Calcium & phosphate Regulation Before we launch a discussion of the metabolic diseases thestudent must have a basic knowledge concerning the regulationof calcium and phosphate metabolism. To help in this discussionI refer you to the Frank Netter schematic from Ciba seen on thenext slide. The three hormonal regulators include parathormone (PTH)produced by the four parathyroid glands on the back side of thethyroid gland, the active form of vitamin D produced in theproximal renal tubule 1,25(OH)2, and calcitonin produced by theparafollicular cells in the thyroid gland. The major function of PTH is to prevent the dangerousreduction in the serum calcium level by increasing the pro-duction of 1,25,(OH)2 vitamin D in the kidney which thenincreases the absorption of calcium from the gut and renaltubule. PTH also activates osteoclastic mobilization of calciumfrom bone mineral. A second role of PTH is to promote urinary
excretion of phosphorous. The major function of 1,25,(OH)2 vitamin D is to activate theabsorption of calcium from the gut and bone. The least important calcium regulator is calcitonin which isdesigned to prevent an increase of serum calcium by inhibitingthe osteoclastic mobilization of calcium at the bone level.
Hormonal regulationof calcium and phosphate
Calcium and Phosphate Regulation The next slide is another Ciba schematic that helps one tounderstand the role of vitamin D in calcium regulation. The crude inactive form of vitamin D comes from the gutand the skin that is exposed to sun light which is then trans-ported to the liver for its first phase of activation by ahydroxylation process at the 25 position of the sterol ring.This still inactive form then goes to the kidney for its finialactivation by a hydroxylation process on the 25 position of thesterol ring. This now activated vitamin D acts as a hormonesimilar to PTH to help absorb calcium from the gut and bone.
Calcium and phosphate metabolism
Mobilization of Ca from Bone The following slide will help you to understand the mech-anism for the mobilization of calcium from bone mineral. When the serum calcium level drops below normal the para-thyroid gland puts out PTH which then activates resting bonecells to differentiate into an active lytic osteoclast as seen in thefollowing schematic. On the bone surface the active brushborder of the cell secrets collagenase enzyme which dissolvesbone mineral thus liberating calcium and phosphorous ionswhich are then transported across the cell to its outer membranewhere a 1,25,(OH)2 pumping mechanism transports thecalcium and phosphorous into the blood stream.
Primary Hyperparathyroidism As you will see in the following Ciba schematic there are threetypes of primary hyperparathyroidism. The most common 80%is a solitary adenoma found in the posterior capsule of thethyroid gland or ectopically further down the neck or into themediastinum. The next most common is the 18% hyperplasiacases involving all four parathyroid glands. The least commonis the 2% parathyroid carcinoma cases. As you can see in theschematic the major affect of the elevated PTH level is a stateof hypercalcemia second to increased osteoclastic activity inbone and an increased flow of calcium into the blood from therenal tubule and gut. The bone is weakened by the osteolyticprocess and the kidneys may become calcified. Initially the serumphosphorous level is depressed from phosphate loss in therenal tubule but may reverse if the kidney fails second tonephrocalcinosis. The secondary forms of hyperparathroidismwill be discussed later under rachitic syndromes includingrenal osteodystrophy.
Case #1 Primary Hyperparathyroidism 43 yr female with acute onset of elbow pain
X-ray showing generalizedosteomalacia with aspecific lysis of the outerend of clavical
Resected adenomaLump in throat Chief cells
Reversal lineOsteolysis Cutting cone
Salt and pepper granular osteolysis of the skull
Digital clubbing Subperiosteal osteolysis
Another case ofof early handhyperparathroidism
Case #1.1 Primary Hyperparathroidism 2008 56 year female with anterior knee pain for 2 years
Sag T-2 PD FS
Axial PD FS Cor PD FS
2009 2011Two new aneurysmal lesions in foot two years apart with bone graft to 3rd metatarsal ABC in 2009
2011Osteomalacic looking bones
Bell shaped chest cage Dorsal kyphosis
2011 T-5 Sag T-2 Axial T-2 at T-5CT and MRI images of spinal defects with paraparesis
Post op spinal decompression and posterior stabilization
Case #2 Healed hyperparathyroidism 40 year female with parathyroid adenoma removed 8 yrs ago
Chronic deformation of the skull bones
Chronic bell shaped deformity of rib cage
Case #3 Primary hyperparathyroidism48 yr female with multiple brown tumors of hyperparathyroidism
Case #4 Primary hyperparathyroidism 39 yr female with right hip and left hand pain for 6 mos
Case #5 Brown Tumor of Hyperparathyroidism 25 yr female Pain 3 mos
Biopsy specimen showing benign giant cells
Trabecular bone with with thick pink staining osteoid seams
Case #6 Brown tumors of hyperparathyroidism49 yr female withparathyroid adenomawith bilateral leg pain
Case #7 & 8 Brown tumors of tibia 41 year old female 43 yr female
Case #9 Brown tumor tibia Axial T-2 Sag T-2 46 yr male with pain in leg for 6 months
Case #10 Brown tumor hand30 year old female withhyperparathyroidism anda secondary brown tumorof the index finger
Case #11 Nephrocalcinosis 2nd to parathyroid CA43 yr male with history of primary hyperparathyroidism 2nd to a parathyroid carcinoma
Hypoparathyroidism As you will see in the following Ciba schematic, the mostcommon form of hypoparathyroidism is second to theinadvertant removal of the parathyroid glands during athyroid surgery. The rare idiopathic form is either sporadic,familial or the result of an autoimmune destructive mechanismwhich can result in chronic mucocutaneous candidiasis. The lack of PTH results in hypocalcemia second to a decreaseof calcium absorption from the gut, renal tubule and bone.The serum phosphorous is increased because of an increasedabsorption from the renal tubule. Although the reduction ofPTH inhibits calcium absorption from bone, the formation ofbone is reduced which results in a normal or slightly increasedbone mass. The blood calcium deficiency is treated with comb-inations of oral calcium and the 1,25(OH)2 form of vitamin D. The symptoms of chronic hypocalcemia include mentallassitude, irritability, depression and even psychosis.
Despite their hypocalcemia, these patients may developcalcification in their lens and basal ganglion of the brain.Hypocalcemia can also result in spotty alopecia and neuro-musculular excitability resulting in hyper-reflexia, stridor dueto laryngeal spasm and seizures.
Pathologic physiology of hypoparathyroidism
Pseudohypopararthyroidism (Seabright Bantum’s Disease) The cause for this disorder is due to a failure of response of thekidney and bone to elevated PTH levels. Because the renal tubuleis unable to activate vitamin D there is a lack of absorption ofcalcium from the gut. The resultant hypocalcemia stimulatesthe increased output of PTH from hyperplastic parathyroidglands. Because the blood calcium and phosphorous levelsare the same as in hypoparathyroidism, the signs and symptomsare the same. An additional finding in pseuohypoparathroidismincludes a variant of multiple epiphyseal dysplasia known asAlbright’s hereditary osteodystrophy which includes short stature,obesity, round facies, mental retardation and specific shorteningof the fourth and fifth digits of the hands and feet. In rare cases where the bone responds to the elevated PTH wehave a condition known as pseudohypohyperparathyroidism.
Pseudohypoparathyroidism Case #1 40 year old male with short stature, round face and mental retardation Blood chemistries included a low calcium, high phosphorous and high PTH
Short metatarsals & metacarpalsShort lateral digits
Calcified basal ganglion
Case #2 Pseudohypoparathyroidism 18 yr female with short stature, round face and calcificationin basal ganglion plus a low serum calcium & high phosphorous
Shorting of the ulnar digits of the hand
Shortening of the fibular digits of the feet
Rachitic Syndromes & Renal Osteodystrophy Nutritional - deficiency rickets Renal tubular syndromes Vit D resistant rickets (prox tubule) Vit D resistant (prox and distal tubule) Vit D resistant (renal tubular acidosis) Renal failure rickets (renal osteodystrophy) Vit D dependent (pseudodeficiency rickets) Hypophosphatasia
Vitamin D metabolism In order to discuss the rachitic syndromes one needs to under-stand the metabolism of vitamin D by referring to the followingschematic. The major source of crude inactive vit D is from theupper two thirds of the GI tract. The second and least commonsource is from the skin which is activated by UV light. Both ofthese inactive forms then travel to the liver where a partialactivation occurs by a hydroxylation process on the 25 positionof the sterol ring. The final activation occurs in the kidney withthe help of PTH by a hydroxylation process on the 1 position ofthe sterol ring to form the active form of vit D known as 1-25dihydroxycholecalciferol. This final renal activation is regulatedby the serum calcium and phosphorous level which must be lowat the time in order to activate the needed PTH stimulus. If theserum calcium and phosphorous level is high, then the PTHlevel drops and instead we see an activation of calcitonin (CT)
which switches the second hydroxylation to the 24 positionwhich results in an inactive form of vit D thus decreasing thetransfer of calcium to the blood from the gut, bone and renaltubule. Notice that despite the increased absorption of P2from the gut and bone with increased PTH and 1,25 D-3activation, the resultant P2 blood level will be down becauseof the dominating loss if P2 at the renal tubular level. From all this discussion it becomes apparent that 1,25dihydroxycholecalciforal is acting as a hormonal regulatorof calcium and phosphorous metabolism along with PTH andcalcitonin.
Nutritional - Deficiency Rickets The following Ciba schematic helps to understand the patho-physiology of the pediatric nutritional or intestinal deficiencyrickets and the adult osteomalacia. The classic form of ricketsis due to the lack of sunshine and vit D intake. Other deficiencydisorders include liver damage or bile duct stenosis: dilantinmedication which blocks the formation of 25(OH)3; lack ofdigestive enzymes and bile; high intake of P2, phytate oroxalate; gastectomy patients; intestinal sprue (malabsorptiondiseases); and patients on steroids will block calcium absorptionat the gut level. Pregnancy and lactation can cause a calciumdeficiency. The result of all these conditions results in a decreased calciumlevel which then stimulates the production of PTH by theparathryroid chief cells. The PTH then helps to reabsorb calciumfrom the renal tubule and at the same time cause a loss of P2
from the blood into the glomerular filtrate. The PTH thenactivates the formation of 1,25 D3 in the kidney which thencauses the gut to absorb Ca and P2 from the gut. At the bonelevel we see the activation of dormant bone cells to becomeactive osteoclasts that digest bone mineral to mobilize Caand P2 into the blood stream. As the result of bone destructionthere is a responsive osteoblastic healing process that causesan increase of alkaline phosphatase in the blood serum. The clinical manifestations of rickets include short stature,frontal bossing, dental defects, chest deformities, enlarged endsof long bones and bowing of the lower extremities. Radiographicfindings include widening and a fuzzy appearing growthplate next to a widened and cupped metaphysis. In adultosteomalacia we find symptoms of generalized bone painand muscle weakness. Bowing of the lower extremities is seenalong with x-ray evidence of cortical thinning and multiplestress fractures thru Looser’s zones (Milkman’s syndrome)
seen in the medial aspect of weight baring long bonemetaphyses. Treatment consists of a correction of the nutritional defectthat caused the disease.
Nutritional - deficiencyrickets & osteomalacia
Case #1 Vit D deficient rickets One year old with bowing of the lower extremities
More knee x-rays
Case #2 Terminal rickets Epiphyseal bone XMacro section and radiology of autopsy specimen Microscopic growth plate
Chest deformityRachitic rosery nodularity at costochondral junctures
Case #3 Rickets at the wristRachitic swelling at the wristssecond to metaphyseal flaring
Case #4 Intestinal rickets 6 month old with congenital bile duct atresia
Case #5 Deficiency rickets4 year old rachiticchild with knock-knee deformity
Case #6 Healing rickets 2 yr male with epiphyseal rings second to treated rickets
Case #7 Jan 6 Feb 2Adult IntestinalOsteomalacia49 yr female withsevere obesity andgastric bypass 2 yrago and now recentgradual onset ofpain in leg withouttrauma
Isotope bone scan
Cor T-1 T-2 GadIncreased alkaline phosphatase and PTH levels
Sag T-1 T-2
Case #7 Physiologic bowing (pseudorickets) 2 year old male with physiologic bowing of the lower extremities that looks like rickets
Case #7 Jansen’s disease (pseudorickets) 3 yr male with bowing of lower extremities and wide plates
Vitamin D Resistant Rickets & Osteomalacia Second To Proximal Renal Tubular Defects (Hypophosphatemic Rickets) By far the most common form of rickets or adult osteomalcia inthe USA is the proximal renal tubular defect condition knownas hypophosphatemic vitamin D resistant rickets (phosphatediabetes). This condition is transmitted as a sex-linked dominanttrait seen more common in males. There is an oncogenic form ofhypophosphatemic rickets that is induced by certain low gradesoft & bone tumors. The defective proximal renal tubule is unableto reabsorb P2 from the glomerular tubular filtrate resulting insevere hypophosphatemia. The serum calcium and PTH levelsare usually normal but at times the calcium is slightly depressed,resulting in an elevated PTH with resultant loss of bone mineraland resultant increased alkaline phosphatase activity. In moresevere cases there can be a loss of glucose and even amino acids(proximal Fanconi syndrome).
The clinical picture and radiologic findings are like those ofnutritional rickets except the renal forms do not respond tonormal intake of vitamin D. The treatment consists of an in-creased intake of P2 and vitamin D.
Vitamin D ResistantRickets & osteomalciaSecond to Proximal RenalTubular Defects(HypophosphatemicRickets)
Case #1 X-linked Hypophosphatemic Rickets 10 year happy female with short stature and bowed legs
Case #2 X-linked Hypophosphatemic Rickets 7 year male from a family of short stature and bowed lower extremities
Tibial bowing with mild growth plate changes
Case #3 X-linked hypophosphatemic Osteomalacia54 yr 5’2” male with low serum P and life time of universal bone pain
He had a subtotal parathyroid resection for high PTH levels
Case #4 Hypophosphatemic Osteomalcia 26 yr female with short stature and bowed lower extremities since childhood Looser’s zone or stress Fracture in bowed femur
Microscopic picture ofosteomalcia showingthickened and poorlymineralized osteoid seams
Case 5 Hypophosphatemic osteomalacia25 yr male with recent onset ofpain in the feet and proximalright tibia with x-ray evidenceof multiple Looser’s zones
Photomicrographs ofosteomalacic bone withthickened poorly calcifiedosteoid seams
Case #6 Non Familial Hypophosphatemic Osteomalacia
Stress fractures of foot and tibia
Vitamin D Resistant Rickets & Osteomalcia second To Proximal & distal Tubular Defects (Fanconi syndrome) This form of vitamin D resistant rickets includes a defect inboth the proximal and distal renal tubules resulting in a loss ofcalcium, P2, glucose, amino acids, protein, water, fixed base, (Na& K) and bicarbinate (hyperchloremic acidosis). The calcium losscauses secondary hyperparathyroidism which along withacidosis results in a severe form of rickets or osteomalcia withLooser’s zones and cystic brown tumors seen on x-ray. Theserum P2 is very low. The low K can result in severe muscleweakness. The serum vitamin D levels are normal. The Lignac-Fanconi syndrome is a rare variant that includes ageneralized cystine metabolic disorder with resultant depositsof cystine crystals in the macrophages of the liver, spleen, bonemarrow and lymph nodes. Cystine crystals are seen in thecornea of the eye.
Other variants including oculocerebrorenal syndrome(Lowe’s disease) and superglycine syndrome all have a poorprognosis because of severe renal tubular defects.
Vitamin D resistantRickets & Osteo-malcia Second toProximal & DistalTubular Defects(Fanconi syndrome)
Case #1 Fatal case of Fanconi’s Syndrome X-ray MacrosectionAutopsy specimen of the upper femur in a young child who died of severe renal disease with advanced hyperparathyroidism
Vitamin D Resistant Rickets & Osteomalacia 2nd to Renal Tubular Acidosis This is another severe form of renal tubular rickets involvingthe entire tubule. This can be genetic in origin or can result fromacquired pyelonephritis or heavy metal poisoning. There is arenal tubular loss of calcium, P2, Na, K, water and bicarbinateresulting in hyperchloremic acidosis. The calcium loss resultsin secondary hyperparathroidism which along with acidosis,results in severe rickets or osteomalacia with associated X-rayevidence of stress fractures and cystic brown tumors of hyper-parathyroidism. The hypokalemia results in severe muscle weak-ness. The excessive loss of calcium in the kidney can result innephrocalcinosis. All of these metabolic problems can result ina poor prognosis for survival.
Vitamin D Resistant Rickets & Osteomalcia Renal Tubular Acidosis
Vitamin D Dependent (pseudodefciency) Rickets & Osteomalacia This rare form of rickets is usually inherited and has the sameclinical, radiographic findings and chemistries as vitamindeficient rickets but is not cured with a normal intake ofvitamin D in the diet. The primary cause for this conditionis due to either a renal failure to convert 25(OH)2D to 1,25(OH)2Dor a failure of the gut to respond to 1,25(OH)2D both of whichresult in hypocalcemia and secondary hyperparathyroidismwhich then results in hypophosphatemia and osteoclasticresorption of bone with its osteomalacic appearance on x-ray(bowing, cytic changes and Looser’s zones) with a responsiveelevation of serum alkaline phosphatase. This conditionresponds well to treatment with 1,25(OH)2D.
Vitamin D Dependent(pseudodeficiency) Rickets& Osteomalcia
Renal Failure Rickets & Osteomalacia (Renal Osteodystrophy) All the previous types of renal rickets resulted from a defectin the renal tubule, whereas in renal failure rickets or its adultosteomalacic form results from a complete failure of the entirenephron including the tubule and glomerulus. Glomerulartubular nephritis is a common cause of chronic renal failure. Thekidney’s failure to produce 1,25(OH)2D3 results in hypocalcemiawhich then results in secondary hyperparathroidism whichalong with renal tubular acidosis causes severe osteolysis withresultant osteitis fibrosa cystica, brown tumors, pseudofracturesand slipped proximal femoral epiphyses. Compared to mostforms of renal rickets which have hypophosphatemia, in renalosteodystrophy we have hyperphosphatemia second to thedamaged glomerulus. The high serum P2 results in a highCa - P2 product which causes calcification of vessels, depositionof calcium about joints (tumoral calcinosis) and nephrocalcinosis. Treatment consists of oral aluminum hydroxide to absorb P2
in the gut, 1,25(OH)2D3 to restore serum calcium, subtotalparathroidectomy to reduce PTH levels and the ultimatereplacement of the damaged kidney.
Renal failure Rickets(Renal Osteodystrophy)
Case #1 Renal Osteodystrophy 13 yr female with past history of glomular tubular nephritis &now shows deformities of extremities with hyperphosphatemia
X-ray evidence of bowed long bonesof forearm and wide fuzzy growthplates of distal radius and ulna
Slipped prox femoral epiphysis iscommon in renal failure ricketsalong with bowing of the femur
Osteitis fibrosa cystica with active cutting coneOsteolysis at the outer end of clavicle
Case #2 Renal Osteodystrophy 10 year old female with chronic renal failure 2nd to myelomeningocele and paraplegia with multiple pathologic fractures
Case #3 Terminal Renal Osteodystrophy Female child died of severe renal failure rickets and 2ndary hyperparathyroidism with path fracture distal femur and rachitic rosary and subperiosteal osteolysis of ribs
Case #4 Terminal Renal OsteodystrophyAutopsy x-ray specimen of achild with wide growth platesand severe metaphyseal endplate osteolysis from severesecondary hyperparathyroidism
Autopsy macrosection prox femur Cutting cone of 2ndary hyperparathytoidismWide and weakened growth platemade up of excessive hypertrophiccartilage and no zone of provisionalcalcification or osteoid
Case #5 Renal Osteodystrophy Juxtra articular and vascular calcification in adult
Case #6 Renal Osteodystrophy with Brown Tumor 63 yr male with renal failure rickets and brown tumor of tibia resulting from secondary hyperparathyroidism
T-1 MRI T-2Hemorrhagic cysts seen in T-2 image of brown tumor
Hypophosphatasia Hypophosphatasia is a rare rachitic like syndrome that isinherited as either an autonomic recessive or dominant trait.It results from a deficient alkaline phosphatase which isrequired to allow for normal minineralization of young osteoidrecently formed off a growth plate or on a trabecular bone surface.Pyrophosphate in newly formed osteoid inhibits calciumdeposition thus creating an excess of calcium in the serum andurine that can result in nephrocalcinosis, renal failure and death.The normal role of alkaline phosphatase is to remove pyro-phosphate from young osteoid so as to allow for normal mineral-ization. In hypophosphatasia, serum pyrophosphate, phospho-ethanolamine and phosphoserine are excreted by the kidney.Serum P2 is normal compared to the changes seen in all otherforms of rickets. The clinical picture and x-ray abnormalities ofbone is the same as in other more common forms of ricketsexcept for cranial stenosis that can result in an elevated
intracranial pressure. The autosomal recessive pediatric formshave a worse prognosis compared to the adult autosomaldominant forms.
Case #1 HypophosphatasiaInfant female with short statureand rachitic deformities of theextremitiesHigh serum calcium with normalP2 and no alkaline phosphatase
Rib macrosection X microscopic image XMacro and microscopic changes at rib growth plate
HyperphosphatasiaJuvenile Paget’s Disease2 year old female withShort stature bowedextremities with osteopenicbones and heart shapedpelvis similar to ricketsDeformed bell shaped ribcage with osteopenia likericketsAll chemistries normalexcept for elevated alkalinephosphatase
Scurvy Scurvy is a well know nutritional disorder second to a lack ofvitamin C (ascorbic acid) which is necessary for the productionof collagen fiber, osteoid, dentine and intercellular cementsubstance in the vascular endothelium. Vitamin C acts as acatalyst for the hydroylation of proline to hydroxyproline in thesynthesis of collagen of bone and soft tissue structures. Theclinical end result is osteoporosis and ligamentous weakness.The intercellular cement substance deficiency results in increasedcapillary fragility with ecchymoses, bleeding gums, hemorrhagicperiostitis and painful hemarthoses. The painful hemorrhagicperiostitis can produce radiographic changes similar to thoseseen in congenital lues, Caffey’s disease, leukemia and hyper-vitaminosis A. Enlargement of the costochondral rib juncturescan result in a scorbutic rosary similar to that seen in rickets.The classic radiographic changes seen in a scorbutic growth plateinclude a dense white band across the distal end of the
metaphyseal face that represents excessive calification in thezone of provisional calcification known as Frankel’s white line.At the peripheral edge of the physeal line one may see the so-called Pelkan’s spur which is second to callous formationresulting from repeated stress fracture thru the osteopenicbone on the metaphyseal side of the physis. A thin white linecan be seen around the epiphyseal ossification center whichis known as Wimberger’s ring which is second to the excessivecalcification in the zone of provisional calcification as we seein Frankel’s line. On the metaphyseal side of Frankel’s line onewill see a radiolucent band second to a deficiency of osteoidformation and is an area thru which pathologic fracturescan be seen. This same radiolucent band can be seen inleukemia patients. The diaphyseal bones have a osteopeniclook with a ground glass appearance with thin cortices secondto a bone volume deficiency.
Case #1 Scurvy Osteoid deficient Radiolucent zone Frankel’s line 8 mo female with scurvy comparing radiographic and pathologic findings
Case #2 Hemorrhagic Periostitis in Scurvy periostium cortex 15 mo female with severe thigh pain from scurvy
Case #3 Slipped epiphyses in Scurvy 1 year old child with multiple slipped epiphyses second to scurvy
Case #3 Scorbutic Rosary1 year old child withwidened costochondralrib junctures as inrickets
Gaucher’s Disease Gaucher’s disease is the more common of a group of familialdiseases in which there is a metabolic disturbance of lipidmetabolism resulting in an abnormal accumulation of sphingo-lipids in the macrophage system of organs such as the liver,spleen and bone marrow. Along with Gaucher’s disease, theother spingolipidoses include Tay-Sachs disease, Niemann-Pick’s disease, metachromatic leukodystrophy and Fabry’s diseasemany of which are found in Jewish families. The specific sphingo-lipid found in Gauchers disease is kerasin found in the foamycytoplasm of large foam cells found on bone marrow biopsyknown as Gaucher cells. There are two clinical forms of Gaucher’s disease. The infantileform is the least common and die early from acute neurologicmanifestations. The more common chronic adult form is oftentimes asymptomatic until early adult life when they are foundwith a large liver and spleen and perhaps a pathologic fracture
or collapse of a femoral head second to weakened bone fromfoam cell infiltration. Generalized bone marrow replacementand hypersplenism can result in anemia, thrombocytopeniaand leukopenia that increases the chance for post op infectionin these patients. The most common bone deformity inGaucher’s disease include flatening of the proximal femoralepiphysis producing a Perthes’ like syndrome, a widened distalfemoral metaphysis producing an Erlenmeyer flask deformitylike fibrous dysplasia, flatened vertebral bodies and similarchanges seen in the tibia and skull. Currently, these lipid storage disorders can be treated withthe specific deficient enzymes that are required to catabolizethe excessive sphingolipids. Cerezyme is the specific enzymeused for Gaucher’s disease at a cost of $200,000 per year.
Case #1 Gaucher’s Disease29 yr male with pathologic fracture femur and family history of Gaucher’s disease
R L LX-ray both humeri and L elbow with prior fracture R humerus
Case #2 Gaucher’s Disease9 yr male with a Perthes likecollapse of the right femoral headand an Erlenmeyer flask deformityof the distal femori second toGaucher’s disease
Case #3 Gaucher’s Disease17 year male with path fracture right humerus & Gaucher’s
Case #4 Gaucher’s Disease 45 yr male with Gaucher’s of the long bones
Case #5 Gaucher’s Disease 55 yr male with Gaucher’s of humerus, femur and tibia
Gaucher’s Disease Epiphyseal lesions looking like GCT
Gout & Pseudo Gout
Gout Gout is a well known clinical condition resulting from hyperuricemia due to a purine metabolic disorder with an overproduction of uric acid or a decrease in renal excretion of uricacid which is usually familial but more common in older malesthen females. The hyperuricemia is present early in life but theclinical symptoms related to the deposition of Na urate crystalsin and around joints does not occur until the fifth decade. Themost common location for gouty arthritis is the great toe MP jointfollowed by the intertarsal joints, ankle and knees. The diagnosiscan be made by viewing the needle shaped Na urate crystalsin synovial fluid which show strong negative birefringence underpolarized light. The typical radiographic finding is that of juxta-articular bony erosion with minimal evidence of chondrolysiseven though urate deposits can be seen on the joint surface witharthroscopic viewing. 50-60% of gout patients will developtophi consisting of visible deposits of chalky white Na urate in
synovial linings and other juxta-articular soft tissues which cango on to calcify similar to patients with tumoral calcinosissecond to renal failure. Tophi are common in the ear pinna andin bursae about the elbow, knee, hand and foot. There are many medical conditions that can result in hyperuricemia such as myeloproliferative disorders, bone marrowneoplasms, and inflammatory renal disease. However, theclinical diagnosis of gout can only be made with the discoveryof Na urate crystals in synovial fluid or juxta-articular tissue.medical treatment includes symptomatic relief with colchicine,Anti inflammatory agents or allopurinol which blocks theformation of Na urate at the cellular level.
Case #1 Tophaceous Gout45 yr male with painful lump medial 1st MP joint foot 2 yrs
Case #2 Tophaceous Gout Foot Early disease age 40 Older disease age 65
Case #3 Tophaceous Gout Hand Late changes Early changes
Case #4 Gouty Changes in Hand 58 yr male with advanced gouty changes in hand with macro section of metacarpal head with early subchondral gouty granuloma
Case #5 Tophaceous Gout of Hand with Amputation Two advanced cases of tophaceous gout with secondary infection of ulcerating tophi resulting in amputation
Case #6 Tophaceous gout synovial sarcoma pseudotumor 51 year male with tender prepatellar lump for three years
Axial T-1 T-2 Gad
Sag T-1 T-2 Gad
Case #7 Gouty Arthritis of Ankle Sag T-1 Cor T-2 80 year old female with large subchondral gouty granulomas
Case #8 Soft Tissue Changes in Gout Olecranon Bursa Ear Pinna Deposits Cutaneous deposits Photomicrograph
Pseudo GoutCalcium Pyrophosphate Dihydrate Crystal Deposition Disease (CPPD) - Chondrocalcinosis Pseudo gout is a clinical condition that presents in mid andolder aged patients with painful arthritic pains similar to patientswith true gouty arthritis. In both conditions, the inflammatorysynovitis is induced by an irritating crystal which in the case ofgout is the Na urate crystal and in the case of pseudo gout it iscalcium pyrophosphate. In the Pseudo gout patients the mostcommonly involved joint is the knee which on radiographicexam will show evidence of chondrocalcinosis of the joint surfaceand menisci. Calcium pyprophosphate crystals must be foundin the synovial fluid and confirmed with polarized light micro-scopy with a weakly positive birefingence compared to thestrongly negative birefringence seen with the Na urate crystalsof gout. Many cases of chondrocalcinosis second to CPPD disease
will have no painful pseudo gout symptoms but those that dohave painful synovitis will experience destructive chondrolysisinduced by proteolytic enzymes produced by the inflammatorysynovitis. The most common cause for CPPD depositiondisease is degenerative osteoarthritis but can also be seen indiabetic patients, hyperparathyroidism, hemochromatosis,Wilson’s disease, neuropathic arthropathy, ochronosis, andeven true gout patients can have CPPD crystal depositiondisease.
Pseudo Gout - Chondrocalcinosis62 year old male with painfulsynovitis of knee and x-rayevidence of chondrocalcinosis
Common Crystal Origin of Gout and Pseudo Gout
Alkaptonuria - Ochronosis Alkaptonuria is a rare autosomal recessive hereditarymetabolic disorder created by an absence of homogentistic acidoxidase which is required for the normal catabolism of phenyl-alanine and tyrosine. As a result, excessive homogentistic acid inurine becomes oxidized to a melanin-like product that turns theurine dark. In the third decade the dark pigmented form ofhomogentistic acid will appear in various mesenchymalstructures such as the intervertebral disc space, articular cartilage,laryngeal, trachial, bronchial and rib cartilage, eye sclera andcornea, heart valves, prostate gland and kidneys. The articularcartilage deposition over time leads to early chondromalacia andchondrocalcinosis. The pigmented chondromalacic articularcartilage flakes off the joint surface and is picked up by thesynovial lining producing a secondary pigmented synovialchondromatosis. In the intervertebral disc space one sees earlycalcification of the pigmented disc material with resultant loss ofdisc height and hypertrophic spur formation.
Case #1 Ochronosis Knee62 yr male with ochronosis resulting in TKA
2ndary Synovial Osteochondromatosis in Ochronos Macrosection knee Synovial microscopic
Case #2 Ochronosis HipAutopsy specimen Microscopic joint surface chondromalcia
Case #3 Spinal Ochronosis X-ray and autopsy specimen of ochronosis of spine
Case #4 Spinal Ochronosis71 year male with spinal ochronosis with autopsy specimen
Case #5 Facial changes with Alkaptonuria 54 year old maleDark pigmentation in the ears, nose and sclera of the eye
Osteoporosis Osteoporosis is a condition of bone resulting from anabnormal decrease in total bone volume taking in a consider-ation of normal variation second to body size, age, sex andgenetic background. In contrast, osteomalcia is a specific lossof the mineral component of bone second to a metabolicdisturbance affecting the normal remodeling process which iflasts over a long period of time will lead to an osteoporoticstate of total bone volume deficiency. The loss of bone volumein osteoporosis is not homogenous throughout the entireskeletal system and usually starts in the less radiodense areasof cancellous trabecular bone with a large surface area locatedin the meta-epiphyseal areas at the ends of long bones andin vertebral bodies. As the condition becomes more chronicwith age one will see loss of bone volume in dense corticalbone. The disabling problem with more advanced symptomaticosteoporosis is pathologic fracture of the spine associated with
kyphotic axial shortening and fractures of the proximal femurand distal radius. There are a multitude of conditions anddisease states that can lead to osteoporosis as listed in thefollowing slide Cibagram. Disuse osteoporosis is a common problem in any age orsex group which can be generalized as in any illness thatforces inactivity or can be localized as in the case of a fracturethat requires a cast fixation. Paralytic conditions such as para-plegia will cause osteoporosis in the lower extremities thatbecome inactive. Astronauts in a weightless environment runa risk of loosing bone volume from lack of gravitational pull. Nutritional osteoporosis which may start out as osteo-malacia can result from a lack of calcium, vitamin C and D andprotein. Alcoholism is frequently associated with poornutrition. Drug related osteoporosis can be seen in patients on
heparin, methotrexate and glucocorticoids. Familial or congenital forms of osteoporosis arecommon in patients with genetic defects that regulate thesynthesis of collagen fiber including osteogenesis inperfecta,Marfan’s disease, epiphyseal and spondyloepiphysealdysplasias and in mucopolysacharidosis patients. Chronic illness such as rheumatoid arthritis, hepatitis,nephritis, and myelogenous sarcomas such as myeloma,leukemia and lymphomas can cause generalized osteoporosis. Endocrine disorders associated with osteoporosis includepituitary adenomas, adrenal cortical hyperplasia or adenoma,ovarian deficiency such as post menopausal osteoporosis,testicular deficiency from disease or aging, and over activethyroid and parathyroid conditions. Treatment of osteoporosis depends on the cause of bone losswhich can be extremely varied as seen above. However, in the
case of type I post menopausal osteoporosis the therapeuticfocus is on prevention including increased physical activity,nutritional supplements of vitamin D and calcium, earlyreplacement estrogen therapy in high risk cases with a strongfamilial background, and diphosphonate therapy for thosepatients with abnormal bone mineral densitometry findings ofthe spine and hip areas.
Causes of Osteoporosis
Advanced Spinal Osteoporosis disc75 year female with multiple biconcave codfish vertebrae
Spinal Osteoporosis vs Metastatic CA 80 yr female with 64 yr female withOsteoporotic collapse Metastatic CA collapse
Sacral Osteoporotic Stress Fracture71 year old female with LBP for 4 weeks
T-1 MRI study to ruleout metastatic disease
Axial CT scan Isotope bone scanThe CT scan clearly shows thesymmetric stress fracture lineswith a bridge across at S-2The isotope scan shows the diagnostic Honda sign
20 yr Normal Vertebral Body Aging 56 yrCoronal CT scans of normalvertebral bodies at early,middle and late adulthood autopsy specimens 80 yr
30 yr Normal Vertebral Body Aging 50 yrAxial CT scans thru vertebralbodies in normal young and mid aged adults - autopsy
Normal Femoral Cortex Aging I - Axial CT scan of normal femoral cortex in 20 yr old II - age 40 yr with early sub- endosteal loss of boneIII - 60 yr old with progressive lateral porotic changesIV - 80 yr old with only 2 mm of cortical bone remaining l
Histology of Cortical Osteoporosis Advanced OsteoporosisModerate Osteoporosis
Histology of Osteoporosis vs Osteomalacia OsteomalciaAdvanced Osteoporosis Von Kossa stain
Hyperadrenalism of Bone (Cushing’s Syndrome) 42 yr male with low turnover osteoporosis from anadrenal cortical adenoma resulting in stress fractures
Thyroid Disorders Thyroid deficiency in infants and young children results incretinism associated with mental retardation, retarded growth,lethargy, abdominal distention, enlarged and protruding tongue,hypotonic, dry hair and skin and delayed dentition. Radio-graphic features of cretin bones include retarded and irregularmaturation of ossification centers and delayed closure of growthplates and cranial suture lines. One may find transverse scleroticmetaphyseal bands in tubular hand bones second to a deficiencyof osteoclastic remodeling similar to that seen in osteopetrosispatients and in patients with phosphorous, arsenic, lead, orfluoride toxicity. Hypothyroidism in older children and adultscan result in soft tissue myxedema. Hyperthyroidism or thyrotoxicosis is seen in adult patientswith toxic diffuse goiter (Graves’ disease) and toxic nodular goiterproduced by a single thyroid adenoma. Symptoms includefatigue, nervousness, increased sweating, weight loss, diarrhea
and tachycardia. Bony abnormalities seen on x-ray includeosteoporsis and can be seen in patients who take thyroxineover a long period of time to control obesity.
Case #1 Cretinism 8 year old female with mental retardation and dwarfism second to retarded epiphyseal maturation in cretinism
Hand Cretinism 8 yr oldX-ray of hand showingretarded epiphysealossification and scleroticmetaphyseal bands
Teen-age Hypothyroidism12.5 yr male at time of firstdiagnosis of hypothyroidismwith delayed closure ofgrowth plates & osteoporosisOne year later after treatmentwith thyroxine with rapidclosure of growth plates andreturn of normal bonedensity
Paget’s Disease(Osteitis Deformans)
Paget’s Disease (osteitis deformans) Paget’s disease is seen in 3% of middle aged humans but in10% in the ninth decade. It is rare under forty years and morecommon in males in colder climates such as England, USA, NewZealand and Australia. Paget’s is not really a metabolic diseasebecause of its patchy involvement but has features similar tohyperparathyroidism. The early phase of the disease results fromincreased osteoclastic activity and bone resorption followed by acoupling osteoblastic response with increased alkaline phos-phatase found in the blood serum. Hydroxyproline will be foundin the urine as a result of increased bone break down. Inflam-matory hyperemia and bone pain is associated with the earlyosteolysis. The etiology of this condition still remains unknownbut in some cases, intranuclear inclusions have been found in thepagetic osteoclasts suggesting a slow viral infectious etiology. Themost common form of Paget’s disease is the monostotic form inolder patients. However, the more aggressive symptomatic form
is a painful polyostotic disease involving the skull, spine, pelvisand lower extremities. The cranial involvement can causecranial nerve entrapment resulting in visual and hearingproblems. Bowing of the lower extremities with increasedwarmth and tenderness results from early inflammatoryosteolysis. Later complications result from transverse pathologicfractures, early degenerative osteoarthritis, and pagetic sarcomasseen in less than 1% of patients. Paget’s presents as a focal osteolytic process that looks morelike a lytic tumor such as a hemangioma, giant cell tumor,metastatic tumor or a myelogenous sarcoma. As the healingosteoblastic phase appears we see extensive reparative osteo-blastic activity with patchy sclerotic changes and an increasedcourse stress line oriented trabecular pattern as the bonebecomes enlarged and deformed. Treatment is only required for the more aggressive earlysymptomatic phase of the disease which is focused on inhibiting
early osteoclastic activity. The two agents that inhibit osteoclasticactivity include human calcitonin for the more severe cases anddiphosphonates for the less severe cases. Care must be exercisedwhen using these agents for more than six months for fear ofcreating a remodeling deficiency osteomalacia that can increasethe incidence of pathologic fracture. For a discussion of pagetic sarcomas, refer to Vol #3 underosteosarcoma variants.
Case #1 Paget’s of Femur 68 year female with Paget’s of femur with pain
MRI Study of Paget’sCor T-1 Sag T-1
Gross and microscopic changessimilar to hyperparathyroidismwith increased osteoclastic andosteoblastic activity along witha reversal line mosaic pattern
Late changes in Paget’s with Stress FracturesCase #2 68 year old male with multiple stress fracture lines in lateral femoral cortex with macroscopic specimen
Case #3 Path Fracture Femur in Paget’s 59 yr male Paget’s patient with transverse femur fracture treated with IM nail
Case #4 Early vs Late Changes in Paget’s54 yr male with early lytic changes L compared to late changesR with multiple convex cortical stress fracture lines 15 yrs later
Case #5 Early Paget’s of Pelvis 32 year male with early pelvic deformity from Paget’s
Case #6 Late Paget’s of Pelvis 70 year old patient with late burned out pelvic changes
Case #7 Early vs Late Paget’s of Skull Blastic phase 20 yrs later 40 yr female with early lytic phase Paget’s with a headache known as osteoporosis circumscripta
Case 8 & 9 Early vs Intermediate Paget’s Skulls 48 yr male with moderate blastic response to Paget’s of the skull41 yr male with early lyticphase Paget’s of skullosteoporosis circumscripta
Case #10 Paget’s Lumbar Spine CT scan51 year old male with earlyPaget’s L-5 and CT scanlooking like hemangioma After diphosphonate therapy
Case #10.1 Early Paget’s of L-2 49 yr old male with LBP for 6 months
Sag STIR Gad
Case #11 & 12 Asymptomatic Paget’s 68 yr male with monostotic 60 yr male with C-2 & Paget’s of os calcis C-4 incidental Paget’s
Pituitary Disorders Pituitary gigantism is usually the result of an adenoma ofthe anterior portion of the pituitary gland which becomes activeduring the growing years of a child that results in over growthof the entire musculoskeletal system which by age 16 yearsproduces a seven to eight foot giant with strong muscles and longstrong bones. This form of gigantism is easily separated from aeunuchoid giant with testosterone insufficiency because theeunuch’s seven to eight foot height is not reached until theearly twenties as the result of delayed growth plate closure.Eunuchs also have weak muscles and long frail bones. Aspituitary giants get older their pituitary glands atrophy withassociated adrenal insufficiency leading to physical weakness,osteoporosis and decreased resistance to infections that leads toan early demise. Acromegaly is usually the result of a pituitary adenoma that
doesn’t become active until after the normal closure of thegrowth plates. The clinical manifestations include a bull dogface with a protruding jaw plus abnormal thickness of arms andlegs with soft tissue hypertrophy of enlarged hands and feet.The skull x-rays will show an enlarged sell tursica from enlarge-ment of the pituitary gland and one will notice a hyperostosisfrontalis interna along with a prominent external occipitalprotuberance. Hand x-rays will show early hypertrophic osteo-arthritis of the IP joints along with prominent tufts of the distalphalanges.
Acromegaly Skull and Face45 year male with a pituitary adenoma in enlarged sella tursicaa Dick Tracy jaw, hyperostosis frontalis interna & large sinuses
Acromegaly Hand and Foot Prominent tufts on distalphalanges with early distal IPjoints OA & soft tissue hypertrophy Thick heal pads
Hypogonadism (eunuchoid giant)21 yr testosterone deficient7 foot tall male with longfingers and persistent growthbecause of open growth plates
Hypervitaminosis DThis young child was given a largeamount of vitamin D resulting indense bone in calvarium similar tothat of osteopetrosisDense sclerotic bands seen inmetaphyses similar to cretinismand phosphorous poisoning
Hypervitaminosis AComparison of subperiosteal seroma of long bone in a cat vs human with macrosection of cat specimen
Soft Tissue Cholesteotomas Second to Hypercholesterolemia45 yr female with familialhypercholesterolemia andsecondary cholesteotomasHand specimen with microevidence of cholesteral cleft
Cholesteotomas of KneesSame case with subQ lesions of both knees
Bilateral Heel Cord Cholesteotomas Surgical result from resection of both heel cords
Phosphorous Toxicity Lines12 yr male with multiple growth arrest lines second to repeated ingestion of phosphorous in match heads.