• Hypo or hyperthyroidism
• Others

B. Neoplasia
• Multiple myeloma
• Carcinomatosis 

C. Gastrointestinal disorders
• Malnutrition & malabsorption
• Vit D & C deficiency
• Hepatic insufficiency 

D. Drugs
• Corticosteroids
• Anticoagulants
• Chemotherapy
• Alcohol 

E. Miscellaneous
• osteogenesis imperfecta
• immobilization
• pulmonary disease 

Senile and postmenopausal osteoporosis are the most common forms. In the fourth decade in both sexes, bone resorption begins to overrun bone deposition. Such losses generally occur in areas containing abundant cancelloues bone such as the vertebrae & femoral neck. The postmenopausal state accelerates the rate of loss; that is why females are more susceptible to osteoporosis and its complications. 

Gross features
• Because of bone loss, the bony trabeculae are thinner and more widely separated than usual. This leads to obvious porosity of otherwise spongy cancellous bones

Microscopic features
• There is thinning of the trabeculae and widening of Haversian canals.
• The mineral content of the thinned bone is normal, and thus there is no alteration in the ratio of minerals to protein matrix

Etiology & Pathogenesis

• Osteoporosis involves an imbalance of bone formation, bone resorption, & regulation of osteoclast activation. It occurs when the balance tilts in favor of resorption.
• Osteoclasts (as macrophages) bear receptors (called RANK receptors) that when stimulated activate the nuclear factor (NFκB) transcriptional pathway. RANK ligand synthesized by bone stromal cells and osteoblasts activates RANK. RANK activation converts macrophages into bone-crunching osteoclasts and is therefore a major stimulus for bone resorption.
• Osteoprotegerin (OPG) is a receptor secreted by osteoblasts and stromal cells, which can bind RANK ligand and by doing so makes the ligand unavailable to activate RANK, thus limiting osteoclast bone-resorbing activity.
• Dysregulation of RANK, RANK ligand, and OPG interactions seems to be a major contributor in the pathogenesis of osteoporosis. Such dysregulation can occur for a variety of reasons, including aging and estrogen deficiency.
• Influence of age: with increasing age, osteoblasts synthetic activity of bone matrix progressively diminished in the face of fully active osteoclasts.
• The hypoestrogenic effects: the decline in estrogen levels associated with menopause correlates with an annual decline of as much as 2% of cortical bone and 9% of cancellous bone. The hypoestrogenic effects are attributable in part to augmented cytokine production (especially interleukin-1 and TNF). These translate into increased RANK-RANK ligand activity and diminished OPG.
• Physical activity: reduced physical activity increases bone loss. This effect is obvious in an immobilized limb, but also occurs diffusely with decreased physical activity in older individuals.
• Genetic factors: these influence vitamin D receptors efficiency, calcium uptake, or PTH synthesis and responses.
• Calcium nutritional insufficiency: the majority of adolescent girls (but not boys) have insufficient dietary intake of calcium. As a result, they do not achieve the maximal peak bone mass, and are therefore likely to develop clinically significant osteoporosis at an earlier age.
• Secondary causes of osteoporosis: these include prolonged glucocorticoid therapy (increases bone resorption and reduce bone synthesis.)
The clinical outcome of osteoporosis depends on which bones are involved. Thoracic and lumbar vertebral fractures are extremely common, and produce loss of height and various deformities, including kyphoscoliosis that can compromise respiratory function. Pulmonary embolism and pneumonia are common complications of fractures of the femoral neck, pelvis, or spine. 

Herpes zoster, or shingles
 - represents reactivation of a latent varicella-zoster infection.
 - virus lies dormant in sensory dorsal root ganglia and when activated involves the distribution (dermatome) of the sensory nerve with a painful vesicular eruption.
 - trigeminal verve distribution → Ramsay Hunt syndrome
 - may indicate the presence of advanced neoplastic disease or be a complication of chemotherapy.