CNS Pathology

August 29, 2017 | Author: Michael-John Fay | Category: Stroke, Brain Tumor, Human Brain, Multiple Sclerosis, Cerebrospinal Fluid
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PATHOLOGY Brain tumours Remember that the skull is a rigid closed box. There are 3 compartments. Two are above the tentorium cerebelli (divided by the falx cerebri) and 1 below.


There are 3 things inside the head: Blood, brain and CSF Brain: mixture of glial cells and neurones (equal volumes) Relatively small amount of blood inside the brain at any one time. Small volume of CSF and extracellular fluid. Very little space inside the head, when there is an expanding mass inside the head (whether this is tumour, haemorrhage, abscess or anything else) Pressure in adult is about 15mmHg. In newborn baby it is atmospheric pressure (because it is in connection with the outside) You can measure the intracranial pressure by doing a lumbar puncture and attaching a sphygmomanometer to it. Alternatively you can drill a small hole into the head and attach a transducer. As the volume expands the pressure stays more or less the same (however after a certain volume, the pressure expands rapidly). Eventually the pressure inside the head exceeds the cerebral perfusion pressure and you become brain dead. Neurological intensive care units frequently measure the intracranial pressure. Important to recognise it early. As a mass expands (e.g above the tentorium cerebelli) then it initially squashes the ventricles. Then it will eventually cause brain tissue to herniate to the other side. Finally, it will cause herniation of the brain stem (from one side to the other). This is important because the brainstem is supplied by small branches from the basilar artery. The basilar artery itself is anchored and can’t move. Therefore the vessels stretch and tear. This causes secondary haemorrhages which will cause death. Oedema and hydrocephalus Oedema: excess water in the extracellular space Hydrocephalus: excess water in the ventricular system Oedema Normally we don’t produce significant ECF in the brain because we don’t have lymphatics in the brain (and thus we would have no way of removing it).

Additionally, the blood vessels in the brain have tight junctions and unless there is a pathological condition they do not allow fluid to getting across. Thus if breakdown in BBB, fluid gets out into the extracellular space, it builds up (due to lack of lymphatics) There are 2 reasons that you can get cerebral oedema: Vasogenic: tight junctions open. This can be due to trauma or a tumour. This is the one that is most amenable to treatment (putting patient on ventilator etc) Cytotoxic: Here there is a problem with the sodium potassium pump. This is dependent on oxygen and glucose. If this pump fails then sodium cant be pumped out of the cell. Thus water enters and it swells. This is seen in ischaemia. There is not much you can do in this situation.

Hydrocephalus Causes: Loss of brain tissue, as you can’t have a vacuum in your skull, so CSF fills up the space. Commonest cause of this is Alzheimer’s where you have lost brain tissue. Termed hydrocephalus ex vacuo.


Overproduction/blockage/reabsorption failure. Remember the anatomy of the ventricular system. You have the choroids plexus which produces the CSF. This is present throughout the ventricular system. The CSF flows from the lateral ventricles through the foramen of Monro to the third ventricle. It then flows via the cerebral aqueduct to the fourth ventricle. Then it can flow down the spinal cord or through the foramen of


Luschke and the foramen of Megendie. It then flows around the superior saggital sinus to be reabsorbed by the arachnoid villi. This circulates about 3 times a day. You cannot stop CSF from being produced. Thus if there is a blockage then the pressure will rapidly rise and you will die from raised intracranial pressure quickly. Can produce too much CSF – choroids plexus papilloma/carcinoma. Note how the ventricles are equally enlarged (this is sign of papilloma/carcinoma)

Circulation blockage – need to think of the anatomy and find out where the blockage is. (below scan does not show where the blockage is) (on right can see that there is blockage of the foramen of monro)

Chiari malformation Note that there is a congenital defect where you have a small posterior fossa which is not large enough for the contents. You get these scan changes


Treatment is with neurosurgery to decompress the area. Note that newborn infant is when there is the first presentation. Associated with spina bifida. Can also present in later life though (presenting with headaches, raised intracranial pressure etc)


Brain tumours Primary brain tumours are reasonably rare. 10X more common to have secondary brain tumours (especially from lung, breast etc). This often occurs in the context of late stage disseminated disease. However, there may be the presentation of a single brain tumour met as the first presentation. They are common in children (as common as childhood leukaemia) Survival not improved in 60 years. 1 year median survival.


Causes Not really known Maybe some familial, radiation, viral factors etc. (Most have no known cause) Some conditions have increased risk e.g neurofibromatosis, von-Hippel Lindau etc Not really any carcinoma sequence that we are aware of (e.g dysplasia, CIS etc). Don’t find incidental brain tumours (not known what the precancerous state is)


Clinical presentation Raised intracranial pressure e.g headache. Especially worse in morning (because when lying down, venous drainage from head is not as good as when standing up), then it progresses to persisting throughout the day. Eventually patient begins to vomit (remember this is a cardinal feature of raised ICP). As vomiting persists the patient will begin to get drowsy (as the raised ICP is having an effect on cerebral perfusion). Then only matter of hours before coma Behavioural change not as common presentation now because all psychiatric patients have brain imaging. Seizure: first time patient has a seizure after the age of 4-5 then the patient has a brain tumour until proven otherwise. (this is because seizures are common in childhood and vast majority are not due to brain tumours – as child gets older and especially adult who gets this must get MRI – CT is useless, not good resolution) Neurological deficit – (as opposed to stroke, the deficit comes on gradually over time – as the tumour expands). -



Classification Tend not to use term benign or malignant. Unlike other tumours in the body, ALL brain tumours are potentially lethal (irrespective of type and grade) due to raised ICP Major biological difference between infiltrating gliomas (these arise in the substance of the brain. They infiltrate the brain by following line of least resistance). These will kill you within a year. Tumours from the surface that push into the brain but don’t invade the brain tissue e.g pituitary or meningeal tumours are a very different entity. Easily treated The first type is referred to as of glial origin. Remember that neurones are post mitotic cells and thus you cannot get neuronal tumours. Glioma These tumours proliferate and invade adjacent brain tissue. They are capable of developing a new blood vessel for themselves. Astrocyte: scaffolding of the brain tissue, they support the brain. Also contribute to BBB and provide nutrition to the brain. They turnover regularly Oligodendrocytes: lay down myelin over the axons. Note neural development. You have proliferation, differentiation (the cells are very undifferentiated – can become astrocyte, oligodendrocyte or neurone). There is then migration to the site of the developing cortex. First the astrocytes go up. Then the neurones move up and they wrap themselves around the astrocytes (like a vine). Then they make connections to other cells. The cells then begin apoptosis (if this doesn’t occur then half their brain will be twice the size as the other) Sometimes there is arrested migration and you result in a double cortex

In brain tumours the opposite occurs Glioma classification Astrocytoma, oligodendroglioma ependymoma (remember the ependymal cells are the cells which line the ventricles and contribute to the choroids plexus)

Key thing is to remember that these are highly malignant and will kill you (only matter of time)


Astrocytoma Two different groups: non-infiltrating and infiltrating Non infiltrating are juvenile pilocystic, subependymal giant cell and subependynoma Infiltrating include astrocytoma, anaplastic astrocytoma and glioblastoma multiforme. These infiltrate surrounding brain, show progression to higher grade and very difficult to remove (as they look like normal brain). Only on MRI is there a difference. Also problem as often presents late. The CT underestimates the tumour extent. The isolated tumour cells invade widely and it is impossible for the surgeon to remove it all (need to add a couple of cm into the perimeter of the apparent tumour) They never metastastise because there are no lymphatics in the brain (additionally they lack enzyme – metalloproteinase to invade blood vessels). However by contrast, secondaries can easily metastasise to the brain because can spread by blood If they do reoccur then they do so in the same place (however still cannot be removed as it invades the brain tissue) They are very leaky as they don’t have the normal tight junctions of normal brain. Thus they leak fluid into the extracellular space and cause brain oedema and raised ICP (which is how they kill you) Grade: Grade 1 = don’t progress to later grades and can often not present problems Grade 2 = hypercellular Grade 3 = has mitosis Grade 4 = has necrosis and neovascularisation.

Progression is inevitable (except grade 1). You try to delay progression with surgery/chemotherapy/radiotherapy but not very effective. Can do surgery as below (you can use image guidance to locate the tumour amidst the surrounding brain. It has not helped mortality but it has helped reduce morbidity. -

Extent of resection depends on the location (how much neurological deficit you will do by performing the procedure)


Oligodendroglioma These are another form of glioma They have a unique genetic signature (1p 19q deletions). Those with this deletion respond much better to chemotherapy. Either way, all the patients with these brain tumours will end up with a highly malignant stage 4 glioma called a glioblastoma (most die within year). In summary, grade is very good predictor of survival. Additionally amount of neurological deficit is a good predictor.


Glioma treatments Removal Biopsy is not a treatment. Maximum safe debulking of the tumour. Can also do craniotomy (where a portion of the skull is removed) and decompression Radiation: Conventional external beam can be used. However, internal beams can also be used. Chemotherapy Can also be used.



Therapeutic resistance These tumours do so badly because radical resection is difficult (due to problem of removing brain tissue and resulting in severe neurological deficit/death) Radiotherapy constraints Tumour heterogeneity (i.e multiple cell lines are involved and therefore as you kill off one cell line, another takes its place) Blood tumour barrier (which makes it difficult for chemotherapy to act).

CHILD BRAIN TUMOURS These are as frequent as leukaemia but are more devastating. The impact of treatment on the developing nervous system is a problem.


There are psychological and neurological effects of the treatment on it. There may be endocrine effects (e.g damage to the pituitary glands). If you e.g operate on a spinal cord in a child < 2 then they will not grow beyond that length. Most adult brain tumours occur above tentorium while most child ones occur below the tentorium.

Cerebellar astrocytoma Cystic and it is easily resected. No other Treatment is necessary. There is excellent long term survival. -

Brainstem astrocytoma Same tumour, same histology but different location. Now very different prognosis. Impossible to resect. There are major neurologic deficits. There is low grade histology but LOCATION and NOT the grade dictates the outcome. Only palliative care is possible. Medulloblastoma This is a primitive neuroepidermal tumour (it is the equivalent of a nephroblastoma, retinoblastoma etc) Develops from the primitive developing cerebellum. They spread down the spinal cord through the CSF. There are small round cells (they look kind of like small cell carcinoma in the lungs)

Treatment in a child over 2: resection (as much as you can) and radiotherapy to the spinal cord. Treatment under 2: intrathecal chemotherapy (not as effective) and resection as much as you can. However there are devastating neurological affects as the effects on the developing nervous system are extensive. NON GLIAL TUMOURS These arise from the structures that cover the brain (and structures around it)

Meningioma. This pushes into the brain tissue but does not invade (unlike a glioma). Thus relatively easy to be removed.


Pituitary adenoma Can produce too much or too little hormone Can also compress surrounding structures e.g optic nerve – remember that patients often do not notice visual field defects, cavernous sinus (remember, collection of veins), brainstem.

Schwannoma These are tumours of the cranial nerves (except II). Remember that the optic nerve is covered by oligodendrocytes (which is why it is the only cranial nerve which is affected by MS). This is a schwannoma in the cerebello-pontine angle. Thus affecting 7th and 8th nerves. Thus probably complaining of deafness. This is a difficult area to operate (and may be left with a 7th nerve palsy afterwards)

Note that if you get it on both sides you almost definitely have type 2 neurofibromatosis. Pinealoma Back of the brainstem is in a very inaccessible place of the brainstem, can press on back of brainstem damaging nerves so cannot have vertical gaze, cannot move up or down. makes sense – arises posteriorly from the brainstem – supplies the superior oblique – which is responsible for making the eye look down


Also compresses the aqueduct of Sylvius – so patients get hydrocephalus.

Cerebral haemangioblastoma: This is a vascular tumour which arises from stem cells that produce blood vessels It is associated with von-Hippel Lindau disease. Remember this is a disease where there is a mutation in a tumour suppressor gene – this causes them to be at increased risk of this as well as phaochromocytoma but most importantly renal cell carcinoma. Since it is very vascular, it is prone to bleed. Craniopharyngioma Benign tumour but due to where it is – right by the hypothalamus, it is very problematic Can be blind due to damage to pituitary stalk, they can have dwarfism due to damage to pituitary, diabetes insipidus due to damage to posterior pituitary etc. 4 C’s Childhood, cystic, calcified and cholesterol in cyst. Microscopically composed of remnants of Rathke’s pouch. -



Stroke is the rapidly developing loss of brain function due to disruption of the normal blood supply to the brain You cannot manage a patient unless you can do a CT scan within 2 hours of the onset of symptoms. Scan needs to tell you if you have a haemorrhage or an infarct (this is only thing you need to initially know) Stroke units: need full work up within 3-4 hours Need early recognition with neuroimaging Early treatment with thrombolysis Need to have good prevention (with risk factor management). Remember that stroke risk is exactly the same as heart disease risk except heart disease is an additional factor. Neurorehabilitation is essential. Recovery after stroke takes at least 2 years. Thus cant give up. Need to make sure have access to speech therapy, physiotherapy etc. This makes a difference. Stroke is either an infarct or a haemorrhage. Infarct can be embolus or thrombus Haemorrhage can be intracerebral or subarachnoid. (you can get haemorrhages in other areas e.g extradural haemorrhages in trauma) Stroke incidence/mortality Declining mortality due to improved BP control (one of the main risk factors haemorrhagic stroke) and other risk factor management. Case fatality is also declining due to improved acute stroke care. The stroke events are less severe and there is an increased dx of mild cases (i.e picked up earlier) Frequency of stroke type Infarction is most common (65%) Haemorrhage is about 1/10 (of which half are subarachnoid haemorrhage and half are intracerebral haemorrhage). This is on the decline because of better BP control. TIA = 20%. (transient loss of unction within 20 mins. Platelets then break up and move on. However, important thing is that high chance of then developing infarct. (i.e warning sign). (traditional definition: hypocalcaemia (lack of Vitamin D) and phosphate retention (decrease in reabsorption) Thus secondary hyperparathyroidism and thus osteitis fibrosa cystica. Osteomalacia Due to less activation of vitamin D (I believe thus calcium decrease), Thus reduction in mineralization of bone Another cause is dialysis units which contain aluminum (bind osteoid and inhibit mineralization of bone)


Can also be due to metabolic acidosis – get bone resorption and release of hydroxyapatite from the bone. (i.e you are releasing Ca2+ - another positive ion being exchanged for hydrogen, from the bone) Osteoporosis Usually due to steroid therapy (given to those with renal failure, especially those with glomerulonephritis) -



Osteitis fibrosa cystica: Due to hypocalcaemia/phosphate retention and thus increased parathyroidism. Can also get amyloid deposition (B2 microglobulin) – associated with dialysis Paget’s disease (osteitis deformans) Epidemiology Can effect one bone but much more commonly it affects multiple bones. You get “collagen matrix madness” You have initial osteolytic phase (hence reduction in bone formation) Mixed phase: get both osteolytic and osteoblastic. However this is haphazardly laid down (which means that this is woven bone – see above) Osteoblastic activity prevails: thus you get gain in bone mass. Thus fibrosis of bone marrow and thickening of bone trabeculae (osteosclerotic phase – thus get mosaic pattern) Pathogenesis Unknown cause More common in whites Slow virus: paramyxovirus potentially implicated. Also genetic predisposition (18q is locus implicated in Paget’s disease) Morphology At late phase get sclerosis, thickening of bone mass. Especially affects skull and long bones


Complications of Paget’s disease Fractures (because even though increase in bone mass, it is laid down quickly and haphazardly) Bone pain (due to fractures) Deformity (due to increased bone mass) Nerve or cord compression Deafness (due to compression of nerves) Osteoarthritis Heart failure (because have increase in vascularity of the bone – resulting in shunts) Rarely – can have malignant transformation (to osteosarcoma – makes sense, increase in proliferation) SUMMARY Abnormal matrix/osteoid: osteogenesis imperfecta (inherited) or acquired (osteoporosis) Abnormal mineralization: rickets/osteomalacia or renal osteodystrophy (I believe this is the main one, even though other 2 also) Abnormal parathyroid: osteitis fibrosa cystica Abnormal osteoclastic function: Paget’s disease or osteopetrosis (these 2 seem very similar, just seems to me like Paget’s difference is that the osteoblastic activity comes at the end rather than primarily) AVASCULAR NECROSIS (OSTEONECROSIS) This is due to infarction of bone and bone marrow.

Due to ischaemia: (Can be vascular injury – usually tauma) thrombosis Steroids Radiation Alcoholism Idiopathic Major sites Head of femur and scaphoid bone. May be asymptomatic or associated with pain. If not treated then can predispose to severe osteoarthritis. Fractures/Tumours Fractures can be complete (where you get 2 fragments of bone) or incomplete (also called greenstick fractures. This is where the bone is cracked but not brocken into two pieces)* Often seen in young, immature bone (this is common in children) Theycan also be simple or compound. Simple = closed – the surrounding skin is intact

Compound = open, the skin is broken and the bone may protrude through (thus risk of infection)

They can be comminuted – where the bone is splintered into multiple bone fragments.

They can be displaced – where the ends of the bone are not aligned

. Spiral fracture = seen in twisting injury (common in dancers)

Complicated = when there is injury to adjacent tissues (e.g blood vessels and nerves) Depressed fracture = commonly seen in the skull (where the fractures can compress underlying tissue – with risk of damaging the brain)

Stress fracture (bone fracture after repetitive stress). E.g tibia, fibula and metatarsals (e.g athletes, dancers and army recruits) Pathologic fractures = fracture of a bone that has been damaged by disease. Pathological fracture Any condition that affects the bone, weakening it can result in this. Osteoporosis Osteomalacia Pagets disease Tumours (both primary or secondary) Congenial bone disorders e.g osteogenesis imperfecta.

Fractures cont Incomplete simple fractures heal the most quickly. Communitated fractures are characterized by multiple fragments and so it will delay healing. Compound fractures communicate with the overlying skin and thus are more likely to become infected. Healing of bone You injure the blood vessels and thus you get haematoma formation (collection of blood) Then you get inflammatory phase (get neutrophils, then macrophages and then granulation tissue formation). This is called procallus (remember this is fibroblasts and blood vessels) (formation of granulation tissue at the site of the fracture) Osteoprogenitor cells give rise to osteoblasts which migrate to the site of the granulation tissue. They proliferate and produce osteoid. You get external callus bridges at the fracture site and outside of bone, internal callus bridges the fracture in he medullary cavity. You get ossification (need it to make the bone strong) This bone is formed quickly and thus it is woven bone. Therefore you need to replace it with lamellar bone. This is called remodeling. Factors that affect healing of bone fracture Type – e.g simple heals more quickly than comminuted and compound Alignment (if not aligned then impaired healing) Degree of immobilization – need it for callous formation (excessive movement stops this – this is why we use plaster of paris in fractures) Interposition of soft tissue Blood supply – because inflammatory phase involves tiny blood vessels. Steroids (because they are anti inflammatory – remember all healing is reduced with steroids) DM (due to lack of poor blood supply, poor function of macrophages and prone to infection) Nutrition – D for calcium deposition, C for function of fibroblasts. Infection Age – due to poor blood supply. Malignancy. Complications of fracture Delayed union Malunion Fibrous union (where you have fibrous tissue instead Non union (failure of 2 ends to meet) Aseptic necrosis (infarction of bone and bone marrow) Osteomyelitis (infection of bone and bone marrow) Treatment of fracture Immobilization (either internal fixation – plates/screws)

External – plaster of paris.

OSTEOMYELITIS This is inflammation of bone and marrow due to infection. Bacterial infection = most common cause. Mycobacteria (Tb), fungi, viruses and parasites Pathology Can spread from bloodstream to extra-osseus site Direct extension from neighbouring site Direct inoculation (e.g traumatic or surgical) Most common cause = staph aureus. E.coli, pseudomonas and klebsiella can occur in patients with GU infection and drug abusers. Patient with sicke cell disease are also prone to osteomyelitis – commonly due to salmonella. Strep B = most common in neonates. (Makes sense – just like it can cause neonatal meningitis) Many of the non haematogenous cases are caused by mixed flora and/or anaerobes. (Again, makes sense – spreading straight from outside world) The initial focus of inflammation (in children) is in the metaphysic (as this is the best vascularised part of the bone in children). Overall osteomyelitis is most common in children Most common (in adults) = vertebrae. When you have osteomyelitis you have necrosis of the bone (necrotic bony fragment is called sequestrum) Reactive bone formation The adjacent bone is trying to heal itself (termed involucrum) Clinical features Often a child (more common) Fever, malaise, bone pain and tenderness. Also reduced movement of limb. Dx Blood culture = best test Blood tests: increased WCC, ESR and C-reactive protein Radiography (can see lytic lesions but it takes time – changes are late) Either ultrasound or MRI = best dx Bone scan hot spot is useful and bone scintigraphy for difficult cases. Complications of ostemyletitis Abscess formation (called Brodie’s abscess) Continuous bone formation – (called Garres sclerosing osteomyelitis) Sinus tract formation – Can get chronic osteomyelitis Can get pathological fractures

Can get amyloidosis (in the chronic condition) Bacteraemia. Tx of osteomyelitis Antibiotics and then PO May also need to do surgical drainage. Tuberculous ostemoyelitis It is rare in developed country. Occurs by haematogenous seeding from extra osseous sites. Most common site is the spine (Potts disease) Get granulomatous inflammation of affected bone (just like any Tb infection) Very difficult to tx. BONE TUMOURS Classification: Benign Malignant (primary or secondary) Most common tumour in tumours/young adults are primary benign bone tumours Most common in older adults = multiple myeloma and mets from other sites Metastatic tumours Common ones are carcinoma of breast, prostate, renal or bronchogenic lung carcinoma. The can be either osteolytic (bone destruction – either due to direct bone erosion or due to stimulation of osteoclasts by cytokines or osteosclerotic (e.g prostatic adenocarcinoma – can cause bone formation) Complications Pain Pathological fracture Replacement of bone marrow (can get anaemia, infection, bleeding etc) Hypercalcaemia (I imagine due to resorption of bone???) Nerve and spinal compression Myeloma There is primary malignant proliferation of plasma cells in the marrow. (see other lecture) Primary bone tumours Primary benign tumours = more common in children and young adults. Primary malignant tumours = more common in elderly. Accurate dx depends on clinical, radiologic and pathologic examination of lesion. Classification Can be bone-producing or cartilage producing (As well as others) Bone forming tumours Can be benign, malignant or locally aggressive (in between) Benign – can be osteoma or osteoid osteoma Locally aggressive (can be osteoblastoma) Malignant (ostesarcoma) Osteoma This is a benign bone forming tumour. Usually seen in craniofacial location. Probably a harmatoma (some people believe) Multiple association are associated with Gardners syndrome (type of FAP) Osteoid osteoma

This is a benign bone forming tumour. Seen in young. (More prevelant in men) Painful (due to production of prostaglandin). Characteristically relieved by aspirin. Commonest in femur or tibia. Charectirsed by a nidus (small focus of blood vessel proliferation). In this site the cells produce prostaglandin (hence can be inhibited by aspirin, causing the pain to be relieved) Therapy = complete excision of nidus. Osteoblastoma This is a benign bone forming tumour. Seen in younger age. Most commonly seen in vertebral column No sclerotic reaction Pain is NOT relieved by aspirin Therapy – curettage/resection. Malignant tumours Ostesarcoma This is a malignant bone forming tumour. Has bimodal age distribution. Seen in young and elderly (i.e 2 peaks) Effects the end of the bones. Most arising from the metaphysic. This is because it is the most metabolically active part of the bone Pathogenesis of osteosarcoma Cabe sporadic or genetic (Rb, p16 and p3 have been implicated) Secondary osteosarcoma can be associated with radiation and pagets disease Clinical features of osteosarcoma Tenderness and/or pain in affected region. Fracture (since the bone is weakened – you can get a pathologic fracture) Distant mets – commonest is lung. Spread Can spread within medullary cavity Through the periosteum Can spread across epiphyseal plate (into the joints) Haematogenous. Osteosarcoma There are characteristic X-ray features in osteosarcoma. Codmans triangle and sunray speculation. Makes sense because this is a bone forming tumour – and thus the osteoid can be deposited perpendicular to the bone (Hence called sunray speculation). You get the codmans triangle due to lifting of the periosteum.

Treatment Patients usually treated pre-operatively by chemotherapy and surgical resection. Prognosis = poor – due to early metastasis (60% 5 year survival rate) CARTILAGE PRODUCING TUMOURS Osteochondroma These are bony lesions with a cartilage cap.

Seen in young patients - 40) This is a malignant tumour of cartilage This is the second most common primary malignant tumour of bone (half after osteosarcoma) Often associated with tiny calicifications Can occur de novo or from a previous benign tumour Axiel skeleton (bones of pelvis, shoulder, ribs and spine) are most common..

This is an aggressive tumour which can metastasize anywhere (lungs, kidney, liver and brain are most common) They are NOT sensitive to chemotherapy (only tx is resection). (Unlike osteosarcoma which can be sensitive to chemotherapy) Comparing osteosarcoma with chondrosarcoma: Osteosarcoma = 10-25 years and elderly (Chondrosarcoma = >40) Osteosarcoma = Affects long bones (chondrosarcoma = affects axial skeleton) Osteosarcoma = Sensitive to chemotherapy (chondrosarcoma = NOT sensitive to chemotherapy). Giant cell tumours (osteoclastoma)

Occurs in adults (20-55). Affects the epiphyseal ends (rather than metaphysic) of long bones. There are stromal cells and multinucleated osteoclast like giant cells It is a locally aggressive tumour (with high recurrence), may also metastasise. May also cause haemorrhage which makes sense – since these are osteoclasts and are breaking down thte bone. (4% metastasise). (I.e this is a benign tumour but it may metastasise infrequently). Not easy to know whether it will metastasise or not based on histological indicators. Ewings sarcoma These are neuroectodermal Seen in children and young adults. Site is medullary cavity (rather than metaphysic or epiphysis) in the diaphysis of long bones, pelvis and ribs. There is a translocation involving chromosome 11 and 22. It is characterized by the proliferation of small blue cells (called this as there is very little cytoplasm and large nuclei). Note these are known as small round cells of childhood, i.e this is another neuroblastoma – e.g nephroblastoma, retinoblastoma, medulloblastoma – all characterized by these small blue cells.)

Characteristic Xray is onion skinning. It is highly aggressive and chemotherapy resistant. With the advent of chemotherapy and surgery then survival has increased, but overall poor prognosis. Joints Joints can be synovial or non synovial. They are a type of connective tissue. Synovial - = movable joints e.g knee joints.

Non synovial joints – allow very limited movement but structural movement (Cartilagenous – e.g intervertebral disks) and fibrous (e.g cranial sutures) Structure of synovial joints

The articular surface is covered by haline cartilage – and the healing is poor. The cartilage acts as a shock absorber between the bones There are cells called chondrocytes which produce the matrix. They also produce enzymes which degrade the matrix. The matrix is made up of collagen type II (compare this to the collagen type one that is found in bone matrix), proteoglycans and water. The joint is surrounded by a capsule – which is rich in nerves (hence this is pain sensitive). The synovial joints are supported by ligaments and bursa (which is a fibrous sac that acts as a cushion to ease movement in areas that are subject to friction). The whole synovial cavity there is a synovial membrane The synovium lacks a basement membrane (therefore there is a quick exchange between blood and synovium). It contains 2 cell types. Type A synovial cells are macrophage-like and type B synovial cells are fibroblast like (and produce protein) The function of the synovial fluid is for lubrication and nourishment for the cartilage. Synovial fluid It is normally colourless and transparent WBC = males It is a oligoarthritis (i.e single joint is usually affected – unlike the polyarthritis in regular RA) Affects the large joints – especially the knees (unlike the small joints in RA)

Lymphadenopathy and splenomegaly RF is usually negative but ANA is usually positive. RHEUMATIC FEVER Remember it is an acute or recurrent inflammatory disease which is usually secondary to group A strep. Joint disease – classically a migratory arthritis (Affects one joint, then moves to another etc) Usually affects large joints (knees, elbows etc) and pain There is usually no deformity SLE This is a systemic autoimmune disease There is usually minimal joint deformity. It results in a non erosive synovitis SERO-NEGATIVE SPONDYLOARTHRITIS A group of diseases with negative RF There is involvement of the sacroiliac joint and spine (sarcoilitis and spondylitis) Usually affects patients with HLA-B27 Ankylosing spondylitis, reactive arthritis (such as reiters syndrome and enteropathic arthritis) and psoriatc arthritis Ankylosing spondylitis (bamboo spine) This is a chronic inflammatory disorder of lumbar spinal and sacroiliac joints. There is fixation and fibrosis of the spine – (which is why it is called bamboo spine) Often affects young males. Most have HLA B27. They have autoantibodies directed at joint elements after infection. Peripheral arthritis, uveitis, aortic incompetence and amyloidosis can occur.

Reiters disease/reactive arthritis It is an autoimmune reaction following especially Chlamydia infection Useful pneumonic = patient cant see, cant pee and cant bend the knee. Can also be due to salmonella, shigella, yersinia and campylobacter Defined by triad of arthritis (affecting knees, ankles and spine), urethritis or cervicitis and conjunctivitis Enteropathic arthritis This occurs with chronic inflammatory bowel diseases (UC/Crohns) (remember the non GI problems that these patients can get) It can also occur following a bowel infection – e.g after salmonella, shigella, yersinia and campylobacter Psoriatic arthritis Affects 5% of patients with psoriasis.

Arthritis which affects the distal interphalangeal joints, ankles, knees and spine Again HLA-B27 is implicated INFECTIVE ARTHRITIS Haematogenous spread = most common Spread from adjacent infective foci – (e.g osteomyelitis) Direct inoculation – local trauma and insertion of surgical prosthesis Suppurative arthritis Staph aureus (most common in both young and old) Haemophilus influenza = in young children Gonoccocus (in healthy young sexually active individuals) Strep, E.coli, pseudomonas and salmonella can all be causes as well. Clinical features Acutely painful Sweollen joints Fever Decreased range of motion Increased WCC Joint aspiration Not really recommended as you can spread the infection. Yellow/green and purulent WBC > 50,000 Polymorphs = >75% (makes sense – as mostly bacterial) Gluocse < blood (makes sense – the bacteria are using up the glucose) Gram stain + culture = often positive TUBERCULOUS ARTHRITIS Spread from adjacent tuberculous osteomyelitis or haematogenous spread Spine = most commonly affected (Potts disease) followed by the hip. It can cross cartilage barriers (unlike other bacterial infections) There is a destructive arthritis and deformity There is granulomatous inflammation LYME DISEASE Transmitted by tic. Borrelia brgdoferi = pathogen. It can also cause arthritis. Remember skin manifestation – erythema migrans (seen at site of tic bite) Second stage = CNS and heart involvement Late stage = when you get destructive arthritis. GOUT ARTHRITIS (Note used to be called a disease of kings, because meat and wine cause it, which is more expensive) Males > females Peak incidence = in 5th decades ¼ arfamilial It is a disorder of purine metabolism which results in hyperucricaemia. Serum urate level is above 7mg/dl Hyperucricaemia can be primary or secondary Primary Can be due to undersecretion of uric acid (90%) Overproduction of uric acid Risk factors Age (rare before 30) Family history Alcohol consumption

Obesity Meat etc Secondary gout Secondary – affects 10% of cases. Due to overproduction of uric acid usually associated with excessive breakdown of nucleic acids (e.g due to leukaemia, multiple myeloma and massive cell lysis that results from cytotoxic drug therapy). Renal undersecrteion (e.g renal failure, diuretics (Both thiazide and loop. Remember loop = hyperurcaemia, hypocalcaemia, hypokalaemia while thiazide = hypercalcaemia, hypocalaemia and hyperuricaemia. Potassium appearing = hyperkalaemia) Can also be due to an enzyme deficiency – (Hypoxanthine guanine phosphorybosyl transferase (HGPRT) – this is important in uric acid metabolism. Pathogenisis of gout You have deposition of urate crystals on the surface of the articular cartilage This results in interaction with leucocytes which result in degenerative changes. Classical joint affected = big toe. (Metacarpophalangeal joint of big toe). ¾ affecrting the ig toe with first attack. (Note that apparently external joints are more readily affeceted because these joints are more typically colder and therefore the uric acid is more readily able to precipitate). Sometimes there can be deposition of uric acid in tissue which results in tophus formation (gouty tophi) – commonly in ear lobe. (Remember, differential is calcinosis and I imagine also rheumatoid nodules?) They occur in chronic hyperuricaemia and is due to the deoposition of uric acid in tissue. Stages of gout You have an acute inflammatory arthritis and asymptomatic periods in between the attacks. Eventually it becomes a chronic inflammatory conditions You have chronic deposition of urate in and around the joints (Known as tophi) Complications of gout Interstitial nephritis Renal calculi (made of uric acid) Renal failure Diagnosis Need to examine aspirated synovial fluid. It will show needle shaped crystals and neutrophils.

Can do synovial biopsy. Note that don’t put tissue in formalin container (as the crystals will dissolve in this, thus have to put it in alcohol). Treatment Colchicine (remember, this is a drug that binds to tubulin and causes damage to mitotic cells. Hence also used for cancer – and side effects = anaemia and neutropenia for this reason, it is killing rapidly dividing cells. However, it also inhibits uric acid deposition and

for this reason it is used in gout). It is also an anti inflammatory effect – due to slowing down the immune response – I imagine this is again due to the white cells are rapidly dividing) Allopurinol (this inhibits uric acid synthesis) (It is a purine analogue that binds to the enyme. It is not useful for acute gout but is more useful for chronic treatment = to lower the uric acid levels in the plasma. It is commonly used in prophylaxis for patients who are receiving chemotherapy. Makes sense, as the chemotherapy is likely to increase the uric acid levels). PSEUDOGOUT Also known as chondrocalcinosis This is the deposition of calcium pyrophosphate on arcticular cartilage. (I.e different crystal deposition) Most commonly seen in over 50’s Classification They are classified into primary (idiopathic), hereditary and secondary (due to hyperparathyroidism, hypothyroidism, haemochromatosis and DM) Pathology Asymptomatic until the crystals are shed into the joint space (spontaneous or due to trauma) Unlike the crystals in gout, the crystals here are rhomboid in shape.

Hypertrophic osteoarthropathy This is new bone formation at the distal ends of the long bones, especially the metacarpal and metatarsal bones. It is a syndrome of painful, swollen joints, cubbing of the digits and the above. (I believe it is clubbing with these other things associated) Rarely it appears as an idiopathic disorder but the main significance is that there is usually underlying disease – (usually bronchogenic carcinoma).

TUMOURS OF THE SOFT TISSUE Extremely rare. They are tumours of mesenchymal origin. (mesenchyme is the conncentive tissue of fetal and developing organs which will develop into the stroma) and are classified based on their histological differentiation. They can be benign or malignant Pathogenesis Poorly understood but risk factors Radiation, viruses (e.g kaposis sarcoma) and genetic syndromes (e.g li fraumeni) Classification of soft tissue (benign and malignant) Tuours of adipose tissue = lipoma and liposarcoma Tumours of smooth uscle = leiomyoma and leiomyosarcoma Tumours of skeletal muscle = rhabdomyoma and rhabdomyosarcoma Fibrohistiocytic tumours = fibrous histiocytoma and malignant fibrous tumours Vascular tumours = haemangioma and angiosarcoma Peripheral nerve tumours = neurofibroma and malignant peripheral nerve sheath tumours

Tumours of uncertain histiogenesis e.g synovial sarcoma (not does not originate from synovium – uncertain origin) More information about the soft tissue sarcomas Note – this is not that important, main thing is to know the prognosis. Malignant fibrous histiocytoma This is the most common malignant soft tissue tumour of adults. Usually occurs in deep soft tissues of an extremity. More common in adults over 50 Liposarcomas Second most common. Characterized by presence of lipoblasts Rhabdomyosarcoma Tumours with skeletal muscle differentiation Most common sarcomas of childhood/young Charactersed by rhabdomyoblasts Synovial sarcoma Typically affects young adults. Occur in proximity to joints but do not arise from the synovium. Pathogenesis of soft tissue sarcomas Need to know this Histologic type Tumour grade: (as any type) Degree of differentiation, cellularity, pleoorphism, number of mitoses, presence of necrosis Stage of tumour Location (the more superficial have a better prognosis) Dx Histologic examination Immunohistochemistry. Nearly all vimentin positive (remember from last year, vimentin in all sarcomas) Leiomyosarcoma (desmin and actin positive) Rhabdomyosarcoma (myoglobin positive) Molecular dx – some have specific genetic abnormality (e.g Ewings sarcoma – t(11;22) and synovial sarcoma = t(X;18). I.e specific. There are others as well. GISTS Remember these originate from the interstitial cells of cajal. Remember that most have mutations in c-kit (a protooncogene) and gleevec is a selective c-kit receptor inhibitor. Remember this is also used for CML (chronic myeloid leukaemia) Skin diseases There is a wide range of conditions – from inflammatory to neoplastic. It is a common reason for consultation to GP’s Skin neoplsms rarely poste threat to patients life. The exception is a melanoma. Pigmented skin lesions are common but they are not necessarily melanoma (e.g some squamous cell carcinoma can have melanocytes in it but it is not a melanoma). They may sometimes be clinically distinguished, but it may be difficult. Some benign lesions that form a tumour are not true lesions (e.g malformations, harmatomas, infection (i.e warts) or cysts. Structure of skin The layers from superficial to [email protected]

Stratified squamous epithelium. This is specialized for keratin production and is exposed to UV light. It also contains melanocytes and Langerhans cells (which are specialized antigen presenting cells). Dermis Subcutaneous fat.

Stratified squamous epithelium There is a layered, orderly maturation from the base to the surface. There is a basal layer of small dark round cells. The superficial layers flatten and acquire more abundant cytoplasm and produce keratin Dysplasia = showing disorderly maturation and abnormal cytological features. UV light (especially UV-B) causes DNA damage. Melanocytes These are neural crest in origin. They migrate at 6 weeks in utero to the skin. They produce melanin pigment and the melanin is transferred to adjacent squamous cells. The melanin protects the nucleus of squamous cells against UV damage to the DNA. (Hence this is the reason why in human evolution those that lived closer to the equator/hot countries developed darker skin (in order to protect themselves from skin cancer etc) Dermis This is a loose connective tissue which supports the epidermis. It contains: Fibrous and adipose connective tissue, blood and lymphatic vessels, nerves, smooth muscle (to control blood vessels, arrector pili – the smooth muscle that makes your hair stand on end – etc). Additionally there are inflammatory cells (lymphocytes, macrophages, mast cells etc) Skin appendages (e.g sweat glands, sebaceous glands, arrector pili etc) Can get tumours of any of these – they are generally benign. E.g can get haemangiomas, lyomyomas, neurofibromas, scwannomas, dermatomycomas, skin appendage tumours etc Skin appendages Pilo-sebaceous units e.g hair follicles and attached sebaceous glands. There are also sweat glands If the epidermis and superficial dermis is damaged/removed then the epidermis will regenerate from surviving skin appendage epithelium (Hence you can do a split skin graft and there can be regeneration. Additionally if you burn off the epidermis then it will regenerate, while if you burn off deeper layers then there is no regeneration) Skin tumours These may be benign or malignant

May arise from epidermis (i.e squamous cell carcinoma), melanocytes (i.e malignant melanoma), appendages or the dermis (from any of its constituent elements e.g haemangioma, schwannoma etc) The treatment of benign lesions is usually cosmetic (or to exclude malignancy). Malignant tumours of the skin may be locally aggressive (i.e grow and destroy the area they are in). However only very rarely will they have the potential to metastasise. The exception to this, however is a melanoma. Also note that malignant skin tumours are usually primary and you ill only develop secondaries very late when there is a disseminated primary malignancy. Primary skin malignancy Squamous epithelium = much more common. They are basal cell carcinoma or squamous cell carcinoma. Collectively they are known as non-melanoma skin cancer. Melanocytes = much less common origin for malignancy. However if it is not identified early enough it poses significant risk for metastasis. Also other types of primary skin malignancy (from dermal elements – e.g lymphoma, appendages etc. These are rare though). NMSC may be locally invasive however they rarely cause metastasis or death. Melanoma however is more aggressive and the outcome depends on stage at dx. Skin malignancy = related to UV-B light exposure: Light skin, fair, red hair, pale eyes, tendency to freckling are prone to developing freckling. Outdoor work especially in areas in the equator SCC is related to cumulative exposure (you usually also see some other UV related skin damage) Most melanoma however is NOT related to cumulative exposure but instead to intense, intermittent exposures BCC appears to be intermediate UV-A is also important (which is used in sunbeds and to tx psoriasis patients). Epidemiology of skin cancer NMSK = commonest cancer but rarely causes death (I think). Melanoma on the other hand (although is much rarer) causes far more deaths (than NMSC) Epidemiology of NMSC Incidence is strongle linked to age. (most occurring >65 years old) Often multiple and usually in sun-exposed sites. I.e face, legs, ears, nose, scalp (in bald men) etc Small numbers will be on difficult areas to excise e.g eyelid, BCC is exceptionally rare cause of metastasis. SCC are uncommon cause of mets/death (however much more common than BCC). Mainstay of treatment is local excision. Basal cell carcinoma

It is derived from squamous epidermis

What characterizes it histologically are basal cells thataare palisading (i.e at the edge of the groups of tumour cells, the cells and nucli are arranged in parallel) Metastasis = incredibly rare There can e local invasion with lisk of local destruction. (especially near the nose and eye – termed a rodent ulcer) Different histological types are less or more prone to recurrence – and this guides treatment) Risk factors UV light (UV-B), radiation, immune suppression. Age and faire skin Treatment Surgical excision. Mohs micrographic surgery if high risk (this is where you take slices (you remove as much as you can see, then you takiceand look at them under the microscope, if you see tumour then you take another slice, wheras if you don’t then you stop).. Useful for tricky arlocal destruction eas, or recurrent tumours etc. Local destruction (cryotherapy, electrosurgery, radiotherapy etc) Topical treatment – with 5-fluorouracil (an antimetabolite) or imiquimod. (This is an immune modulating drug which is felt to help by altering immune targeting of the tumour) High risk cases require specialist treatment (e.g if difficult to define, recurrent, post radiation or large. As well as critical sites (mid face including eyes, nose etc) Invasive squamous cell carcinoma

Derived from squamous epithelium of epidermis Shows differentiation towards keratin production. Metastasis can occur (but rare and late) Overall good prognosis If does metastasise then will go to regional lymph nodes. Poorer prognosis – if lip, deep tumours and arising in non-sun damaged skin (e.g genital area) Also poorer if arising from chronic ulcers or skin disease Tx = excision. (Tend not to do the cryotherapy, electrotherapy etc that you get with basal cell. Probably because more risk of spread/invasion?) Histological hallmark = keratinisation

Risk factors By far, sun exposure = most important risk factor. Historic (chimneysweapers being at risk for scrotal SCC – due to hydrocarbons) Radiation treatment (over irradiated areas) Edge of old scars, burns, sinuses, chronic ulcers etc (Makes sense – as rapid turnover etc there) Genetic – e.g xeroderma pigmentosum (being unable to repair UV induced DNA damage – hence lots of skin cancer) and people with albianism (makes sense, as lack of protectivemelanin) Immunosupression – post transplant, HIV – related to specific HPV types (not the common HPV that causes warts (I imagine that this is because not immunosupressed individuals will not get infected by these HPV virii) Common HPV infection = NOT risk factor. Dysplastic epidermal lesions

These show varying degrees of dyplasia but do not show invasion. They can develop into invasive SCC (but unlikely and long time) Tend to present as irregular crusted, keratotic lesions (or red patches) Actinic (solar) keratosis This is epithelium that shows dysplasia (ranging from mild to severe) but short of in situe SCC. Bowens disease

This is the term for in situ squamous cell carcinoma (i.e full thickness dysplasia/ keratosis) This seems to be a rather flat lesion – which makes sense since it is a carcinoma in situ.

Pigmented skin lesions Melanoma = typically pigmented. However not all melanomas are pigmented and not all pigmented skin are melanomas. (e.g BCC, keratosis etc). Vascular lesions are usually blue/red rather than brown Thus can be difficult to diagnose. Thus important to send all lumps and bumps to pathology. Benign melanocytic lesions Freckle - ephelisFreckle – ephelis This is a localised area of increased melanin production. It is induced by the sun but there are no increase in melanocytes Benign lentigo This is a flat lesion with increased numbers of melanocytes in the basal layer of the epidermis. They are fixed but may sometimes be promoted by long term sun exposure

Melanocytic naevus (pigmented mole). This is a clonal proliferation of melanocytes as nests Naevus Naevus = benign proliferation of skin element (commonly refers to melanocytes – i.e mole) Implies a pigmented lesion which is present at birth Commonest example is melanocytic naevus (which may be congenital or aquired). Normally you stop producing naevi after 20 (if new naevi are formed after then you should be converned).. The lesions evolve with time – the location of the nests, amount of pigmentation and degree of nodularity typically change with time. They can be junctional (confined to basal layer), compound (basal layer and epidermis,. May be slightly raised) or intradermal (they are only in the epidermis, usually form raised areas) MALIGNANT MELANOMA

Can be aggressive and life threatening Doesn’t cause high amount of deaths, but potentially easily recognised. Also even though it is more common in elderly, it does not infrequently affect the young. Usually associated with intense sun exposure not cumulative. Can arise in sites outside the skin. E.g eye (most common malignant tumour affecting the eye), meninges, mucosa etc. Does NOT always produce pigment (i.e can be amelontic). There has been a rise in incidence (with travel of fair skinned people to hot countries) as well as increased detection. It is an important dx (even if early – for insurance problems etc) Development Goes through stages. Goes through in situ (confined to epidermis) – which is always cured. (i.e in these they grow upwards into the epidermis) Some of the in situ tumours will invade into the dermis (and then into the subcutaneous fat). From there they can spread through the lymphatics to other sites (e.g skin, local lymph nodes) and by blood stream to liver, brain etc. Can also spread within skin and form satellite tumour nodules (which is why wide excision of invasive melanoma is therefore performed) Note that these tumours can be problematic, can be bizarre (e.g can excise melanoma, live 10 years and then present with a met)

Prognostic factors Stage Most important If there are mets (lymph nodes or distant). Distant mets = very bad prognosis, lymph mets then poor prognosis If the melanoma hasn’t metastasised then thickness Breslow thickness If no mets (i.e only primary lesion) then the thickness of invasion becomes important. Best single thing for prognosis. 2mm thick (about half way through the dermis) then drops to 50% 5 year survival.

Clarkes level of invasion This was related to the level of invasion (was used, but in reality corresponds to thickness. Other prognostic features Ulceration = bad, mitosis. Presence of tumour infiltrating lymphocytes then this is good. Histological classification Not that important because doesn’t have independent outcome in Superficial spreading (where an in situ component can be identified), nodular (invasive at the outset), acral (palms, soles and nails, rare but commonest form in black people – as they don’t get them elsewhere (I imagine because these areas are relatively unprotected, with paler skin), lentigo maligna melanoma (invasive melanoma developing in sun exposed skin on background of lentigo maligna) Also note lentigo maligna (hutchinson melanotic freckle) – this is a big flat pigmented lesion (related to chronic sun exposed skin – especially in face of elderly). Evolves towards in situ malignant melanoma (but low frequency will become this)

Treatment of melanoma Primary excision of any suspicious lesion. (However don’t do incisional biopsies or shave/hit etc it, as it can alter the morphology) If it is melanoma then do re-excision to get clear margin. (As there is risk of satellites). The margin of clearance relates to tumour invasion. If more than 1mm in thickness then do sentinel lymph node biopsy (assessing for subclinical lymph node metastasis). Remember that purpose is to target the single lymph node that if one were to be involved you can targe it, rather than take out all the nodes and get lymphoedema.) – you inject blue die and radiolabel and see which nodes light up (nodes where tumour would have first spread – then remove them and check for metastatic deposits. (If doesn’t have met then unlikely that other nodes have met) Note that not therapeutic (possibly marginal). Mainly done for prognosis 1/3 of melanomas arise from preexiting melanocytic naevi however most don’t. Also note that any single naevi (even if they are strange, big etc) it is unlikely to become a melanoma. Also very rare families with high risk melanoma have unusual clinical features. E.g atypical multiple moles and melanoma syndrome (have dysplastic naevi). Risk factors: fair skin, tendancy to freckle and burn, blue eyes and red/blonde hair. Congenital naevi: risk depends on size (only significant if very large) Multiple dysplastic naevi (increased risk) No excess risk in typical sporadic naevi or small congenital naevi. Early detection Clinical suspicion A,B,C,D,E A = asymmetry B = border irregularity C= colour variation

D = diameter >0.5cm E = expanding However most moles = harmless. Sequential photography may help. Other worrying singns = changing moles, new moles (beyond young adulthood), irregular outline, bleeding, ulceration and development of satellite lesions. Calcium metabolism Normal calcium homeostasis Remember that the bones that support us are not static. There is a constant turnover. We absorb calcium from the diet, it is present in the ECF, soft tissue and bone etc. We are constantly laying down calcium in the bone – as hydroxyapetite (as calcium phosphate) and we are absorbing the calcium from bone

Also, it is removed by the kdieny. Bone is the resevoir of calcium (hence the reason why when you have disorders of calcium then it will affect bone). Calcium is bound in plasma. Half is free (1.1mmol) – this is the biologically active form About half is bound mostly to albumin (about 1 mmol). With total being about 2.4 (other bound in other proteins as well as bicarbonate and phosphate). This is another resevoir of calcium. Thus when albumin falls then the total calcium falls. (Most simple/cheap method of calcium measurement measures the total calcium). (However point of care testing – e.g in ICU, the blood gas analyser (in all the electrolytes – compared to lab result), then it measures free calcium – which is about half the total calcium). Note that no pathological conditions that give high albumin. Note that there are various formulas that you can use to correct the ionised calcium for when albumin falls. Also note that free calcium can be displaced from albumin by hydrogen ions. Thus in acidosis you will have higher calcium in the ionised fraction. In renal disease you get total fall in calcium. This is due to a combination of lack of vit D activation and phosphate increase (which causes fall in calcium) However note that renal disease can also cause metabolic alkalosis (which causes an increase in the proportion of free ionised calcium (I.e kind of like a correction, although not really as it is a disease process). Thus if a patient with renal failure develops tetany, confusion etc then don’t be immediately tempted to give calcium (as this may be due to the uraemia rather than the calcium as the free calcium may not as low as you may think it is – if patient wasn’t acidotic). Factors affecting plasma calcium concentration That is, the total concentration. Plasma albumin concentration (see above Dietry calcium intake/urinary loss

Hormones + vitamins Parathyroid hormone Vitamin D (active – dihydroxy vitamin D) – depends on dietary intake and intestinal absorption Calcitonin. (Doesn’t have a big role in physiological regulation, but can be used exogenously to lower calcium) End organ function – e.g celiac disease (causing impaired absorption), renal disease (impair hydroxyilation of vit D), liver (the same, hydroxylation),parathyroid glands (e.g adenoma etc) Action of parathyroid hormone It is a protein that stimulates osteoclasts in bone. This results in bone resorption (which releases calcium AND phosphate from bone). In kidney – it activates 1 alpha hydroxylase – which results in hydroxylation of 25 hydroxy vit D to 1,25 hydroxy vit D. (Note that 25 hydroxy vit D is a kind of “storage form” of vitamin D – as there are much higher concentrations of it) It also enhance the reabsorption of calcium from the renal tubules, but it also inhibits phosphate reabsorption. This is significant because plasma calcium and phosphate are at a concentration close to saturation point. (Thus if you alter the concentration of one then it will precipitate – calcium and phosphate). Thus if you increase calcium AND phosphate in plasma then you will get calcium phosphate precipitation (especially in kidneys – resulting in nephrocalcinosis). Thus by increasing calcium but decrease phosphate then this does not happen. Thus overall effect is increase calcium conc and decrease in phosphate conc. Vit D structure and synthesis Remember you have vit D3 (generated through sunlight) Vit D2 – This comes from ergosterol (a plant source) (Vit D2 or D3 ) is then metabolized in the liver to 25-hydroxycholecalciferol (by 25hydroxylase) In the kidney it is metabolized to 1,25 dihydroxycholecalciferol (1,25 hydroxy vitamin D) – which is the active form. The half life of the 25 hydroxy form = several weeks while the 1,25 dihydroxy is only a few hours. Note that have to have very extensive liver disease before you will have fall in 25 hydroxy vit D. (Thus most patients with liver disease do not have fall in vit D). Note that there are other forms of vit D that are not biologically active. Note that anticonvulsants – e.g phenytoin will enhance the hydroxylation of 25 hydroxy vit D to number of non active forms. (Hence metabolic bone disease/osteomalacia can result. Control of calcium concentration

Parathyroid glands release parathyroid hormone in response to lowered calcium level. This acts on bone to increase bone resorption (increase in calcium in phosphate). Thus by negative feedback it reduces parathyroid hormone level. Also acts on kidneys to increase conc of 1,25 vit D, increased calcium in tubules. The active Vit D will also increase calcium absorption. Disorders of bone Pyerparathyroidism Primary, secondary or tertiary. This increases Decreased bone mineralization Osteomalacia (in adults) and rickets (in children) E.g vit D deficiency and malabsorption. This is associated with low plasma calcium levels. Reduced bone matrix (type 1 collagen and proteoglycan remember) Osteoporosis Postmenopausal and senile osteoporosis. (also due to slight reduction in 1,25 vit D due to reduction in renal function) This does not cause a disturbance in plasma calcium levels. Disordered bone mineralization I.e Pagets disease of bone. Disorder of osteoclast and osteoblast function (these 2 cell types no longer work in tandem, hence disorgonisation of bone mineralization). BIOCHEMICAL INVESTIGATIONS TO DX METABOLIC BONE DISORDERS Plasma Calcium – should be measured with albumin. (So can interpret total albumin/free albumin levels etc.). Note how sample taken is important. (Ideally should take off tourniquet for 20 seconds before taking the sample (so that you don’t concentrate the vascular compartment – due to increased pressure causing movement of water out of vascular compartment) Phosphate (increases in patients with renal glomerular damage) – hence need to know what renal function is (either creatinine or urea). Alkaline phosphatase (bone isoenzmye) – marker of osteoblastic activity (remember that this is also in the liver and other places) PTH 25-OH vit D (don’t measure active vitamin D routinely due to the low levels of the active form, so more expensive) Urine Calcium and phosphate Pyridinoline and deoxypridinoline (markers of osteoclastic activity) – thus along with alk phos can have knowledge of osteoblastic and osteoclastic activity. How to investigate the disorders If plasma calcium is high – then look at plasma phosphate. If have normal then would suspect hyperthyroidism or hypervitaminosis (not sure why hyperthyroidism would cause this, but TFT’s would naturally be used to dx hyperthyroidism) If it was low then you would suspect hyperparathyroidism (makes sense – high calcium but low phosphate – which is what parathyroid hormone does). You would do an X-ray to look for

cystic lesions (subperiosteal erosions in terminal phalynx – early sign, eventually can go on to get osteitis fibrosa cystica). Also naturally do PTH hormones. Can also be malignancy since some tumours can produce parathyroid like hormone. (Thus in this case the parathyroid hormone will be undetectable) If low calcium and low phosphate then differentials could be secondary hyperparathyroidism due to vitamin D deficiency (i.e low calcium that is then causing too much parathyroid hormone which decreases phosphate levels). Hence makes sense to measure the vitamin D levels. low calcium but normal/high phosphate suggests hypoparathyroidism (makes sense – not enough calcium reabsorpion and too much phosphate reabsorption) It can also due to renal failure (causing a secondary hyperparathyroidism) – in this case the calcium would be down, however the phosphate would be up due to decreased reabsorption.

Clinical presentations of hypercalcaemia General Non specific ill health (malaise, weakness, vomiting). Most patients picked up through routine screening now. Psychiatric disturbances (“groans” Renal Polyuria and thus polydypsia (along with hypokalaemia, as inhibit concentration mechanisms) Renal stones and nephrocalcinosis (“stones”) – makes ses Bones Bone pain (“bones”) Abdominal (“abdominal moans”) Constipation (increases gastrin release) Duodenal ulceration Cardiac Dysarrhythmias – (Prolongation of latent phase I think?) Differential dx of hypercalcaemia Hypercalcaemia associated with low plasma phosphate Primary hyperparathyroidism (e.g adenoma), causing bone resorption and calcium goes up, and phosphate goes down Malignancy (ectopic hormone production – PTHrP) Tertiary hyperparathyroidism (after treatment of secondary hyperparathyroidism – because the hyperparathyroid glands have become autonomous – they may not be suppressed when the calcium returns back to normal) Normal plasma phosphate Hypervitaminosis D and thiazide diuretics (makes sense, they cause calcium reabsorption) Rarely – thyrotoxicosis, sarcoidosis, immobiliation with pagets disease of bone etc. Sarcoidosis and other macrophage disfunction disease are associated with increased activated vit D Primary hyperparathyroidism note Note suppression of other hyperparathyroid glands due to the single adenoma.

Note the symptoms and hypertension are due to the hyperparathyroidism. Note that the calcium is not that high (because it isn’t in primary hyperparathyroidism – in malignancy it is usually much higher). Note that the albmin is a bit high (probably due to incorrect sampling technique) (and hence the calcium is actually a little lower) Note how the phosphate is at the lower end of the reference range (you would expect a higher phosphate for that calcium, hence you can dx hyperparathyroidism based on these results alone.) Also the alk phos is high end of reference range (because early in the dx). Note the parathyroid hormone is only slightly elevated. Note how even if PTH was e.g 10 and calcium was high you would still dx hyperparathyroidism. (I.e need to compare the results with each other) Note that post op the patient became hypoparathyroid. Note that the alk phos has probably rised because of immobilisation for a week. The reason he got hypoparathyroidism is because the other 3 parathyroid glands remain suppressed (after being suppressed by the adenoma). Thus need to maintain low normal calcium levels in order to reactivate the parathyroid glands. I.e DON’T be tempted to give calcium (unless very low) So patient became hypoparathyroid but then was going back to normal.

Note how levels of calcium is very high and even lower phosphate (than previous example). Also note that when you get hypercalcaemia then you get polyuria and thus water depletion. (Thus note how the sodium and urea are elevated in conc) Also note that hypercalcaemia is frequently related to hypokalaemia (hence would think about correcting the low potassium). Also note the metabolic alkalosis (I believe this is secondary to the low potassium – possibly due to potassium leaving cells and H+ entering?) This is all due to ectopic hormone production (PTHrelated peptide) by breast carcinoma recurrence. Compare the 2 cases – note how in malignancy you get much higher calcium. Clinical features of hypocalcaemia Numbness and tingling of fingers and toes Muscle cramps/spasms Positive Trousseau’s sign (increase of 20 mm Hg over systolic pressure causing a claw like appearance the hand) and Chvosteks sign (when tapping the facial nerve you get contractions in the face) Laryngeal spasm and stridor Convulsions (mostly in newborn and infancy) Proximal myopathy (causing waddling gait – especially in children) Bone pain Psychiatric disturbances Cataracts Differential dx of hypocalcaemia Low plasma PTH concentration Idiopathic and acquired hypoparathyroidism High plasma PTH Secondary hyPERparathyroidism With low phosphate conc – due to Vit D deficiency (either nutritional, malabsorption – e.g coeliacs and anticonvulsant therapy – due to conversion into inactive forms) With high plasma phosphate – due to renal failure Note that these secondary causes – when treated can result in tertiary hyperparathyroidism (i.e going from low calcium to high calcium, but with the parathyroid hormone not changing) Pseudohypoparathyroidism – (see previous lecture) Miscellaneous conditions Renal tubular acidosis (not sure why) Acute pancreatitis – (main reason is due to low albumin – also because of dystrophic calcification?)

Note the high urea due to renal failure Sodium – Would expect it to be low in person with renal failure (hence this is normal for someone with renal failure) Metabolic acidosis and hyperkalaemia (what you would expect) Phosphate retention and calcium falls The alk phos rises due to secondary hyperparathyroidism. Classical findings in someone with renal disease.

Note low calcium and low phosphate. Urea is normal so not renal failure. Since the phosphate is low rather than high (which is what you would expect with primary hypoparathyroidism) this is a secondary hyperparathyroidism Since it is not due to renal failure, most likely cause is due to vit D deficiency. Additionally the raised alk phos gives a clue as to it being a hyperparathyroidism and that she has metabolic bone disease and osteomalacia. All this is worked out without having to measure the PTH and Vit D levels – which would take much longer.

Note the high calcium and low phosphate is suggestive of a primary hyperparathyroidism. However the urine shows that the phosphate is low. Thus this is due to a phosphate deficiency (which has caused the metabolic bone disease and increase in calciu,) Summary of investigation of ostemalacia

Osteoporosis – classification Primary Type 1 = postmenopausal Type 2 = senile Also idiopathic (which occurs in under 50s) Secondary Endocrine e.g cushings, hyperthyroidism and hyperparathyroidism (I understand cushings but not sure about the hyperthyroidism and especially the hyperparathyroidism, I would think this would cause osteitis fibrosa cystica) GI – malabsorption, liver disease (due to low calcium?) Malignancy – multiple myeloma (possibly because it causes invasion of the bone marrow) Drugs – steroids, anticonvulsants (again – due to vitamin D conversion to inactive forms) Bone turnover markers Note there are lots, but main ones for bone resorption are urine hydroxyproline and pyridinole while for bone formation then alkaline phosphotase (especially skeletal isoenzymes) General considerations in using biochemical markers

Urinary markers are usually corrected for creatinine. Also need to be corrected by circardian rhythm and are affected by age, oestrogen etc. Summary of bone function level tests Note how phosphate is increased in someone with primary/tertiary but is variable in someone with secondary (as it is down in someone with renal failure, but decreased in someone with rickets/osteomalacia) Remember that in osteoporosis. (I believe that can be lower end calcium? But overall no metabolic disturbance I think) Pagets disease – you have normal but is very increased alk phos because of rapid bone turnover. (If increases again then suggestive of a complication of pagets disease – namely sarcoma) Also note that immobilisation can be associated with hypercalcaemia. Non-organ specific autoimmune disease Revision of tolerance Remember that tolerance = failure of immune system to respond to an antigen. Remember that this is a leaky process and the failure in self tolerance results in autoimmunity Maintenance of tolerance Central T cell tolerance (thymic education) Peripheral T cell tolerance (active regulation and absence of secondary signal/danger signal) B cell tolerance Thymus Remember you have positive selection (T cells that can bind to own HLA type are selected out – so you don’t waste time making T cells that cannot protect you from infection). Negative selection = where T cell receptors that bind strongly to the T cell receptor undergo elimination by apoptosis. Tolerance is a leaky process (thus everyone has some self reactive T cells). However there are mechanisms in the periphery to switch off the autoreactive T cells. Thus you need several signals (rather than just contact of the HLA molecule withn the peptide. Thus you need costimulation (e.g CD40-CD40-L). Also what is important is the danger signal (inflammation or infection – much easier to activate the T cells) – note this is what adjuvants try to do in vaccines (to try and drive the immune process) Activation is manifest by proliferation and maturation. However if they only get signal 1 they can either be anergic (“switched off” – but can be reversed) or apoptosis. (remember “cure” for autoimmune disease would be to drive the cells to apoptosis – but I believe all they can do so far is to push them to anergy, which doesn’t help). B cell tolerance They are kept under control mostly because T cell help is absent. However ther are other mechanisms where B cells can be silenced (don’t think I need to know much about this) Remember the simple diagram below, Even if cytotoxic cells/B cells are activated but if Thelper cells are not activated then there will be limited damage.

Remember thate tolerance is leaky. Hence remember that there is a huge difference between autoimmune reactivity and autoimmune disease. In autoimmune disease you have tissue damage and organ dysfunction (while many people will have weakly active autoimmune reactivity and be free from disease) Mechanisms of autoimmunity Often we don’t know why it occurs. However some mechanisms we do understand. Released of sequestered antigen Antigens which the T cells are not used to seeing in the thymus are released (by other disease) and hence they are not tolerised and will react Important in eye and testis. Intraoccular antigens are generally not expressed in the periphery (generally not a problem because the cells don’t usually penetrate into the eye). However if you get penetrating trauma to one eye then you can get release of the antigens and autoimmunity reaction to both eyes. (Previously, if had trauma to eye, then had to quickly remove it to prevent blindness in both eyes. However now immunosupressants are used.) Also occurs in testicular tortion (testicular antigens can activate the immune system and can have both testis attacked, resulting in infertility) Alteration of self With infection or drug Best example is drug induced lupus. Some drugs e.g hydralazine (not a widely used drug for heart failure) can cause this. It alters the DNA (by binding to it) This can result in autoimmune reactivity In most patients it is an autoimmune reaction to the hydrazalazine. (so when you remove the drug, the drug induced lupus goes away) However in some there is binding to the DNA itself. (so that when you remove the drug, the drug induced lupus still remains) Molecular mimicry Some infectious agents are closely related to our antigens. (E.g strep A) hence cross reaction with own tissues Best example is rheumatic fever Antibodies that are made in strep cross react with heart (resulting in pancarditis), brain (chorea?) skin (subcutaneous nodules?) and joints Superantigen stimulation E.g Toxic shock syndrome – after this then it can overwhelm tolerance. Thus many people that recover are left with autoimmune disease. (Makes sense, even though you have recovery from the initial superactivation, you have so much disruption of the normal mechanisms of self tolerance that you subsequently get autoimmunity) Superantigens don’t have to be processed. Thus activate huge numbers of T cells. E.g TSS – (after staph, strep) Another example is Kawasaki syndrome (which some people believe to be due to superantigen activation). This tends to affect young children and effect the coronary artery which can cause MI (obviously concerning in such a young child). Additionally it can cause scalded skin. Also get generalised rash etc

Infection of antigen presenting cell In the periphery the APC’s will usually be able to have signal 1 (self antigen + MHC class I (because they have made it through the negative selection) but not signal 2 (the costimulation – unless it is actually a true infectious process going on However if the APC itselt is infected by a virus then it can cause the costimulation. This is the mechanism that we believe type 1 DM occurs. (That there is a virus which infects the APC and causes activation of autoimmunity causing destruction of the beta cells of the Islet of Langarhans). Mutations in genes controlling immune response E.g ALPS (autoimmune lymphoproliferative syndrome) This is due to mutations in the FAS/FAS ligand. This is a key pathway in switching off the immune system. This pathway induces apoptosis. However if have mutation then once you switch on an immune response then you cant switch it off. (Hence get lymphadenopathy, hepatomegaly etc). Mechanisms of tissue injury Type 1 = IgE influenced. Forms basis for most allergy. However no known autoimmunity showing this mechanism yet. Type 2 = humoural immunity Type 3 = immune complexes Type 4 = cellular immune response. Also some that don’t fit neatly to this. Autoantibodies Remember presence doesn’t imply pathogenesis However usually easier to measure than T cell reactions E.g in hashimotos thyroiditis, the injury is actually T cell mediated, but the anti thyroid antibody is used for Dx (as easier to measure) Type II This is antibody mediated cytotoxicity Antibody binds, complement is activated and there is influx of inflammatory cells which leads to tissue damage. E.g anti GMB disease Lab tests: look for the specific antibodies. (variable efficacy e.g GBM is 100% sensitive, others less good). Note that complement consumption is often masked (wont see change in complement levels, because not that much is activated) Gold standard = immunoglobulin deposition on biopsy. Type III Immune complex deposition. Antibody binds to antigen (soluble or in tissue) Complement is activated. If it is not cleared then it may get lodged in tissue. E.g SLE and rheumatoid vasculitis Remember that people have a way of removing antibody complexes.

This is by the complex binding to RBC’s which then go to the spleen. These are then stripped off by macrophages. Only when mechanism doesn’t work properly or it is overwhelmed, that you get immune complex disease When you get immune complexes in tissues then you get inflammatory cells that migrate into the tissue, causing tissue damage. Here you often find a fall in serum complex levels C3 and C4 especially. Also need to do CH100 to rule out complement deficiency Also will do specific antibody tests e.g ANF/ANA (screening test, then go with ENA) , RF (e.g rheumatoid arthritis), anti ds DNA (e.g lupus) and anti – ENA (I believe this is a group of antibodies, e.g anti ds DNA) Type IV One of commonest mechanism Delayed hypersensitivity. Antigen is presented to T cells, the T cell is activated and secretes chemokines Macrophages are activated by interferon and you get tissue injury E.g RA and cellular rejection in grafts Also what arises with granulomatous inflammation ORGAN SPECIFIC VS NON ORGAN SPECIFIC Organ specific e.g autoimmune thyroiditis, IDDM, pernicious anaemia, autoimmune hepatitis etc. Key is that the antigen that is targeted is specific to these organs. In non organ specific then the antigen is expressed throughout the body (and thus any organ can be effected) Non organ specific 3 main categories are rheumatoid disease (key thing is that it is not just an arthritis – but other effects) Also connective tissue disease (e.g SLE, scleroderma, polymyocytis, dermatomyositis, mixed connective tissue disease and Sjogrens syndrome) And third main one is primary vasculitis Also others e.g anti phospholipids syndrome VASCULITIS SHOULD BE COVERED IN NEXT LECTURE, IF NOT THEN COME BACK TO VASCULITIS, SIZES, GRANULOMA OR NO GRANULOMA USE OF LAB TESTS Remember they are useful to rule in, rule out or monitor disease activity. Remember that false positives and false negative results are common. Thus need to take history, have differential and have targeted tests. Detection of autoantibodies (skipped in lecture, probably not that important) Agglutination assays The antigen coated beads and serum If there is no antibody then it remains in suspension The antibody agglutinates to form a button (due to bridges that are formed between the beads) Simple and quick assay

Indirect immunofluorescence Use slides with cultured cells. Patient serum is added and incubated on the slides. If there is antibody then it will stick to the nucleus of the cells. (I.e testing for ANF) Then use fluorescent anti humoural antibody against the antibody (and see if there is positive). Strong lighting in the nuclei is suggestive of lupus. (Need to do more specific tests to refine the dx)

ELISA Antigen coated well, incubate patients serum, wash away excess Then use enzymed linked antibodies (that are then washed away again). The enzyme is used to catalyse a reaction with a colour change. (Thus the more antibody that has linked, the more reaction occurs) The intensity of the colour is suggestive of the level of antigen. (come back if time) RHEUMATOID ARTHRITIS Arthritis = most common presentation. However it can affect most tissues in the body Also note that some extraarticular features may occur alone (atypical presentation) Side note, very painful ulcers can occur due to vasculitis. Note that the arthritis is mainly due to T cell mediated immunity while the vasculitis and other extra articular is due to the immune complex deposition. Epidemiologyu Uncertain peak age 3:1 female male ratio 1% prevelance and 30/100,000 incidence (makes sense, much larger prevelance due to it being a chronic condition) There are genetic influences e.g HLA- DR4 (DR1 associated with Hispanic/jewish and asian popns) Presentations Acute polyarthritis = common presentation

Will complain of inflammatory symptoms/signs. Mainly morning stiffness. (not really fever, although may have some low grade). Key difference between mechanical osteoarthrosis. Minimum of 6 weeks to get dx. Can be other presentations though. E.g slow monoarthritis, acute monoarthritis, local and systemic extra-articular disease Patterns of progression Most = polycyclic. (I.e relapsing remitting) Some have monocyclc (more benign – i.e have few episodes) Also progressive (where they have aggressive disease causing massive joint destruction) Note currently no way of knowing who will progress in what way. RA pathology Have chronic widespread synovitis Lymphocyte infiltration and hyperplastic synovium Pannus formation at synovial interface which can eat in (causing marginal erosions). This is an invasive type of altered connective tissue which eats its way into the the cartilage (goes on to destroy the joint). This can cause collapse of the bone and cause an irreversible deformity. Nodules Occur on the extensor surfaces in 20% of seropositive patients (I believe this is by definition seropositive) There is focal central fibrinoid necrosis. Thought to be due to a form of vasculitis They are small HARD nodules. Commonly occur by the elbow Rheumatoid vasculitis Can be small vessel – i.e nailfold infarcts and spinter haemorrhages. (They don’t tend to cause too many problems). (side note, remember that splinter haemorrhages can be cuased by trauma but also vasculitis. This is why RA, SLE, scleroderma and other connective tissue diseases can cause splinter haemorrhages. Also remember that infective endocarditis can cause this, which makes sense since infective endocarditis is a cause of vasculitis.

Can also be medium vessel – i.e leg ulcers and neuropathy

The vasculitis is generally immune complex mediated. It may also be ANCA psotive Rheumatoid factor This is an antibody to the Fc portion of IgG and is present in about half of patients with RA. However lots of weak positives (non specific) – e.g infection and especially older females Strong positive however is highly suggestive of RA. RA complications Felty’s syndrome Splenomegaly, RA and neutropenia Amyloidosis Remember, any chronic disease can cause amyloidosis Vasculitis (See above) Pulmonary disease Nodules, pleural effusion Interstitial fibrosis Obliterative bronchiolitis (small airways scar up and air cannot get in, most devastating) (Note that may not notice getting restless on exertion due to lack of mobility due to the arthritis) Occlar disease Keratoconjunctivitis sicca (conjunctivitis and keratosis – inflammation of the cornea that is associated with dry eyes/lack of tear production)

Episcleritis (inflammation of the episclera, the layer in between the conjunctiva and the sclera).

Scleritis (more severe, effecting the sclera, commonly in rheumatic conditions e.g RA, wegeners granulomatosis etc)

Sleromalacia (Thinning of the sclera, exposing the choroids underneath, I believe this is the wost) The eye can perforate from damage to the eye wall.

Making the diagnosis To rule in Clinical picture Rheumatoid factor and anti-CCP antibodies Xrays of hands and any affected joints. This is because erosions on Xray (see below) help to make dx even in the event of seronegative RA. Additionally it shows that the rheumatoid arthritis is an aggressive form.

Rule out alternative dx ANF (to rule out the connective tissue diseases – e.g SLE, and follow up (i.e ENA I believe) ANCA to rule out vasculitis Also need to think about the seronegative arthritis (with Hx and exam) Also note that you can get transient arthritis in a viral arthritis (commonly following rubella in adult). Dx by history and serology. (Need to think about this, especially if the first line tests come up negative). Monitoring disease activity Clinical activity scores CRP (best non specific – used to monitor inflammation) ESR (but affected by lots of things, e.g NSAIDS, anaemia etc) FBC – anaemia (normocytic normochromatic (anaemia of chronic disease – check why), but may also see iron deficiency anaemia due to gastric irritation/bleeding from the medications that these patients are on). Monitor function of affected organs Serial RF = little benefit Immunology 2 CONNECTIVE TISSUE DISEASE This is rheumatoid arthritis (says rheumatoid disease, but I assume she means this) SLE Polymyositis Scleroderma and CREST Mixed connective tissue disease Sjogrens syndrome (Vasculitidies). Remember that there can be a lot of overlap between these diseases. However many have well defined syndromes Many respond to immunosupression. Notable exception is scleroderma. SLE Inflammatory multisystem disease

Unknown aetiology Diverse clinical and lab abnormalities Variable course and prognosis (can range from arthritis/skin rash to life threatening and aggressive disease). (note about 5% of renal transplant lists are due to lupus) Multiple autoantibodies. Cytotoxic function (type 2 hypersensitivity to platelets, RBC’s etc) Immune complex deposition (type 3 hypersensitivity) I.e more than 1 mechanism of autoimmunity in this one disease. Other lupus This is classical lupus but there are others Drug-induced lupus (e.g hydralazine which results in loss of tolerance due to altered self – usually remit after removing the drug) Neonatal lupus (antibodies (IgG – remember, IgM cant cross the placenta as it is too large) from a mother with lupus may cross the placenta to induce lupus in the newborn. Typically takes form of skin rash and congenital heart block. Note that especially the anti Ro antibodies can bind to the conducting system (causing heart block and hearf failure – thus needed to treat with pacing). Latent lupus (those with serological evidence of lupus but don’t have symptoms – however may go on to develop lupus themselves. Additionally can result in neonatal lupus (if woman gets pregnant). However remember that vica versa (not all will get disease in those that have antibodies) Antiphospholipid syndrome (associated with thrombophilia, 30% of those with lupus have this, although may get on its own) End stage lupus (there is no more inflammation due to “burn out” of inflammation – but can still have renal failure etc. Thus steroids/immunosupression is not necessary (as no benefit, just giving toxicity)

Epidemiology 9:1 female to male Peak age = 2nd – 3rd decade (young females = common) Large geographical incidence (America more than Scandinavia for example) Prevelance = about 50/100,000 Racial – black>white Genetic: some genetic factors such as complement deficiencies and problems in the mechanism for desposing immune complexes. (makes sense, if you don’t have a good mechanism to dispose of complexes then you are more likely to get lupus) Clinical features Inflammation of any organ, predominantly: Skin (classical rash = butterfly rash). (Remember it is one of the few rashes that goes up above the nose – rather than just the cheeks). Generally is not itchy or sore. Also classically photosensitive (so commonly after being in the sun it comes out)

Note that another rash that they can get is discoid lupus. (can be chronic, slightly raised. Skin follicles plugged wth debris). Classically on biopsy then you can demonstrate immune complex along the dermo-epidermal junction) Also mouth ulcers etc

Joints (usually). (Skin and joint manifestation is generally Kidneys (need potent immunosupression to prevent renal failure) Brain (cerebral manifestation is one of the most severe Serosal surfaces (can get pleural effusions and pericarditis) Immune cytopenias and haemolytic anaemia is common. (Remember, anyone with haemolytic anaemia should be tested for lupus) Note that skin manifestations only = cutaneous lupus. However this may be part of Renal pathology Many different types you can get. Focal segmental glomerulonephritis Focal proliferative glomerulonephritis Diffuse proliferative glomerulonephritis Membranous glomerulonephritis (glomerulonephrosis) Sclerosis. Morbidity and mortality Due to organ damage of disease itself However also significant morbidity/mortality due to the effects of immunosuppressant drugs. E.g those with renal lesion treated with high dose steroids and cyclophosphamide (alkylating agent that causes leucopenia and infertility) Common autoantibodies ANF = screening test. If positive then go on to do other tests (anti dsDNA) ENA (anti extractable nuclear antibodies) – especially Anti-Ro, Anti-La and Anti-Sm Antibodies to RBC, WBC and platelets (especially if have neutropenias, anaemias etc) Making the dx Clinical hx and exam. Uranalysis and urine microscopy (because patients may have silent renal failure) ANF (if negative then unlikely dx of SLE) If positive then go on to measure Anti-dsDNA Also anti-ENA (note that anti-sm is an especially specific test – although only found in 30% of those with lupus). Anti ro and anti la (found in other connective tissue disease, but support dx) Also need to assess function of potentially involved organs. Monitoring disease activity Function of affected organs FBC and ESR (remember that CRP = poor measure in SLE) Complement levels (level of consumption – remember there is type 3 hypersensitivity and thus could be lower levels of complement) Anti-dsDNA levels reflects disease activity. Examples

5 day old girl Rash Enlarged Liver & Spleen Severe hepatitis Normal heart rate Mother had mild SLE diagnosed 1999 (intrauterine infections e.g rubella, herpes etc would be differential The mild lupus is mother was key. Intrauterine viral antibodies were negative Infection screen negative Anti-Ro positive Anti-DNA negative Rapidly worsening liver failure Working diagnosis - Neonatal lupus Note that IgG tests are used for this. Remember that in most neonatal diseases you are looking for IgM (because IgG are mostly from the mother). However, since you are looking for a disease that has been transferred from the mother to the child you are looking for IgG. (mother) Mother had been well during pregnancy Never had systemic therapy for SLE Generally unwell Fatigue – anaemia (anaemia is common after pregnancy, but this was haemolytic anaemia, not expected after pregnancy) Joint pains ANF >1/400 S&H Anti-DNA 297iu/ml (Ref 50) (i.e this is a disease of the elderly) M and Black = more affected than F and white. Pathogenesis Very complicated and many interconnected pathologies

Previous exposure to irradiation Exposure to asbestos, petroleum products, rubber or plastic products HH8 (not sure why, I know that this causes kaposis sarcoma, as far as multiple myeloma is concerned I am not too sure) Cytogenetics (e.g deletion of 13q or translocation of 4;14) Myeloma cells produce Il-6. This is important because it induces myeloma cell growth and induces osteoclast activation. Hence you get breakdown of the bone. (This makes sense, this is the reason why even if there is no direct infiltration of the myeloma cells, there is osteoclast activity and hence lytic lesions. E.g in the skull it is called a pepperpot skull The plasma cells secrete a MONOCLONAL Ig. Usually they are IgG or IgA (the other types are uncommon) In 2/3 of patients they have Bence Jones proteins. These are light chains of immunoglobulins that are found in the urine. They are able to be found in the urine because they are light chains (hence they can be filtered in the glomerulus) (possibly the reason why only 2/3 of patients have this is because the other 1/3 produce heavy chains?) Dx of MM Radiology You may see specific punched out lytic lesions (makes sense, since these would be due to the osteoclast activation) E.g (e.g note below the multiple lytic lesions in the metaphysic and diaphysis of the humerus and in the ribs. There is also a small fracture in the proximal metaphysic) Also note the pepper pot skull on the right

You can see multifocal destructive lesions ( Bone marrow sampling (a bone marrow aspirate or biopsy) Serum and urine electrophoresis and immunoglobulin levels (You would have a monoclonal spike, urine electrophoresis would be the Bence Jones criteria I would imagine). Could also see multifocal destructive lesions (multiple punched out lytic lesions) They can soap bubble appearance Can also have pathologic fractures (makes sense, they have bony infiltration and lytic lesions) Note that you mal also get a diffuse osteoporosis (because of Il-6 secretion which results in infiltration of the bone even if there is no infiltration of the bone) Bone marrow sampling Can do a bone marrow aspirate or a bone marrow biopsy Normally plasma cells form about 10-20% of the bone marrow. (I think lecturer is saying that normally 10-30% but when there is multiple myeloma there is a greater percentage. Not sure. Remember the normal morphology of plasma cells. You have a nucleus which is pushed to one side and perinuclear clearing (because of golgi bodies - to make the immunoglobulins I believe)

However, in multiple myeloma you can have abnormal cells e.g bi-nucleated, trinucleated or multi-nucleated forms.

Can have immature blasts Intracytoplasmic inclusions (Russle bodies large eosinophilic cells) Immunohistochemistry (will see a single type of Ig – monoclonal remember). They can be either kappa or lambda (never both, usually kappa). Remember that they are the type of light chains?) Serum and urine analysis Monoclonal globulin spike on serum electrophoresis (note that small percentage, 1% secrete neither Bence Jones proteins or monoclonal spike) The absence of Ig or its components from blood or urine does NOT exclude myeloma (because of the 1% of the non secretors I would imagine)

Clinical features of multiple myeloma CRAB (hypercalcaemia, renal failure, anemia and bone lesions) Infiltration of bones (hence bone lytic lesions) (the hypercalcaemia would cause hyperparathyroidism too I would imagine? Additionaly there would be il-6 secretion and therefore resulting in osteoclasts being activated also causing lytic lesions?) (Remember that a patient with back pain especially if it is unremitting even in the night then suspect MM. Additionally another feature that maybe present is tender ribcage) Hence get bone pain and pathologic fractures Hypercalcaemia – (due to resorption of bone I would imagine, Not all patients get this I believe it is 10%) Infiltration of bone marrow (hence the anaemia) Renal insufficiency (just due to amyloid or due to infiltration as well?)

Infiltration of other organs is rare. Amyloidosis – AL chain. Recurrent infections This is the most common cause for death (renal failure being the second most common) This is due to a combination of decreased production of normal immunoglobulins (and hence there is particular risk from encapsulated organisms) (antibody mediated immunity) Additionally infiltration of the bone marrow causes leucopenia (and hence cell mediated immunity is also reduced) Hypercalcaemia Additional symptoms due to this (Bones, stones, groans and psychiatric moans remember) Lethargy, nausea, vomiting, abdominal pain (due to ulcers or pancreatitis I believe) Renal stones Depression (psychiatric moans) Bone lesions Amyloidosis Remember that you can get a AL type of a amyloidosis (it is the most common type of systemic amyloidosis I believe) It is a systemic amyloidosis with deposits in many places Remember from BED. It occurs with about 10% of MM patients and when you have this then generally very poor prognosis. Note however that most people with Al amyloid do not have MM (but probably some lymphproliferative disorder. Not known if they will eventually develop myeloma because the amyloid will usually kill the patient first. Dx = kidney (more invasive) or rectal biopsy (remember, rectal is often used I believe in systemic amyloidosis, possibly because it is a good and minimally invasive procedure) Then stained with congo red stain Complications associated with amyloid deposition Restrictive cardiomyopathy Enlargement of the tongue

Athropathy (basically the same as arthritis) Tendency for prolonged bleeding (due to binding of clotting factor X by the amyloid fibril) Skin changes

Renal failure This is the second most common cause of death The renal failure is multifactorial Obviously if the patient has amyloidosis then amyloid deposits can cause

However myeloma kidney (myeloma cast nephropathy due to deposition of cast within the tubules) (just a feature that suggests myeloma I would imagine – I think just meaning direct invasion of the myeloma cells?) Light chain nephropathy (this is due to deposition of light chain in the glomeruli) Hypercalcaemia (causing renal calcinosis?) and hyperuricaemia Pyelonephritis (not sure the mechanism) Prognosis of multiple myeloma Very poor 6-12 months if untreated Median survival = 3 years if treated Causes of death = infection and renal failure. Treatment of multiple myeoma Currently it is not curable However, chemotherapy, steroids, and radiation may help Bisphosphonates are also used (I imagine as symptomatic therapy in order to prevent fractures and build up bone bulk) Thalidomide = tx for multiple myeloma (remember, it caused birt defects in women before, but now used again as a tx for this condition). Thalidomide used in combination with dexamethasone Bone marrow transplant (either autologous or allogenic can also be used) SOLITARY PLASTMACYTOMA This is like a multiple myeloma but it is a solitary tumor which is growing within the soft tissue or skeleton The serum immunoglobulin concentrations are within normal limits The patients are younger than patients with multiple myeloma It involves the spine, pelvis and femur Can present with a single symptomatic area of bone destruction. Plasma cells account for more than 15% in the bone marrow It may however progress to multiple myeoma (10-20 years later) Extra medullary plasmocytoma = often involved in the lung, oronosopharynx and nasal sinuses Extra-osseus lesions can be cured by local resection or chemotherapy. Progression to multiple myeloma is rare. (I believe the skeletal forms are worse because you are far more likely to progress to multiple myeloma) WALDENSTROMS MACROGLOBUMINAEMIA (apparently not that important) Just know a bit about it Occurs in the elderly and more in females The neoplastic cells this time produce IgM (whereas multiple myeloma usually produces IgG, but can produce others) and this is the reason why it is called macroglobuminaemia (as the immunoglobulins are large) Weakness and weight loss Lymphadenopathy, hepatosplenomegaly, autoimmune haemolysis and hyperviscosity syndrome Hyperviscosity syndrome = visual impairment due to distention of the retinal blood vessels. There can also be neurological symptoms, bleeding (due to macroglobulins binding to clotting factors and interfering with platelet function), cryoglobuminaemia and Raynauds phenomenon HEAVY CHAIN DISEAES These are monoclonal proliferations of B cells with increased production of heavy chains (kind of like amyloidosis in a way. Light chain production forms AL amyloidosis, while this is heavy chain disease)

Note that this, amyloidosis and waldenstroms macroglobuminaemias are all types of paraproteinemias (which indicate an underlying immunoproliferative disorder). That is, excessive amounts of single monoclonal gammaglobulins. (Light chains – amyloidosis, heavy chains – heavy chain disease or full polymers – waldenstroms macroglobuminaemia) There can be production of alpha heavy chain disease, gamma heavy chain disease or mu heavy chain disease (more information about this in the lecture, come back to this in the very unlikely situation of having excess time) MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE This is the most common cause of monoclonal gammopathy 3% of adults >70 will have this. This is a monoclonal immunoglobulin spike in the serum or urine without evidence of MM or other disease It is asymptomatic and usually picked up incidentally The plasma cells form
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