CLINICAL PATHOLOGY CONFERENCE

Transcription

1 CLINICAL PATHOLOGY CONFERENCE DEPARTMENT OF MEDICINE JANUARY 13, 2006 Alex Esana MD

2 Case 43 y/o Caucasian female referred to Endocrinology clinic in July 2005 from Orthopedics for evaluation of recurrent stress fractures. First fractures in 2000-bilateral femur stress fractures requiring an intra- medullary rod on the left

3 Case DEXA in 2000 showed T-score +1.4 at L2- L4 T-score -0.4 at femoral neck Treated with: Fosamax 70 mg weekly for 2 years without follow up studies. Calcium supplements 600 mg (with vitamin D) daily

4 Case Lab work in 2000 revealed: Unremarkable CBC Comprehensive metabolic profile within normal limits with serum calcium=9.8 mg/dl and reduced alkaline phosphatase=8 IU/L [normal ] Normal serum immunoelectrophoresis

5 Case In October 2004, she was stepping over a fence and suffered a right fifth metatarsal stress fracture which was casted. In February 2005, she suffered a traumatic left fifth metatarsal fracture managed with a orthopedic boot. She had mild residual left foot and right femur aching not requiring narcotic analgesia.

6 Past Medical History History of hypothyroidism treated with L-L thyroxine mg daily for 25 years with normal TSH values on therapy Hysterectomy without oophorectomy in 1998 but was not experiencing hot flashes No history of joint laxity or kidney stones She lost her baby teeth at age 4 and had multiple root canals in the past with history of widened pulp spaces

7 Family History No history of osteoporosis No history suggestive of malabsorption or steatorrhea No history of hypercortisolism.

8 Physical Exam Basically unremarkable Normal sclera No bony tenderness No goiter with clinically euthyroid appearance

9 Laboratory Studies Normal serum calcium, 25-hydroxy hydroxy-vitamin D and 1,25-dihydroxy dihydroxy-vitamin D levels Serum phosphorus was 5.2 mg/dl [ mg/dl] PTH level was 15 pg/dl [6-40 pg/dl] 24-hour urine calcium was 228 mg Urine free cortisol was 7 mcg [ mcg] Serum TSH was 1.9 [ ]

10 Further Work-up Repeat DEXA showed: L1-4 4 T-score T was +1.6 (1.4) Right femoral neck T-score T was +0.3 (-( 0.4) A diagnostic study was obtained and a treatment approach was decided.

11 Significant case findings Dexa.multiple fx, with Nl bone density Low Alk Phos, Normal calcium, NL SPEP Hypothyroidism Tx,...? Euthyroid Hysterectomy.Ovaries intact, (Estrogen problem) No family history of osteoporosis (congenital) No history suggestive of malabsorption or steatorrhea No hypercortisolism No joint laxity No history of nephrolithiasis Lost her baby teeth at age 4

12 Regulation of bone cell function Parathyroid hormone The most important regulator of calcium homeostasis Maintains serum calcium concentrations by stimulating bone resorption, increasing renal tubular calcium reabsorption, and increasing renal calcitriol production Stimulates bone formation when given intermittently, but inhibits collagen synthesis at high concentrations Stimulates bone resorption when given (or secreted) continuously, a process mediated by osteoclasts

13 Regulation of bone cell function Calcitriol Increases intestinal calcium and phosphorus absorption, thereby promoting bone mineralization At high concentrations, under conditions of calcium and phosphate deficiency, it also stimulates bone resorption, thereby helping to maintain the supply of these ions to other tissues Stimulates osteoclastogenesis in cell cultures, but animals lacking vitamin D have relatively normal bone growth and remodeling during development

14 Regulation of bone cell function Calcitonin inhibits osteoclasts and therefore bone resorption in pharmacologic doses. However, its physiologic role is minimal in the adult skeleton. Growth hormone and IGFs The GH/IGF-1 1 system and IGF-2 2 are important for skeletal growth, especially growth at the cartilaginous end plates and endochondral bone formation. Glucocorticoids have both stimulatory and inhibitory effects on bone cells. Inhibition of bone formation is the major cause of glucocorticoid-induced induced osteoporosis and may be due to accelerated apoptosis of osteoblasts and osteocytes

15 Bone Remodeling The renewal of bone is responsible for bone strength throughout our life. Old bone is removed (resorption) and new bone is created (formation). During childhood and the beginning of adulthood, bone becomes larger, heavier and denser.

16 Bone Remodeling The Bone Mass increases until the ages of where it reaches its maximum value: the Peak Bone Mass (Maximum Bone Density and Strength). The higher the Peak Bone Mass is, the lower the risk of osteoporosis. Bone Mass remains stable for a few years (for women, till about 45 years old): a perfect equilibrium between bone formation and resorption exists. After a certain age, bone mass starts to decrease. For women, this bone loss starts a few years before menopause and becomes more and more important until death.

17 Bone remodeling Osteoblasts Responsible for bone matrix synthesis Secrete a collagen rich ground substance essential for later mineralization of hydroxyapatite and other crystals Collagen strands to form osteoids: : spiral fibers of bone matrix. Cause calcium salts and phosphorus to precipitate from the blood, Calcium & Phosphorus bond with the newly formed osteoid to mineralize the bone tissue. Contain alkaline phosphatase that is secreted during osteoblastic activity. Have estrogen receptors. Estrogens increase the number of osteoblasts, increasing therefore collagen production.

18 Bone remodeling Osteocytes Osteocytes are osteoblasts that have been trapped in the osteoids produced by surrounding osteoblasts. Function of Osteocytes includes maintain bones, control the extracellular concentration of calcium and phosphate Osteocytes are directly stimulated by calcitonin and inhibited by PTH Their exact role is actually still to be defined.

19 Bone remodeling Osteoclasts OSTEOCLASTS are derive from bone marrow mononuclear cells. Their characteristic feature is a ruffled edge where active resorption takes place. secrete bone-reabsorbing enzymes, which digest bone matrix. The osteoclasts have estrogen receptors Estrogens can inhibit their recruitment.

20 Fracture Risk Bone strength, as estimated indirectly from both bone mineral density and medullary and periosteal diameter of the distal radius, may be a useful predictor of fracture risk. Low serum levels of RANKL (receptor activator of nuclear factor kb ligand; an essential factor for osteoclast, and possibly osteoblast activation) Aortic calcification on CT scan (a marker of atherosclerosis. A previous history of breast cancer (independent of estrogen deficiency)

21 Fracture Risk In spite of being a source of caffeine, tea may have a beneficial effect on bone density. Habitual tea consumption for 10 or more years has been associated with higher bone density. A possible explanation for this observation is that tea contains both flouride and phytoestrogens.

22 Other Aspects of Fracture Risk Previous fracture between the ages of 20 and 50 year History of fracture in a first degree relative Cigarette smoking (men and women) Inflammatory bowel disease Celiac disease (osteopenia in one-third of asymptomatic adults) Cystic fibrosis Previous hyperthyroidism Sedentary life style Consumption of large amounts of caffeine Anxiolytic, anticonvulsant, or neuroleptic drugs Low body weight or weight loss Above average height Type 2 diabetes mellitus

23 Differential Diagnosis Primary Osteoporosis Secondary Osteoporosis Postmenopausal Osteoporosis Juvenile Osteoporosis Drug induced Osteoporosis Hyperthyroidism induced Osteoporosis Rickets/osteomalacia Metabolic bone disease( GI, Pancreatic, hepatobiliary) Vitamin D dependant Rickets Renal Osteodystrophy

24 Differential Diagnosis continued Fanconi Syndrome/Renal Tubular Acidosis Hypophosphatemic syndromes Multiple Myeloma Breast cancer Chronic anemias Mastocytosis Heparin Therapy Pregnancy induced Osteoporosis Osteogenesis Imperfecta

25 Osteoporosis Osteoporosis is the most common bone disease. The estimated cost of osteoporotic fractures in the United States in 1995 was $13.8 billion. Osteoporosis is characterized by low bone mass and micro-architectural loss of bone tissue, leading to enhanced bone fragility and an increase in fracture risk. In practice, one deals mainly with decreased bone density, or osteopenia, without examining bone histology.

26 Osteoporosis WHO has defined normal bone density as a value within one standard deviation of the mean value in young adults of the same sex and race. BMD in any adult that is between 1 and 2.5 standard deviations below the mean is defined as osteopenia, and a value more than 2.5 standard deviations below the mean is defined as osteoporosis. These values are referred to as T-scores. T One standard deviation below the mean at the hip in women is associated with a relative risk of 2.6 for hip fracture One standard deviation below the mean at the femur in women is associated with a relative risk of 2.4 for vertebral fracture.

27 Primary Osteoporosis Defined as the progressive loss of bone with increasing age. Type 1 is related to lack of estrogen and therefore primarily occurs curs in postmenopausal women. It is largely responsible for wrist and vertebral crush fractures. It is estimated that more than 25 percent of all women older than 65 years of age have sustained such a crush fracture. Type 2 or senile osteoporosis is due to progressive loss of bone mass after the age of 35, fractures of the hip, proximal humerus, and pelvis. The prevalence of hip fractures in the United States reaches 15 percent by age 80 and exceeds 25 percent by age 90.

28 Secondary Osteoporosis Results from an underlying medical condition, such as malabsorption, hypogonadism, hyperthyroidism, or multiple myeloma, or to the administration of drugs, primarily corticosteroids. Corticosteroid therapy is the second most common cause of osteoporosis; the cumulative dose correlates with the severity of disease and the fracture incidence, with higher incidence of rib and vertebral fractures. Pathogenesis of glucocorticoid-induced induced osteoporosis is unclear. It most likely involves impaired bone formation, increased bone resorption, and a negative calcium balance.

29 Laboratory tests All standard laboratory values should be normal in the patient with primary osteoporosis. These include measurement of the serum concentrations of calcium, phosphorus, alkaline phosphatase, and parathyroid hormone, tests of thyroid and liver function, and serum and urine protein electrophoresis. If clinically appropriate, tests to assess adreno-cortical function should also be considered.

30 Imaging studies Plain radiography reveal changes in bone density in patients with at least 30 percent loss of bone mass and therefore do not detect early disease. Characteristic changes in vertebral bodies, such as "codfishing" and compression and crush fractures, may also be observed.

31 Imaging studies Bone densitometry Quantitative x-ray x densitometry may be utilized to help determine the fracture risk and the need for therapeutic intervention. A single bone mass measurement has a far greater predictive value for fracture than the presence of any other single risk factor or combination of factors. Candidates for densitometric measurement include menopausal women in whom hormone replacement therapy is being considered, patients with either demonstrable radiographic changes or primary hyperparathyroidism, and those administered glucocorticoid therapy.

32 Osteomalacia A disorder of mineralization of newly formed organic matrix In children, abnormal calcification of matrix results in rickets The requirements for mineralization of newly formed bone include Normal concentrations of calcium and phosphate in blood The presence of alkaline phosphatase and mature bone matrix The absence of excess quantities of inhibitors of mineralization

33 Causes of osteomalacia Vitamin D deficiency Negative calcium balance, hypophosphatemia, and mild hypocalcemia occur in the absence of sufficient quantities of calciterol (1,25 dihydroxycholecalciferol), the active metabolite of vitamin D. Secondary hyperparathyroidism may contribute to the defective mineralization. Malnutrition and intestinal malabsorption are the most common causes of vitamin D deficiency.

34 Causes of osteomalacia Hypophosphatemia Marked hypophosphatemia results in defective mineralization of bone. In addition to vitamin D deficiency, hypophosphatemia leading to osteomalacia occurs with primary renal tubular wasting of phosphate in disorders such as: oncogenic osteomalacia, sporadic and X-linked X hypophosphatemic rickets, Fanconi syndrome.

35 Osteomalacia Clinical findings and diagnosis Major symptom of osteomalacia is diffuse, dull, aching skeletal pain that is worsened by activity. Muscle weakness, usually involving the proximal musculature, is often present Most common radiologic finding is reduced bone density Other abnormalities include Looser's zones or pseudofractures.

36 Osteomalacia Clinical findings and diagnosis The most common abnormalities-not not present in osteoporosis: Hypophosphatemia Elevation in serum alkaline phosphatase Hypophosphatemia with hypocalcemia usually indicates vitamin D deficiency, Isolated hypophosphatemia is most consistent with a renal tubular phosphate wasting syndrome.

37 Hyperparathyroidism Results in osteitis fibrosa cystica, characterized by marrow fibrosis, woven osteoid, expansion of osteoid surfaces, and numerous collections of osteoclasts. The finding of osteopenia alone may be a characteristic radiographic finding in primary hyperparathyroidism. The diagnosis is made by the combination of hypercalcemia and an inappropriately elevated serum parathyroid hormone concentration. The findings are different in patients with secondary hyperparathyroidism due to renal failure. The serum calcium is usually reduced or normal, the serum phosphate is elevated, and serum PTH is markedly increased.

38 Vitamin D deficiency Osteomalacia can occur with an impairment of vitamin D metabolism. Causes of vitamin D deficiency dietary deficiency gastrointestinal disease reduced exposure to sunlight Incidence Gastrectomy 43 percent Celiac sprue 26 percent Intestinal bypass 15 percent Intestinal resection 8 percent Chronic pancreatitis 4 percent Primary biliary cirrhosis 4 percent

39 Intestinal malabsorption Intestinal malabsorption with impaired vitamin D absorption frequently seen with: celiac disease regional enteritis, scleroderma, Whipple's syndrome, intestinal lymphoma, amyloidosis, and blind-loop loop syndrome.

40 Intestinal Malabsorption Diagnosis: Hypoalbuminemia, Increased stool fat, and Characteristic changes on jejunal biopsy Low levels of calcidiol are low or low normal Low levels of calcitriol or inappropriately normal in the face of elevated levels of PTH and hypophosphatemia.

41 Intestinal malabsorption Osteomalacia occurs as a complication of hepatocellular disorders, is infrequent in pancreatic disorders. The increasing life expectancy in patients with cystic fibrosis may lead to a rising incidence of osteomalacia. The major cause osteomalacia in these disorders is malabsorption of vitamin D. Hypoparathyroidism and pseudohypoparathyroidism are associated with low levels of calcitriol.. Rarely, there is associated osteomalacia which responds to calcitriol therapy. Metabolic bone disease, including osteomalacia,, has also been described after gastric bypass surgery for obesity.

42 The Kidney Chronic renal failure Bone disease in renal insufficiency occurs because of: reduced formation of calcitriol, metabolic acidosis, administration of aluminum (phosphate binder), and secondary hyperparathyroidism.

43 The Kidney Renal tubular acidosis Osteomalacia or rickets is most often seen with proximal (type 2) renal tubular acidosis. Acidosis leads to proximal phosphate wasting, increased calcium loss due, Secondary hyperparathyroidism. Similar findings can occur with the acidosis seen after ureterosigmoidostomy.

44 Other causes Fibrogenesis imperfecta A sporadic, idiopathic disorder with defective bone matrix formation. Symptoms begin in adult life with pain, fractures and weakness. Effects the entire skeleton and is characterized pathologically by the absence of normal birefringent collagen fibrils.

45 Osteogenesis imperfecta An inherited connective tissue disorder with many phenotypic presentations. Called "brittle bone disease. Severely affected patients suffer multiple fractures with minimal or no trauma, and infants with the worst form of OI die in the perinatal period. Mild forms of OI may be manifested by only premature osteoporosis or severe postmenopausal bone mineral loss.

46 Mild (type I) Types of OI few or no fractures before puberty or numerous fractures throughout their lives. occasionally present in the perinatal period with intrauterine fractures, but usually see fractures when they begin toddling or walking. Adults with OI type I may present with premature osteoporosis or accelerated osteoporosis following menopause. Adults may present with premature hearing loss. Moderate to severe (types III - VII) Hearing loss and osteoporosis. Mothers are prone to accelerated bone loss following pregnancy and a breastfeeding. Lethal perinatal form (type II) Patients with lethal perinatal OI (type II) usually die in utero or in early infancy.

47 Lab findings in OI Elevated levels of serum alkaline phosphatase. Hypercalciuria Decreased urinary excretion of calcium.

48 Bruck syndrome Previously called OI with congenital joint contractures, An autosomal recessive disorder Clinical features that distinguish it from OI include: congenital contractures of the knees, ankles, and feet; webbing of the elbow and knee, clubfoot (talipes equinovarus).

49 Osteoporosis-pseudoglioma pseudoglioma syndrome Previously called the ocular form of OI. An autosomal recessive disorder Caused by deletion of the gene for low-density density- lipoprotein (LDL) receptor-related related protein 5 (LRP-5). Present with: microcephaly; pseudoglioma (inflammatory changes of vitreous body) blindness (with onset in infancy); and hypotonia.

50 Causes of Hypophosphatemia Hungry bone syndrome Parathyroidectomy Associated with marked hypocalcemia and hypo-phosphatemia. phosphatemia. Decreased Intestinal Absorption Normal adults are in phosphate balance. Dietary intake of phosphate usually ranges from 800 to 1500 mg/day, Dietary intake is in excess of gastrointestinal losses, and Variations in intake usually have little effect on phosphate homeostasis. There is little regulation of gut absorption

51 Systemic conditions associated with childhood periodontitis Histiocytosis (Langerhans cell histiocytosis, histiocytosis X, or eosinophilic granuloma) A rare disorder affects infants, children, and young adults Characterized by histiocytic infiltration of the bones, skin, live, or other organs Skin, oral mucosa, bone, and lymph nodes are typical locations for single site involvement.

52 Systemic conditions associated with Leukemia childhood periodontitis Particularly the monocytic type, causes gingival enlargement due to infiltration of the gingival tissues. Typically painless, shiny, red, and edematous. Bleeding is common making oral hygiene difficult. Necrotic ulceration and involvement of the underlying bone can occur. The inflammation may act as a stimulus for further gingival swelling. Additional symptoms include fever, malaise, easy bruising or bleeding, and bone or joint pain.

53 Systemic conditions associated with childhood periodontitis Down Syndrome Papillon-Lefevre Syndrome Characterized by premature loss of the primary and permanent teeth Hyperkeratosis of the palms, soles, and sometimes of the knees and elbows Caused by mutations in the cathepsin C gene (CTSC) on chromosome 11q14.

54 Menopause related bone loss Bone loss, particularly trabecular bone, begins soon after the onset of menopause After the menopause, the ovary secretes little or no estrogen. Undetectable serum estradilo concentrations after menopause correlate with low bone density

55 Menopause related bone loss Data on serum estradiol concentrations and fracture risk are conflicting. Excess bone loss in women can be prevented by estrogen therapy. Estrogen is no longer a first-line therapy for prevention of bone loss, due to its other potential cardiovascular and breast cancer risks. Progestins, SERMs,, and bisphosphonates can also attenuate the loss of bone. Menopause-related bone loss lasts for about 10 years. After this time, the rate of bone loss is diminished to near the rate with aging

56 Pregnancy Bone loss can be seen during pregnancy (sometimes called transient osteoporosis of pregnancy). There does not appear to be an increased risk of fracture after menopause.

57 Lactation Lactation is associated with loss of bone of up to 4.0 percent, Lost bone is regained after lactation ceases; there is no increased risk of fractures in postmenopausal women who lactated earlier in life. PTHrP,, which is secreted by the lactating mammary gland, may play a role in the rapid bone loss that occurs in lactating women. Calcium supplements during lactation have no effect on the lactation-related change in bone turnover.

58 Organ transplant/b12 Glucocorticoids and cyclosporine contribute to post-transplant transplant osteoporosis; an additional factor after renal transplantation is secondary hyperparathyroidism. Vitamin B12 deficiency Vitamin B12 deficiency (pernicious anemia) is associated with an increased risk of osteoporosis, and hip and spine fractures, due to suppression of osteoblast activity as reported in in-vitro studies.

59 Cancer Treatment Osteoporosis in most patients treated for cancer is due to Hypogonadism that results from chemotherapy and radiation therapy, or Glucocorticoid therapy, Direct negative skeletal effects have been described for specific tumors and drug therapies. High-dose methotrexate regimens (eg( eg. Osteosarcoma or ALL) result in osteoporosis and fractures due to: Increase in bone resorption and Inhibition of bone formation, Some children with ALL have osteopenia before the initiation of treatment, suggesting a role for the leukemia itself on bone metabolism.

60 Homocysteine Homocystinuria, a rare autosomal recessive disease in children characterized by high plasma concentrations of homocysteine, lens dislocations, and thromboembolism, is also associated with the early onset of osteoporosis. High homocysteine levels in adults may be a predictor of osteoporotic fracture The mechanism for the effect of high homocysteine concentrations on fracture risk is not known, administering folate and vitamin B12 supplements (that lower serum homocysteine levels) reduce the risk of fracture.

61 Rickets Causes slow growth, bone deformities, elevation of alkaline phosphatase, and in some forms, abnormal tooth formation. Radiographic findings in rickets are characteristic and include: an increased width of the epiphyseal plate, irregular hazy margins of the distal metaphysis and marginal metaphyseal overgrowth that results in a ball- in-cup like appearance. Vitamin D resistant rickets in children, or osteomalacia in adults, may be associated with hypophosphatemia, including, Hereditary hypophasphatemic rickets and tumor induced osteomalacia.

62 Panostotic fibrous dysplasia The extreme form of polyostotic fibrous dysplasia (McCune-Albright syndrome), Caused by a somatic mutation Characterized by cystic or ground glass lesions in all bones.

63 Cole-Carpenter Carpenter syndrome Inheritance pattern of Cole-Carpenter Carpenter syndrome is unknown. Characterized by osteoporosis, short stature, craniosynostosis, hydrocephalus, and proptosis

64 Hypophosphatasia A rare, autosomal disease associated with low levels of alkaline phosphatase. Severe forms are usually inherited as an autosomal recessive trait. Leads to development of osteomalacia and severe periodontal disease. May present in the perinatal period, where it is often lethal, and in infancy.

65 Hypophosphatasia Childhood or adult forms have autosomal dominant traits with variable penetrance and clinical expression. Adults present with dental disease before the onset of symptomatic osteomalacia. Levels of phospho-ethanolamine and pyrophosphate are increased in blood and urine and are useful diagnostically.

66 Hypophosphatasia Caused by mutations in the infantile hypophosphatasia HOPS gene on chromosome 1p36. The phenotypic appearance varies. Results in a deficiency of tissue nonspecific alkaline phosphatase Characterized by abnormal mineralization of bone and dental tissues. The earlier the presentation, the more severe the disease.

67 Hypophosphatasia Leads to complete absence of the cementum, which covers the root structure and helps to prevent teeth from becoming fused to or reabsorped by the adjacent alveolar bone. The absence of cementum prevents normal anchoring of the fibers of the periodontal ligament and leads to premature tooth mobility and loss.

68 Hypophosphatasia Diagnostic findings Low serum alkaline phosphatase concentration Elevated concentrations of phospho- ethanolamine Elevated concentrations of pyrophosphate Increased urinary excretion of phosphoethanolamine.

69 Hypophosphatasia Diagnostic findings-continued Pyridoxal 5 phosphate (PLP) is sensitive and specific X-ray shows stress fx, chondrocalcinosis Enlarged pulp chambers

70 Treatment No uniformly successful treatment Palliative therapy for the infantile form may include correction of hypercalcemia (with calcitonin), reduction of hypercalcuria (with Chlorothiazide), reduction of dietary intake of calcium and vitamin D, reduced exposure to sunlight Prevent secondary rickets with administration of 200 IU IU of vitamin D per day. Serial monitoring of 25-hydroxyvitamin D levels is necessary to monitor and titrate intake.

71 Hypoposphatasia

72 Final diagnosis Hypophosphatasia, Diagnostic Lab test: Phosphoethanolaminuria Pyridoxal 5 phosphate (PLP) X-ray shows: stress fx, chondrocalcinosis

73 The End