Systemic Pathology: Musculoskeletal, Nervous and Organ System Disease

Systemic pathology is where the general rules of cell injury, inflammation and neoplasia turn into named diseases with named lab patterns, radiographic signs and red flags. The board loves this material because every disease has a signature (a lab triad, a classic location, a pathognomonic cell), and the chiropractor meets these diseases every week disguised as back pain, neck pain, stiffness or fatigue.

Section 1Disorders of bone

Bone is constantly remodeled: osteoclasts (monocyte lineage, driven by RANKL) resorb it and osteoblasts lay down osteoid that then mineralizes. Most metabolic bone disease is a fault in this cycle: too little matrix (osteoporosis), unmineralized matrix (osteomalacia), chaotic remodeling (Paget disease), failed resorption (osteopetrosis) or hormone-driven resorption (hyperparathyroidism).

Osteoporosis

Osteoporosis is a reduction in bone mass per unit volume with normal mineralization: the bone that remains is normal in quality but there is too little of it. Trabecular (cancellous) bone has the greatest surface area and turnover, so it is lost first, which is why vertebral bodies, the distal radius and the femoral neck fracture first. Peak bone mass is reached around age 30; after that, everyone loses bone, and women lose it rapidly for 5 to 7 years after menopause because estrogen normally restrains osteoclast formation (estrogen loss raises RANKL and IL-6 and lowers osteoprotegerin).

• Type I (postmenopausal): women 50 to 70, mainly trabecular loss, vertebral crush fractures and distal radius (Colles) fractures.
• Type II (senile): both sexes over about 70, cortical and trabecular loss, hip and vertebral fractures.
• Secondary osteoporosis: glucocorticoids (the commonest drug cause), hyperthyroidism, hyperparathyroidism, hypogonadism, heparin, immobilization, alcohol, smoking, malabsorption and myeloma.

Diagnosis is by DEXA. The T-score compares the patient with a young adult: -1.0 or higher is normal, -1.0 to -2.5 is osteopenia, and -2.5 or lower (or any fragility fracture) is osteoporosis. Calcium, phosphate, alkaline phosphatase and PTH are normal. Plain films need 30 to 50 percent bone loss to show osteopenia; they show thin cortices, accentuated vertical trabeculae, anterior wedging and biconcave ("codfish") vertebrae, and multiple wedge fractures produce the dowager's hump.

Osteomalacia and rickets

Osteomalacia is defective mineralization of osteoid in adults; rickets is the same defect in children before physeal closure. The usual cause is vitamin D deficiency (little sun, poor diet, malabsorption, liver or kidney disease, anticonvulsants); phosphate wasting (X-linked hypophosphatemic rickets) is another. Low vitamin D lowers calcium absorption, PTH rises and wastes phosphate, so labs show low or low-normal calcium, low phosphate, high alkaline phosphatase and high PTH.

Adults have diffuse bone pain, proximal weakness and a waddling gait. The signature film finding is the Looser zone (pseudofracture): a bilateral, symmetric lucent band on the concave side of bone, classically the medial femoral neck, pubic rami, axillary border of the scapula and ribs. Rickets adds the rachitic rosary, craniotabes, bowed legs and widened, cupped, frayed metaphyses.

Paget disease of bone (osteitis deformans)

Paget disease is a localized disorder of excessive, disorganized remodeling, usually after age 50 and more common in people of northern European descent. It runs in three phases: a lytic phase of giant, many-nucleated osteoclasts; a mixed phase; and a sclerotic (blastic) phase that leaves thick but structurally weak bone with a mosaic pattern of lamellar bone separated by irregular cement lines. Genetics (SQSTM1 mutations) and a possible slow paramyxovirus infection have been implicated. The pelvis is the most common site, followed by the lumbar spine, femur, skull and tibia; it may be monostotic or polyostotic.

• Labs: markedly elevated alkaline phosphatase (bone isoenzyme) with normal calcium and phosphate; urinary hydroxyproline and other collagen breakdown markers rise.
• Skull: osteoporosis circumscripta (lytic phase), then "cotton wool" thickening; increasing hat size; hearing loss from cranial nerve VIII compression or ossicle involvement; basilar invagination.
• Spine: the picture frame vertebra (thickened cortical rim around a lucent center), the ivory vertebra (uniformly dense and, unlike metastasis or lymphoma, enlarged), spinal stenosis.
• Long bones: a "blade of grass" lytic front, bowing and "banana" fractures.
• Complications: fracture, secondary osteoarthritis, nerve compression, high-output heart failure from arteriovenous shunting in very vascular bone, and osteosarcoma (around 1 percent, usually polyostotic disease).

Osteopetrosis and other developmental bone disease

Osteopetrosis (marble bone disease) is failed osteoclast resorption (for example carbonic anhydrase II deficiency): dense but brittle bone, "bone within bone," sandwich vertebrae, crowded marrow with pancytopenia and cranial nerve palsies. Osteogenesis imperfecta (type I collagen) causes fractures with minimal trauma, blue sclerae and hearing loss. Achondroplasia (activating FGFR3) gives short limbs and congenital lumbar stenosis from short pedicles. Fibrous dysplasia shows ground-glass matrix and the shepherd's crook femur (McCune-Albright when polyostotic with café-au-lait spots and precocious puberty).

Endocrine and metabolic bone disease

Primary hyperparathyroidism, usually a single adenoma, raises calcium and lowers phosphate ("stones, bones, abdominal groans and psychiatric overtones"). Bone signs include subperiosteal resorption on the radial side of the middle phalanges of the index and middle fingers (the most specific sign), distal clavicle resorption, "salt and pepper" skull and brown tumors (osteitis fibrosa cystica). Secondary hyperparathyroidism from chronic kidney disease (retained phosphate, no calcitriol) is part of renal osteodystrophy, with band-like endplate sclerosis (rugger jersey spine) and soft tissue calcification.

Acromegaly widens bones: spade hands, enlarged tufts, heel pad thicker than about 23 mm, posterior vertebral scalloping and early osteoarthritis. Cushing syndrome causes osteoporosis and avascular necrosis; hyperthyroidism accelerates bone loss.

Osteomyelitis

Osteomyelitis is infection of bone and marrow. Staphylococcus aureus is the most common cause overall. Important exceptions are favorites: Salmonella in sickle cell disease (S. aureus is still common), Pseudomonas aeruginosa in intravenous drug users and in nail puncture wounds through a sneaker, Pasteurella multocida after cat or dog bites, group B streptococcus and E. coli in neonates, Neisseria gonorrhoeae causing septic arthritis in sexually active young adults, and Mycobacterium tuberculosis in the spine (Pott disease).

In children, hematogenous infection seeds the metaphysis, where looping vessels slow flow. In adults it favors the vertebral body and disc (discitis), often from a urinary or skin source. Pyogenic infection destroys the disc early (disc space loss with erosion of both endplates); tuberculosis spreads under the anterior longitudinal ligament, relatively spares the disc, involves several levels and causes a gibbus and psoas abscess. The sequestrum is dead bone, the involucrum reactive new bone around it, and a Brodie abscess a walled-off subacute abscess. Films lag 10 to 14 days; MRI is the best early test.

Avascular necrosis (osteonecrosis)

Avascular necrosis is infarction of bone and marrow, most often in the femoral head, where blood supply arrives mainly through the retinacular branches of the medial circumflex femoral artery and is easily interrupted by a displaced femoral neck fracture. Common causes are glucocorticoids, alcoholism, trauma, sickle cell disease, Caisson disease (nitrogen bubbles in divers), Gaucher disease, lupus and pancreatitis. Early films are normal; MRI is the most sensitive test. Later the crescent sign (subchondral fracture lucency) appears, followed by flattening and collapse of the articular surface and secondary osteoarthritis. A large family of eponymous osteochondroses affect children and adolescents:

• Osteochondroses: Legg-Calvé-Perthes (femoral head, boys 4 to 10, limp or knee pain), Kienböck (lunate), Preiser (scaphoid), Freiberg (second metatarsal head), Köhler (navicular), and Scheuermann disease (adolescent thoracic kyphosis with 5 degrees or more of anterior wedging in at least three adjacent vertebrae and Schmorl nodes). Osgood-Schlatter disease is a related traction apophysitis of the tibial tubercle.

Tumors of bone

The most common malignant tumor found in bone is metastatic carcinoma, and the spine is its favorite target because the valveless Batson venous plexus lets tumor cells flow between pelvic and spinal veins. Breast, prostate, lung, kidney and thyroid account for most. Prostate (and often breast) metastases are osteoblastic (dense, "ivory" vertebra in an older man); kidney and thyroid are purely lytic and expansile; lung is usually lytic. Destruction of a pedicle on the AP view (the "winking owl" or one-eyed pedicle sign) points to metastasis, because the tumor spreads through the posterior vertebral body into the pedicle. Metastases typically spare the disc, in contrast to infection.

The most common primary malignancy of bone is multiple myeloma, a monoclonal plasma cell neoplasm of older adults. Remember CRAB: hypercalcemia, renal failure, anemia (rouleaux) and bone lesions (punched-out lytic "raindrop skull," diffuse osteopenia, vertebral collapse). Serum electrophoresis shows an M spike and urine may contain Bence Jones protein. Lesions are purely lytic, so the bone scan may be cold and ALP normal; myeloma tends to spare the pedicles early, unlike metastasis.

Benign lesions are small and well marginated with a narrow zone of transition and solid periosteal reaction; aggressive lesions show a wide zone of transition, moth-eaten or permeative destruction, cortical breakthrough and interrupted periosteal reaction.

Section 2Disorders of joints, connective tissue and muscle

Arthritis questions reduce to four clues: which joints (distribution and symmetry), what the films show (joint space, bone density, new bone versus erosion), what the blood shows (RF, anti-CCP, HLA-B27, ANA, uric acid) and what the joint fluid shows (cell count and crystals). Synovial fluid with fewer than 2,000 WBC/µL is noninflammatory (osteoarthritis, trauma); 2,000 to 50,000 is inflammatory (RA, crystals, spondyloarthropathy); more than 50,000 with mostly neutrophils is septic until proven otherwise.

Osteoarthritis and degenerative spine disease

Osteoarthritis is the most common arthritis. It begins in articular cartilage (proteoglycan loss, fibrillation, fissuring); bone responds with subchondral sclerosis (eburnation), subchondral cysts and marginal osteophytes. Pain worsens with use; morning stiffness lasts under 30 minutes. Typical joints are the hip, knee, spine, first CMC, DIP (Heberden nodes) and PIP (Bouchard nodes); MCPs and wrists are spared. Joint space loss is nonuniform (superolateral hip, medial knee).

In the spine, distinguish intervertebral osteochondrosis (disc degeneration: disc space narrowing, endplate sclerosis, vacuum phenomenon of nitrogen gas, Schmorl nodes), spondylosis deformans (anterior and lateral osteophytes from outer annular fibers), facet (zygapophyseal) arthrosis (true synovial osteoarthritis, which can narrow the lateral recess and intervertebral foramen and contribute to degenerative spondylolisthesis, most often at L4 to L5) and uncovertebral (Luschka) joint hypertrophy, which narrows the cervical foramina and causes radiculopathy.

Rheumatoid arthritis

Rheumatoid arthritis is a systemic autoimmune disease of synovium, three times more common in women, associated with HLA-DR4 (and DR1) and smoking. CD4 T cells, B cells and macrophages drive TNF-α, IL-1 and IL-6, and the synovium becomes a thick, villous, vascular sheet called pannus that invades cartilage and bone at the "bare areas" where synovium touches bone without cartilage cover, producing marginal erosions. Rheumatoid factor (IgM directed against the Fc portion of IgG) is present in about 80 percent but is not specific; anti-cyclic citrullinated peptide (anti-CCP) antibody is far more specific. ESR and CRP track activity.

• Distribution: bilateral and symmetric small joints: MCPs, PIPs, wrists (ulnar styloid erosion is early), MTPs; DIPs spared. Morning stiffness over 1 hour.
• Films: soft tissue swelling, periarticular osteopenia, uniform joint space narrowing, marginal erosions, little or no new bone.
• Deformities: ulnar deviation and volar subluxation at the MCPs, swan neck (PIP hyperextension, DIP flexion), boutonnière (PIP flexion, DIP hyperextension), hitchhiker thumb.
• Extra-articular: rheumatoid nodules (fibrinoid necrosis with palisading histiocytes), anemia of chronic disease, pleuritis, interstitial lung disease, Caplan syndrome (RA plus pneumoconiosis nodules), pericarditis, vasculitis, secondary Sjögren syndrome, Felty syndrome (RA, splenomegaly, neutropenia), Baker cyst (popliteal) that can rupture and mimic DVT.

Seronegative spondyloarthropathies

These share HLA-B27, negative rheumatoid factor, axial and sacroiliac involvement, enthesitis (inflammation where tendon and ligament insert into bone), asymmetric large-joint oligoarthritis, and anterior uveitis. Remember PAIR: psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease (enteropathic) arthritis and reactive arthritis. Inflammatory back pain differs from mechanical pain: onset before 40, insidious, morning stiffness over 30 minutes, improves with exercise but not rest, and wakes the patient in the second half of the night.

• Ankylosing spondylitis: young men, about 90 percent HLA-B27 positive. Starts with bilateral symmetric sacroiliitis (erosions of the iliac side first, then sclerosis, then fusion), then ascends: Romanus lesions (corner erosions), shiny corners, squared vertebrae, thin vertical marginal syndesmophytes that bridge into a bamboo spine, the dagger sign (ossified supraspinous ligament) and trolley track sign. Reduced Schober test and chest expansion (less than 2.5 cm), aortitis with aortic regurgitation, upper-lobe fibrosis.
• Psoriatic arthritis: asymmetric, DIP involvement with nail pitting, sausage digit (dactylitis), pencil-in-cup deformity, fluffy periostitis, acro-osteolysis, ivory phalanx; asymmetric sacroiliitis and bulky nonmarginal ("comma") syndesmophytes.
• Reactive arthritis (formerly Reiter): follows urethritis (Chlamydia trachomatis) or enteric infection (Shigella, Salmonella, Campylobacter, Yersinia); arthritis, urethritis and conjunctivitis ("can't see, can't pee, can't climb a tree"), keratoderma blennorrhagicum, fluffy calcaneal enthesopathy, asymmetric lower limb arthritis and sacroiliitis.
• Enteropathic arthritis: Crohn disease or ulcerative colitis; peripheral arthritis tracks bowel activity, while the spondylitis (looks like AS, bilateral symmetric) runs independently.

Crystal arthropathy and DISH

Gout is deposition of monosodium urate crystals: needle-shaped and negatively birefringent. About 90 percent of hyperuricemia is underexcretion (kidney disease, thiazide and loop diuretics, alcohol); overproduction comes from cell turnover (tumor lysis) or HGPRT deficiency (Lesch-Nyhan). The classic attack is sudden first MTP inflammation (podagra) in a middle-aged man. Chronic tophaceous gout gives "rat bite" erosions with overhanging edges and joint space preserved until late. Treat attacks with NSAIDs, colchicine or steroids; lower urate with allopurinol or febuxostat.

Calcium pyrophosphate deposition disease (CPPD, pseudogout) deposits rhomboid, weakly positively birefringent crystals (blue when parallel). The knee is most common; the radiographic sign is chondrocalcinosis of the knee menisci, the triangular fibrocartilage of the wrist and the pubic symphysis. Associations: aging, primary hyperparathyroidism, hemochromatosis (hook-like osteophytes at the 2nd and 3rd MCPs), hypomagnesemia and hypophosphatasia. Hydroxyapatite deposition causes calcific tendinitis, classically of the supraspinatus.

Diffuse idiopathic skeletal hyperostosis (DISH, Forestier disease) is flowing ossification along the anterolateral spine, especially the right side of the thoracic spine (the pulsating aorta on the left protects that side), across at least four contiguous vertebrae, with preserved disc height and normal facet and sacroiliac joints. It affects older men, is associated with obesity and type 2 diabetes, can cause dysphagia in the neck, and often coexists with ossification of the posterior longitudinal ligament (OPLL).

Lupus and other connective tissue diseases

Systemic lupus erythematosus is the prototype immune complex (type III) disease, mostly in women of childbearing age. Complexes deposit in kidney, skin, joints and serosa and consume complement (low C3 and C4). ANA is the sensitive screen; anti-dsDNA and anti-Smith are specific; anti-histone marks drug-induced lupus (hydralazine, procainamide, isoniazid). Features: malar rash, photosensitivity, oral ulcers, nonerosive arthritis (Jaccoud), serositis, nephritis, cytopenias, Libman-Sacks endocarditis and antiphospholipid syndrome (clots, miscarriage).

Polymyalgia rheumatica (over 50) causes shoulder and hip girdle aching and stiffness with a high ESR, normal CK and a dramatic response to low-dose prednisone. It overlaps with giant cell arteritis: new headache, scalp tenderness, jaw claudication or visual change demands same-day referral to prevent blindness. Marfan syndrome (fibrillin-1) and Ehlers-Danlos (collagen) cause hypermobility and vascular fragility.

Myopathies and neuromuscular junction disease

• Duchenne muscular dystrophy: X-linked recessive frameshift deletion in the dystrophin gene; boys aged 2 to 5 with proximal weakness, Gowers sign (climbing up the thighs to stand), calf pseudohypertrophy (fat and fibrosis), markedly high CK; death in early adulthood from cardiomyopathy or respiratory failure. Becker dystrophy is a milder in-frame mutation with partly functional dystrophin.
• Myotonic dystrophy: autosomal dominant CTG repeat; cannot release a grip, cataracts, frontal balding, arrhythmia.
• Myasthenia gravis: antibodies against the postsynaptic acetylcholine receptor (type II hypersensitivity); fatigable weakness that worsens through the day, ptosis and diplopia first; thymoma or thymic hyperplasia; improves with anticholinesterases.
• Lambert-Eaton myasthenic syndrome: antibodies against presynaptic voltage-gated calcium channels, usually paraneoplastic with small cell lung carcinoma; proximal limb weakness that improves with repeated effort, hyporeflexia, dry mouth.
• Others: statin and steroid myopathy, and rhabdomyolysis with myoglobinuria and acute kidney injury.

Section 3Disorders of the nervous system

Neurons are permanent cells with no energy reserve, so the CNS is highly sensitive to ischemia and heals by liquefactive necrosis and gliosis (astrocytes) rather than fibrous scar. "Red neurons" (shrunken, eosinophilic, pyknotic) appear 12 to 24 hours after irreversible ischemic injury. Localizing the lesion is the core skill: cortex, subcortical white matter, brainstem, cord, root, plexus, nerve, junction or muscle.

Stroke

About 85 percent of strokes are ischemic: thrombotic (on atherosclerotic plaque at the carotid bifurcation or MCA), embolic (sudden and maximal at onset, usually from atrial fibrillation or mural thrombus) or lacunar (hyaline arteriolosclerosis of lenticulostriate vessels in hypertension and diabetes, causing pure motor or pure sensory strokes). A transient ischemic attack is a brief deficit without infarction and warns of stroke within days.

Intracranial hemorrhage and trauma

Closed head trauma produces coup and contrecoup contusions (frontal and temporal poles) and diffuse axonal injury from rotational shear. Concussion is a functional disturbance with normal imaging; second-impact syndrome and repeated injury are the concern. Rising intracranial pressure produces papilledema and the Cushing triad (hypertension, bradycardia, irregular respiration) and leads to herniation: subfalcine (ACA compression), uncal (ipsilateral blown pupil from CN III compression, contralateral hemiparesis or ipsilateral from Kernohan notch) and tonsillar (medullary compression, respiratory arrest).

CNS infections

Bacterial meningitis causes fever, headache, nuchal rigidity and altered mental status (Kernig and Brudzinski signs). Neonates: group B streptococcus, E. coli, Listeria. Children and adults: Streptococcus pneumoniae (most common) and Neisseria meningitidis (young adults, petechial rash, Waterhouse-Friderichsen syndrome). Elderly: S. pneumoniae and Listeria. Viral meningitis is usually enteroviral; HSV-1 encephalitis targets the temporal lobes; tabes dorsalis and the Argyll Robertson pupil mark neurosyphilis.

Demyelinating and degenerative disease

Multiple sclerosis is autoimmune destruction of CNS myelin (oligodendrocytes), commonest in women aged 20 to 40. Plaques separated in time and space favor periventricular white matter (Dawson fingers), optic nerves, brainstem and cervical cord. Classic features: optic neuritis, internuclear ophthalmoplegia (MLF), Lhermitte sign (electric shock down the spine on neck flexion), Uhthoff phenomenon (worse with heat) and nystagmus, intention tremor and scanning speech. CSF shows oligoclonal IgG bands; MRI is the test of choice.

Guillain-Barré syndrome is acute inflammatory demyelination of peripheral nerves (Schwann cell myelin), often 1 to 3 weeks after Campylobacter jejuni or a viral infection, through molecular mimicry. It causes ascending symmetric flaccid weakness with areflexia, mild sensory symptoms and autonomic instability, can paralyze respiration, and shows albuminocytologic dissociation (high CSF protein, normal cell count). Central pontine myelinolysis follows too-rapid correction of hyponatremia.

Normal pressure hydrocephalus gives gait apraxia, incontinence and dementia. In adults, brain metastases outnumber primaries; the commonest primaries are glioblastoma, meningioma (dural-based, psammoma bodies) and schwannoma (CN VIII). Children's tumors are mostly infratentorial (pilocytic astrocytoma, medulloblastoma, ependymoma).

Peripheral neuropathy and spinal cord disorders

Diabetes is the leading cause of peripheral neuropathy: distal symmetric "stocking and glove" loss (vibration and ankle reflexes first), autonomic neuropathy and mononeuropathies. Others include alcohol, B12 deficiency, uremia, lead (wrist drop) and hereditary Charcot-Marie-Tooth disease (pes cavus, "inverted champagne bottle" legs). Severe sensory loss allows a destructive neuropathic (Charcot) joint (distention, density, debris, disorganization, dislocation, destruction): diabetes targets the midfoot, tabes the knee, syringomyelia the shoulder.

• Subacute combined degeneration (vitamin B12 deficiency): dorsal columns plus lateral corticospinal and spinocerebellar tracts; loss of vibration and proprioception, positive Romberg, spastic weakness, Babinski sign, often with megaloblastic anemia.
• Tabes dorsalis (tertiary syphilis): dorsal roots and columns; sensory ataxia, lightning pains, absent reflexes, Argyll Robertson pupils, Charcot knee.
• Syringomyelia: a fluid cavity expanding from the central canal, often with a Chiari I malformation, usually C8 to T1. It first interrupts crossing spinothalamic fibers in the anterior white commissure, giving bilateral cape-like loss of pain and temperature with preserved touch (dissociated sensory loss), then involves the anterior horns (intrinsic hand wasting) and lateral tracts.
• Anterior spinal artery syndrome: infarction of the anterior two thirds (aortic surgery, dissection, hypotension); paralysis and pain and temperature loss below the lesion, with vibration and position spared.
• Brown-Séquard syndrome (hemisection): ipsilateral spastic weakness and loss of vibration and position below the lesion, contralateral loss of pain and temperature starting one or two levels below.
• Central cord syndrome: hyperextension injury in an older spondylotic neck; arms weaker than legs, variable sensory loss.
• Cord tumors: extradural (metastases, most common), intradural extramedullary (meningioma, schwannoma with "dumbbell" foraminal extension) and intramedullary (ependymoma in adults, astrocytoma in children).

Section 4Cardiovascular and respiratory disease

Atherosclerosis and arteriosclerosis

Atherosclerosis is chronic inflammation of the intima of large and medium arteries after endothelial injury (hypertension, smoking, hyperglycemia, turbulent flow at branch points). LDL enters the intima and is oxidized; macrophages ingest it to become foam cells, forming the fatty streak. PDGF draws smooth muscle cells into the intima to build a fibrous cap over a necrotic lipid core. A stenosis over about 70 percent causes exertional ischemia, but the real danger is the complicated plaque: a thin cap ruptures, exposes tissue factor and collagen, and thrombus forms within minutes. Other complications are hemorrhage, embolism, calcification and aneurysm. The abdominal aorta is most severely affected, then the coronary, popliteal and internal carotid arteries.

Risk factors: smoking, hypertension, high LDL and low HDL, diabetes, obesity and inactivity, plus age, male sex and family history. Hyaline arteriolosclerosis (hypertension, diabetes) narrows arterioles; hyperplastic ("onion-skin") change marks malignant hypertension; Mönckeberg medial calcification is a nonobstructive "pipestem" finding.

Hypertension

Hypertension is a sustained pressure of 130/80 mm Hg or higher; 90 to 95 percent is primary. Suspect a secondary cause in young or resistant patients: renal artery stenosis (fibromuscular dysplasia in young women, atherosclerosis in older men), kidney disease, primary aldosteronism, pheochromocytoma, Cushing syndrome, coarctation (arm pressure above leg pressure, rib notching), sleep apnea and drugs such as NSAIDs. Target organ damage includes left ventricular hypertrophy, coronary disease, stroke, aortic dissection, nephrosclerosis and retinopathy.

Ischemic heart disease

Stable angina is predictable exertional pressure relieved by rest; unstable angina and MI are acute coronary syndromes from plaque rupture; Prinzmetal angina is vasospasm at rest. The LAD is most often occluded (anterior wall), then the right coronary (inferior wall, SA and AV nodes, so bradycardia and block), then the circumflex. Pain radiates to the left arm, jaw or epigastrium; women, diabetics and the elderly may have atypical or silent infarcts. Troponin is the marker of choice: it rises in 3 to 4 hours, peaks at 24 hours and stays up 7 to 10 days; CK-MB clears in 2 to 3 days and detects reinfarction.

Heart failure, aneurysm and dissection

Heart failure may have reduced ejection fraction (after MI) or preserved ejection fraction (stiff hypertrophied ventricle). Left-sided failure causes dyspnea, orthopnea, paroxysmal nocturnal dyspnea, pulmonary edema and "heart failure cells." Right-sided failure is usually caused by left-sided failure (cor pulmonale when caused by lung disease) and causes jugular distention, nutmeg liver and pitting edema.

An abdominal aortic aneurysm (over 3 cm, usually infrarenal) is an atherosclerotic disease of older male smokers, seen as a pulsatile mass or curvilinear calcification anterior to the lumbar spine on a lateral film; repair is usually advised at 5.5 cm. Thoracic aneurysms follow hypertension, Marfan syndrome and tertiary syphilis. Aortic dissection (hypertension most common, Marfan) causes sudden tearing chest pain radiating to the back, unequal arm pulses and a widened mediastinum; Stanford type A involves the ascending aorta and is a surgical emergency.

Obstructive and restrictive lung disease

Spirometry separates the two great groups. Obstructive disease narrows airways so air cannot get out: FEV1 falls much more than FVC, so FEV1/FVC is below 0.70, while air trapping raises residual volume and total lung capacity. Restrictive disease limits expansion: all volumes including TLC fall, FEV1 and FVC fall together, and the ratio is normal or high.

Pneumonia and lung cancer

Lobar pneumonia (classically Streptococcus pneumoniae, the most common community-acquired cause) passes through congestion, red hepatization, gray hepatization and resolution. Bronchopneumonia is patchy (S. aureus, H. influenzae, Klebsiella with currant jelly sputum in alcoholics). Atypical pneumonia is interstitial and milder (Mycoplasma, Legionella, viruses). Aspiration favors the right lower lobe. Primary tuberculosis forms a Ghon complex; reactivation favors the apices with caseation and cavitation.

Lung cancer is the leading cause of cancer death. Adenocarcinoma is the most common type, peripheral, and the most common in nonsmokers and women. Squamous cell carcinoma is central, strongly linked to smoking, may cavitate and secretes PTH-related peptide (hypercalcemia). Small cell carcinoma is central, nearly always in smokers, neuroendocrine, metastasizes early (treated with chemotherapy, not surgery) and causes paraneoplastic SIADH, ectopic ACTH and Lambert-Eaton syndrome. Metastases to the lung are more common than primary lung cancer. A Pancoast (superior sulcus) tumor at the apex invades the lower brachial plexus and sympathetic chain.

Section 5Gastrointestinal, renal, endocrine and hematologic disease

Gastrointestinal and liver disease

Peptic ulcer disease is caused mainly by H. pylori and NSAIDs (Zollinger-Ellison gastrinoma when refractory). Duodenal pain improves with meals, gastric pain worsens; posterior duodenal ulcers bleed from the gastroduodenal artery or penetrate the pancreas and refer pain to the back. Reflux can cause Barrett esophagus. Celiac disease (anti-tissue transglutaminase) may present as iron deficiency or osteomalacia. Pancreatitis (gallstones, alcohol) and pancreatic carcinoma bore through to the back. In an older adult, iron deficiency anemia is colon cancer until proven otherwise.

Cirrhosis is diffuse fibrosis with regenerative nodules, mainly from alcohol, hepatitis B and C, and fatty liver disease. Alcoholic disease progresses from fatty change to alcoholic hepatitis (Mallory bodies, AST to ALT above 2) to cirrhosis. Consequences: portal hypertension (varices, caput medusae, ascites, splenomegaly), low albumin and clotting factors, jaundice, encephalopathy with asterixis, and estrogen excess (gynecomastia, spider angiomas). Hemochromatosis (HFE) and Wilson disease (ATP7B, Kayser-Fleischer rings) are metabolic causes.

Renal disease

Acute kidney injury is prerenal (hypoperfusion; BUN to creatinine ratio above 20), intrinsic (acute tubular necrosis with muddy brown casts after ischemia or toxins such as aminoglycosides, contrast or myoglobin) or postrenal (obstruction). Chronic kidney disease is most often caused by diabetes, then hypertension; it produces anemia (lost erythropoietin), renal osteodystrophy, hyperkalemia, metabolic acidosis, hypertension and uremia (pericarditis, encephalopathy, platelet dysfunction). Glomerular disease is sorted into two syndromes:

Most kidney stones are calcium oxalate; struvite staghorn stones come from Proteus. Colicky flank pain radiating to the groin does not change with movement. Pyelonephritis gives fever, costovertebral angle tenderness and WBC casts; renal cell carcinoma gives hematuria, flank pain, polycythemia and lytic expansile bone metastases.

Endocrine disease

Type 1 diabetes is autoimmune beta-cell destruction (HLA-DR3, DR4) with ketoacidosis; type 2 is insulin resistance in obese adults. Diagnosis: fasting glucose 126 mg/dL or more, HbA1c 6.5 percent or more, or 2-hour or random glucose 200 or more. Complications from glycation and the sorbitol pathway: retinopathy, nephropathy, neuropathy, atherosclerosis, infection, Charcot foot, adhesive capsulitis and DISH.

Anemias and leukemias

Anemia is classified first by red cell size (MCV), then by mechanism (decreased production versus increased loss or destruction, judged by the reticulocyte count).

• Iron deficiency (most common anemia worldwide; chronic blood loss in adults): low ferritin, high TIBC, low serum iron, hypochromic microcytes, koilonychia, pica. Anemia of chronic disease (hepcidin traps iron): high ferritin, low TIBC. Thalassemia: target cells, normal iron studies, high RBC count for the degree of anemia; beta-thalassemia major expands the marrow ("hair-on-end" skull).
• Vitamin B12 deficiency (pernicious anemia with antibodies to intrinsic factor and parietal cells, gastrectomy, ileal disease, strict vegan diet, metformin): megaloblastic anemia, hypersegmented neutrophils, raised methylmalonic acid and homocysteine, and neurologic damage (subacute combined degeneration). Folate deficiency looks identical in the blood but has normal methylmalonic acid and no neurologic signs.
• Sickle cell disease: glutamate to valine at position 6 of the beta chain; HbS polymerizes when deoxygenated; vaso-occlusive pain crises, autosplenectomy (infection with encapsulated organisms), avascular necrosis, Salmonella osteomyelitis and central endplate depressions giving H-shaped (Lincoln log) vertebrae. Hereditary spherocytosis (spectrin or ankyrin; high MCHC, osmotic fragility) and G6PD deficiency (oxidant-triggered hemolysis, Heinz bodies, bite cells) are other hemolytic causes.

Bleeding disorders split by pattern: platelet and von Willebrand disease (the most common inherited bleeding disorder) cause mucosal bleeding and petechiae, while coagulation factor deficiencies such as hemophilia A (factor VIII) and B (factor IX), both X-linked, cause deep bleeding into muscles and joints (hemarthrosis, especially the knee) leading to hemophilic arthropathy.

Words worth knowing