Metastatic Tumors 

These are the most common malignant tumor of bone. Certain tumors exhibit a distinct skeletal prediliction. In adults more than 75% of skeletal metastases originate from cancers of the prostate, breast, kidney, and lung. In children, neuroblastoma, Wilms' tumor, osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma are the common sources of bony metastases. Most metastases involve the axial skeleton (vertebral column, pelvis, ribs, skull, sternum), proximal femur, and humerus. The radiologic appearance of metastases can be purely osteolytic, purely osteoblastic, or mixed osteolytic-osteoblastic (majority of cases). In lytic lesions (e.g., kidney& lung), the metastatic cells secrete substances such as prostaglandins, interleukins, etc. that stimulate osteoclastic bone resorption; the tumor cells themselves do not directly resorb bone. Similarly, metastases that elicit a blastic response (e.g., prostate adenocarcinoma) do so by stimulating osteoblastic bone formation.

Biliary cirrhosis(16%)

It is due diffuse chronic cholestaisis (obstruction of the biliary flow) leading to damage and scarring all over the liver. Two types are known  
1. Primary biliary cirrhosis and
2. Secondary biliary cirrhosis. 

Primary biliary cirrhosis
It is destructive chronic inflammation of intrahepatic bile ductules and small ducts leading to micronodular cirrhosis. 
-Typically affects middle aged women. 
- Patients present with fatigue, pruritis and eventually, jaundice. 

Cause:-  Autoimmune. Patients have autoantibodies directed against mitochondrial enzymes (AMA). 

Pathology:- 

 Liver is enlarged, dark green in color (cholestaisis). Cirrhosis is micronodular. 

M/E :-
- Early, portal tracts show lymphocytes and plasma cell infiltrate the bile ducts and destroy them.
- Granulomatous inflammation surrounding the damaged and inflamed bile ducts is the hallmark of (PBC).
- Cholestatic changes such as bile ductular proliferation, periportal Mallory’s hyaline and increased copper in periportal hepatocytes.
- In the end stage disease, micro nodular cirrhosis occurs and the inflammatory changes subside 

Secondary biliary cirrhosis:-
 It is extra hepatic (surgical) cholestaisis due to prolonged extra hepatic major bile duct obstruction. 

Causes - Obstruction of hepatic or common bile duct by: 
   - Congenital biliary atresia.       
   - Pressure by enlarged LN or tumor   * Biliary stones. 
   - Carcinoma of the bile duct, ampulla of Vater or pancreatic head

Effects of obstruction:- 
Complete obstruction leads to back pressure all over the biliary tract           
 - damage by inspessated bile          
 - inflammation and scarring.
Incomplete obstruction  leads to acute suppurative cholangitis and cholangiolitis. 

INFLUENZA

An acute viral respiratory infection with influenza, a virus causing fever, coryza, cough, headache, malaise, and inflamed respiratory mucous membranes.

Influenza B viruses typically cause mild respiratory disease

Symptoms and Signs

mild cases:

Chills and fever up to 39 to 39.5° C

Prostration and generalized aches and pains, Headache, photophobia and retrobulbar aching

Respiratory tract symptoms may be mild at first, with scratchy sore throat, substernal burning, nonproductive cough, and sometimes coryza. Later, the lower respiratory illness becomes dominant; cough can be persistent and productive.

severe cases

sputum may be bloody. Skin is warm and flushed. Soft palate, posterior hard palate, tonsillar pillars, and posterior pharyngeal wall may be reddened, but no exudate appears. Eyes water easily, and the conjunctiva may be mildly inflamed

Encephalitis, myocarditis, and myoglobinuria are infrequent complications of influenza and, if present, usually occur during convalescence

Osteopetrosis (Albers-Schönberg disease or marble bone disease) 

is a group of rare genetic disorders characterized by reduced osteoclast-mediated bone resorption and therefore defective bone remodelling. The bones are solid and heavy with no medullary canal, long ends are bulbous, small neural foramina compress nerves. The affected bone is grossly dense but fractures occur readily like a piece of chalk. 

Patients frequently have cranial nerve compressions by the surrouding bone, and recurrent infections. The latter is attributable to diminished hematopoiesis resulting from reduced marrow space with impressive hepatosplenomegaly due to extramedullary hematopoiesis 
 
a. Caused by abnormal osteoclasts. This results in defective bone remodeling (i.e., abnormally low bone resorption) and increased bone density, which may invade into bone marrow space.
b. Causes severe defects in infants, including:
(1) Anemia and infections—caused by decreased bone marrow.
(2) Blindness, deafness, paralysis of facial muscles—caused by the narrowing of cranial nerve foramina.
(3) Is life-threatening.
(4) Oral findings include delayed eruption of teeth.
c. Disease is less severe in adults

Hyperparathyroidism 

Abnormally high levels of parathyroid hormone (PTH) cause hypercalcemia. This can result from either primary or secondary causes. Primary hyperparathyroidism is caused usually by a parathyroid adenoma, which is associated with autonomous PTH secretion. Secondary  hyperparathyroidism, on the other hand, can occur in the setting of chronic renal failure. In either situation, the presence of excessive amounts of this hormone leads to significant skeletal changes related to a persistently exuberant osteoclast activity that is associated with increased bone resorption and calcium mobilization. The entire skeleton is affected. PTH is directly responsible for the bone changes seen in primary hyperparathyroidism, but in secondary hyperparathyroidism additional influences also contribute. In chronic renal failure there is inadequate 1,25- (OH)2-D synthesis that ultimately affects gastrointestinal calcium absorption. The hyperphosphatemia of renal
failure also suppresses renal α1-hydroxylase, which further impair vitamin D synthesis; all these eventuate in hypocalcemia, which stimulates excessive secretion of PTH by the parathyroid glands, & hence elevation in PTH serum levels. 

Gross features
• There is increased osteoclastic activity, with bone resorption. Cortical and trabecular bone are lost and replaced by loose connective tissue. 
• Bone resorption is especially pronounced in the subperiosteal regions and produces characteristic radiographic changes, best seen along the radial aspect of the middle phalanges of the second and third fingers.

Microscopical features

• There is increased numbers of osteoclasts and accompanying erosion of bone surfaces.
• The marrow space contains increased amounts of loose fibrovascular tissue.
• Hemosiderin deposits are present, reflecting episodes of hemorrhage resulting from microfractures of the weakened bone.
• In some instances, collections of osteoclasts, reactive giant cells, and hemorrhagic debris form a distinct mass, termed "brown tumor of hyperparathyroidism". Cystic change is common in such lesions (hence the name osteitis fibrosa cystica). Patients with hyperparathyroidism have reduced bone mass, and hence are increasingly susceptible to fractures and bone deformities.

Avitaminoses -  Vitamin deficiencies are more commonly secondary disorders associated with malabsorption conditions and chronic alcoholism.

A. Vitamin A - (retinoids, fat soluble compounds derived from ß-carotene) The best-known effect of deficiency is an inability to see in weak light (night blindness due to decreased rhodopsin).
-> The pathology is also characterized by skin lesions (rash on the extremities with punctate erythematous lesions). In malnourished children, vitamin A supplements reduce the incidence of infections such as measles, even in children without signs of preexisting deficiency.

B. Vitamin D - (1, 25 OH2 D3) Deficiency produces osteomalacia (called rickets in children). Many of the effects of osteomalacia overlap with the more common osteoporosis, but the two disordersare significantly different.
-> The specific alteration in osteomalacia and rickets is a failure of mineralization of the osteoid matrix resulting in decreased appositional bone growth. 

C. Vitamin E - Very rare. Occurs as a secondary disorder in conditions associated with fat maladsorption such as cystic fibrosis, pancreatitis, and cholestasis (bile-flow obstruction).
-> Vitamin E deficiency causes a neurological disorder characterized by sensory loss, ataxia and retinitis pigmentosa due to free radical mediated neuronal damage.

D. Vitamin K - (phylloquinone) Present in most leafy plants and also synthesized by intestinal bacteria. Vitamin K is required for the production of specific clotting factors and a deficiency is characterized by impaired coagulation (elevated clotting times). Although this can occur in newborns that are given breast milk low in vitamin K, the deficiency is almost always secondarily associated with the use of certain anti-coagulants or disorders such as obstructive jaundice, celiac, or pancreatic disease.

 E. Thiamine - (B1) The deficiency is known as beriberi. Thiamine deficiency is characterized by a peripheral neuropathy that affects sensation particularly in the legs (associated with demyelination of peripheral nerves), in more severe cases Korsakoff syndrome (neuropathy characterized by impaired ocular motility, ataxia, and mental confusion) and cardiomyopathy can occur.

F. Nicotinamide (niacin) - The deficiency is known as pellagra. Primary deficiencies are associated with diets that consist primarily of a single low quality protein source (i.e. corn). It results most commonly as a complication of alcoholism.

-> The pathology is characterized by hyperkeratosis and vesiculation of skin, atrophy of the tongue epithelium, and a neuropathy that can affect cortex and peripheral neurons.

- Initial symptoms include a smooth, red tongue, a sore mouth, and ulceration of the inside of the cheeks.

- The skin on the neck, chest, and back of the hands may become brown and scaly. 

- Often there is nausea, vomiting, and diarrhea. There may also be insomnia, depression, confusion, and rapid changes of mood. Long-standing pellagra can result in dementia and death.

G. Vitamin B12 - (cobalamin) Because cobalamin is synthesized by intestinal bacteria and is widely available in many foods, deficiencies are almost always secondary disorders associated with gastric atrophy (and decreased uptake via intrinsic factor), microbial proliferation (AIDS), long-term antacids, chronic alcoholism, idiopathic (age-related).

In addition to anemia, the primary clinical symptoms include a sensory neuropathy (polyneuropathy), sclerosis of the spinal cord and atrophy of some mucous tissues.

H. Vitamin C - (ascorbic acid) The classic deficiency is known as scurvy. The essential pathology involves an inability to produce mature collagen and hence affects connective tissue.

This is characterized by an inability to synthesize osteoid and dentin (and results in decreased wound healing) and a loss of integrity of blood vessel walls.

Oral lesions are only a feature of the advanced form of the disease; early signs include fatigue, dermatitis, and purpura. There can be abnormalities in the growing bones of infants. 

I. Vitamin B6 - (Pyridoxine) A deficiency can lead to peripheral neuropathy, most commonly associated with multivitamin B deficiencies in malnutrition and alcoholism. 

V. Major Minerals - Sodium, potassium, chlorine, and magnesium are required for life but dietary deficiencies do not develop.
A. Iodine - Essential for the synthesis of thyroid hormones, and severe iodine deficiency is  associated with hypothyroidism. The compensatory activity of the thyroid gland causes a  characteristic enlargement called goiter.

B. Calcium - Required for bone mineralization, the RDA for adults is 800 mg/day. Clinical trials have shown that 1000-2000 mg/day can delay the bone loss observed in the elderly and decrease the risk of osteoporosis. See also section IV B.

VI. Trace Elements - At least 10 elements (examples: Co, Mn, Si) are required in minute amounts for normal development and metabolism.

A. Zinc - A deficiency can result from inadequate amounts given during total parenteral nutrition or as a secondary effect of acrodermatitis enteropathica (autosomal recessive trait characterized by alopecia, dermatitis, and diarrhea - the disease responds to administration of zinc).

B. Copper - Deficiencies are rare and primarily associated with malabsorption syndromes and total parenteral nutrition. Copper is required for normal hematopoiesis and bone growth. A deficiency resembles iron deficiency anemia and osteoporosis.

C. Fluoride - Levels in drinking water greater than 1 ppm cause mottling of teeth and in areas with chronic naturally induced fluorosis there is abnormal calcification of ligaments and tendons.