IN THE NAME OF

GOD

• The patient is a 57 y/o man ,known case of DM,HTN, and CKD who was referred due to LBP and left hip pain.• The patient is a middle aged man who

complains of bone pain in left femur since 1 year ago .• BMD: NL.

• Uremic symptoms :( N/V, drowsiness, anasarca edema, and Cr=12) since 3 month ago. hemodialysis was begune.• A history of LBP and left hip pain begane since

3 month ago (no history of trauma).• Bone pain worsens with activity , no

radiation.

• Other problems:•Weight loss (30 kg) since 3 years ago,

spontaneous fracture of rib 1 year ago, (Seldom fever and fatigue,no urine obstruction or incontinency.• No stool incontinency.)

Past medical History •

1. DM since 10 years ago2. HTN since 4 years ago3. CKD since 3 years ago4. Coronary artery stenting 3 years ago ( after MI)5. CHF since 3 years ago6. Hospital admission due to uremic symptoms and LBP 7. Hospital admission due to catheter infection 2

month ago8. Hospital admission due to pneumonia 3 weeks ago9. Fistula insertion 2 month ago

Drug History

• Tab ASA 80 /d• Tab Atorvastatin 20/d• Tab carvedilol 3.125/BD • Caplet Renagel 800/d • Tab Folic acid 5/d• Tab Lasix 40 /d• Tab Plavix 75/d • Tab N.C 2.6/ BD• Insulin Lantus 8 IU/qhs

Physical Examination

• GA: The patient is a middle aged man who is pale, and complains of weakness ,bone pain ,and fatigue.

• V/S: BP=120/75, PR= 86, RR=18, T= 37 axillary, and SO2=94% without O2

• H&N: pale conjunctivea, sclera Nl , No LAP , No thyromegaly , Internal double lumen in Rt Jugular vein without erythema or discharge of the site of insertion• Heart: Nl S1,Nl S2,II/VI early systolic

murmur in LSB• Lung: bilateral end inspiration fine rales in

basal part.

• Abdomen: soft, no tenderness , no organomegaly• Ext: bilateral pitting edema in pretibial without size

difference, no cyanosis, no clubbing, left brachial fistula with thrill and bruit• Musculosceletal: tenderness on Lumbar spine(L1),

tenderness in left SIJ, Nl ROM ,Neurology examination: bilateral pinprick abnormality

Problem List

1. Known case of DM ,HTN ,MI, CKD 2. Bone pain3. Weight Loss4. Uremic symptoms5. Fever6. spontaneous fracture7. Edema8. Systolic murmur9. Fine rales in basal part of lung10.Tenderness on lumbar spine and SIJ

Differential diagnosis of Bone pain

1.Injury 2.Mineral deficiency3.Metastatic cancer4.Bone cancer5.Multiple myeloma6.Infection7.Leukemia8.Overuse9.Toddler fracture10.Osteomyelitis

LAB TESTS

• CBC: WBC= 10200(Nl diff), HG= 9.6 , MCV=92 , Plt=293000• Fe= 43, TIBC=387, Ferritin=107, SI=11%• ESR=53, CRP= negative • Na=143,K=5,Ca=9.1,P=6.6,Mg=2.8,urea=102,Cr=

9.6,uric acid=6.2• AST=40,ALT=43,ALP=1393(Nl up to 396),Bil

T=0.7,Bil D=0.2• GGT=220(up to 49)• PTH=28.5(6.3-36.5)• PSA= 0.35

• Blood culture=negative• U/A: Pro 2+, Glu 3+, not WBC , not RBC• U/C: negative• Lipid Profile normal• Alb=4.1• Viral marker = negative

ISOLATED ELEVATION OF THE ALP

• Women in the third trimester of pregnancy• Blood types O and B can have elevated ALP after eating

a fatty meal due to an influx of intestinal ALP• Children and adolescents (physiological osteoblastic

activity)• Gradually increases from age 40 to 65 years particularly

in women.• ALP was increased due to previous fracture healing.

• The first step in the elevation of an elevation ALP is to identify its source.• Either a GGT level or serum 5’-nucleotidase level

should be obtained.• These tests are usually elevated in parallel with the

ALP in liver disorders but are not increased in bone disorders.

ELEVATED GGT • DM• COPD• Alcohol abuse• ESRD• Pancreas disease• Biliary disease• NASH• Chronic Hepatitis(B,C)• Alpha1- antitrypsin deficiency• Medication(phenytoin , barbiturats)

• An elevated GGT with otherwise normal liver biochemical tests should not lead to an exhaustive work-up for liver disease.

• Serum Protein Electrophoresis:

Alb= 56.4(54-66)Alpha 1= 4.9(1.4-2.8)Alpha 2= 18(9.1-13.8)Beta= 14.3(8.7-14.4)Gamma= 11.7(10.6-19.2)

• Serum Immuno Electrophoresis

IgG= 725(700-1600)IgM= 77(40-230)IgA= 61(70-400)IgE= 38(<182)

• 20% of MM produce only light chains

• In nephrotic syndrome(decreased all of the IG)

• Non-secretory multiple myeloma

NON-SECRETORY MULTIPLE MYELOMA

• 3% of patients with MM have no M-protein in the serum or urine on immunofixation at the time of diagnosis.• Free light chain (FLC) assays can be used to detect

monoclonal protein in the absence of M protein with the above studies.• 60% of patients with MM who have a normal serum and

urine immunofixation, monoclonal free light chain can be detected in the serum using FLC assays.

• The FLC assay measures serum Kappa and Lambda light chain levels.

• Patients with myeloma who have normal serum and urine immunofixation and normal serum FLC assay are considered to have nonsecretory myeloma.

• 85% will have M-protein that be detected in the cytoplasm of the neoplastic plasma cells by immunochemistry, but have impaired secretion of this protein,

• 15% do not have immunoglobulin detectable in the plasma cells( non-producer myeloma)

•

• Patients with nonsecretory MM are not at risk for meloma kidney as long as light chains cannot be detected in the urine, but they are at risk for other complication of MM.

• BMA and BMB were done for his which were diagnostic for MM.(16% plasma cells)• PBS: rouleaux formation

Paraclinic finding

• Chest CT Scan: sign of heart is enlarged with significant prominanting venus marking. No Lymphadenopathy

•ECG: LBBB•Echocardiography: EF=35-40% ,

PAP=50, Mild AI, Mild TR, Global LV H.K.Moderate to severe LV disfunction. And RA enlargement.

NEUROSURGERY CONSULT

• EMG & NCV : polyradiculopathy

• Candidate for surgery

Abdominopelvic sonography:• Liver normal in size and echogenicity ,

Gallblodder and biliary ducts were normal without dilatation. Diameter hepatic and portal veins were normal. Spleen was normal in size and echogenicity. Pancrease is normal. Kidney was normal in size and echogenicity. Prostat normal in size and echogenicity.

CKD WITH NORMAL SIZE OF KIDNEY

• Diabetes• Polycystic kidneys• AIDS• Multiple Myeloma• Amyloidosis

WHOLE BODY BONE SCAN• Area of abnormal bone activity are noted in

skeleton especially: prominent hypo-active (lytic) lesion with peripheral increased osseous activity in left iliac wing superior to acetabulum.• Poorly defined but hyper-vascular lesion in

left trochanteric region and suspected one in right proximal femur.

• Area of increased activity in about L1.• Several foci of increased uptake in some ribs

bilaterally.• Suspected lesion on left side of skull.

• Finding are more suggestive of malignant process (MM, Lymphoma,….metastases).More evaluation to exclude hyper-parathyroidism/Brown tumor may also be considered.

• Radiographic survey is also recommended; some lesion may be undetectable or poorly defined by bone scan.

About multiple myeloma

• When a doctor is investigating symptoms that suggest multiple myeloma, such as bone pain, anemia, fatigue, unexplained fractures, or recurrent infections, to look for the presence of a characteristic band (monoclonal immunoglobulin) in the beta or gamma region; if a sharp band is seen, its identity as a monoclonal immunoglobulin is typically confirmed by immunofixation electrophoresis.

• To monitor treatment of multiple myeloma to see if the monoclonal band is reduced in quantity or disappears completely with treatment

• Multiple myeloma (myelo + oma, "marrow" + "tumor"), also known as plasma cell myeloma, myelomatosis, or Kahler's disease (after Otto Kahler), is a cancer of plasma cells, a type of white blood cell normally responsible for producing antibodies.

• Multiple Myeloma is a type of blood cancer that affects the plasma cells. Plasma cells are immune cells that normally make special proteins, called antibodies, to fight off disease. These antibodies are part of the body’s defense system to neutralize infections that invade the blood stream. Patients who have multiple myeloma make plasma cells that are abnormal. These plasma cells do not make normal antibodies anymore, but instead make too much of one kind of protein. When this happens, the levels of these proteins in the blood become higher than normal.

• In multiple myeloma, collections of abnormal plasma cells accumulate in the bone marrow, where they interfere with the production of normal blood cells. Most cases of multiple myeloma also feature the production of a paraprotein —an abnormal antibody which can cause kidney problems. Bone lesions and hypercalcemia (high blood calcium levels) are also often encountered

• Multiple myeloma is diagnosed with blood tests (serum protein electrophoresis, serum free kappa/lambda light chain assay), bone marrow examination, urine protein electrophoresis, and X-rays of commonly involved bones.

• Multiple myeloma is considered to be incurable but treatable. Remissions may be induced with steroids, chemotherapy, proteasome inhibitors, immunomodulatory drugs such as thalidomide or lenalidomide, and stem cell transplants. • Radiation therapy is sometimes used to reduce

pain from bone lesions

• Multiple myeloma develops in 6.1 per 100,000 people per year. It is more common in men and, for unknown reasons, is twice as common in African-Americans as it is in European-Americans. With conventional treatment, median survival is 3–4 years, which may be extended to 5–7 years or longer with advanced treatments. Multiple myeloma is the second most common hematological malignancy in the U.S. (after non-Hodgkin lymphoma), and constitutes 1% of all cancers. The five year survival rate is 45%

• Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember some of the common symptoms of multiple myeloma is CRAB: C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.• Myeloma has many other possible symptoms,

including opportunistic infections (e.g., pneumonia). CRAB symptoms and proliferation of monoclonal plasma cells in the bone marrow are part of the diagnostic criteria of multiple myeloma.

• Illustration showing the most common site of bone lesions in vertebrae

• Bone pain affects almost 70% of patients and is the most common symptom

• Myeloma bone pain usually involves the spine and ribs, and worsens with activity and does not occur at night except with change of position. Persistent localized pain may indicate a pathological bone fracture. Involvement of the vertebrae may lead to spinal cord compression.

• The patient’s height may be reduced because of vertebral collaps.

• Plasmacytomas of the ribs occur and can present with costal lesion or soft tissue mass.

Clinical Manifestation

• Hypercalcemia: The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.• Anemia: The anemia found in myeloma is usually

normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells , kidney damage , and hemolysis . Macrocytosis can presented with unknown reason,investigation must be done to rule out pernicious anemia.

HYPERVISCOSITY

• Increased serum viscosity is occasionally noted in patients with multiple myeloma. It is more frequently noted in patients with heavy chain immunoglobulin(IgM) .• . Hyperviscosity is more frequently noted in patients with

Waldenström's macroglobulinemia.• High viscosity interferes with efficient blood circulation of

the brain, kidneys, and extremities. Symptoms of hyperviscosity include headache, dizziness, vertigo, and severe ischemia

RENAL FAILURE

• Renal failure may develop both acutely and chronically.

• Kidney failure is a common complication of multiple myeloma. When first diagnosed, as many as 20-40% of patients with multiple myeloma will have some amount of kidney failure. Multiple myeloma can affect the kidney in several ways. It can affect the filter (glomerulus), the tubules (pipes), or the tissue of the kidney itself (interstitium).

• The most common cause of renal failure in multiple myeloma is due to proteins secreted by the malignant cells. Myeloma cells produce monoclonal proteins of varying types, most commonly immunoglobulins (antibodies) and free light chains, resulting in abnormally high levels of these proteins in the blood.(myeloma kidney)

• Depending on the size of these proteins, they may be excreted through the kidneys. Kidneys can be damaged by the tubulopathic effects of proteins or light chains. Increased bone resorption leads to hypercalcemia and causes nephrocalcinosis thereby contributing to the renal failure.• Amyloidosis is a distant third in the causation.

Patients with Amyloidosis have high levels of Amyloid protein that can be excreted through the kidneys and cause damage to the kidneys and other organs.

• Light chains produce myriad effects which can manifest as the Fanconi syndrome (type II renal tubular acidosis).• Other causes include hyperuricemia, recurrent

infections (pyelonephritis), and local infiltration of tumor cells.• Medication (NSAIDs,Bisphosphonats)• Contrast exposure

INFECTION• The most common infections are pneumonias and

pyelonephritis.• Common pneumonia pathogens include S. pneumoniae,

S. aureus, and K. pneumoniae, while common pathogens causing pyelonephritis include E. coli and other gram-negative organisms.

• The greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy. The increased risk of infection is due to immune deficiency.

• Although the total immunoglobulin level is typically elevated in multiple myeloma, the majority of the antibodies are ineffective monoclonal antibodies from the clonal plasma cell. A selected group of patients with documented hypogammaglobulinemia may benefit from replacement immunoglobulin therapy to reduce the risk of infection.

NEUROLOGICAL SYMPTOMS

• Some problems (e.g., weakness, confusion and fatigue) may be due to anemia or hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein.

• Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). It may give rise to paraplegia in late presenting cases.

• When the disease is well-controlled, there may be neurological symptoms resulting from current treatments, some of which may cause peripheral neuropathy, manifesting itself as numbness or pain in the hands, feet, and lower legs.

Diagnostic criteria for MM and related disorders

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANT(MGUS)

• Serum monoclonal protein<3g/dl• Bona marrow plasma cells<10%• No end organ damage to plasma dyscrasia

• Often does not need to be treated right away

SMOLDERING (ASYMPTOMATIC) MM

• Serum monoclonal protein>3g/dl• Bona marrow plasma cells>10%• No end organ damage to plasma dyscrasia

• Often does not need to be treated right away

MULTIPLE MYELOMA

• Serum or urinary monoclonal protein• Clonal plasma cells in the BM or a plasmacytoma• End organ damage1. Increased Ca2. Lytic bone lesions3. Anemia4. Renal failure

ISS( INTERNATIONAL STAGING SYSTEM)• I ( B2M < 3.5 , Alb> 3.5) 62 month

• II ( neither stage 1 nor stage 3) 44 month

• III( B2M > 5.5) 29 month

Thanks for your attention