Lymphadenopathy and Splenomegaly

LYMPHADENOPATHY

Exposure to antigen through a break in the skin or mucosa results in antigen

being taken up by an antigen-presenting cell and carried via lymphatic channels

to the nearest lymph node. Lymph channels course throughout the body except

for the brain and the bones. Lymph enters the node through the afferent vessel

and leaves through an efferent vessel. As antigen-presenting cells pass through

lymph nodes,they present antigen to lymphocytes residing there. Lymphocytes

in a node are constantly being replaced by antigen-naive lymphocytes from the

blood. They are retained in the node via special homing receptors. B cells populate

the lymphoid follicles in the cortex; T cells populate the paracortical

regions. When a B cell encounters an antigen to which its surface immunoglobulin

can bind,it stays in the follicle for a few days and forms a germinal

center where the immunoglobulin gene is mutated in an effort to make an antibody

with higher affinity for the antigen. The B cell then migrates to the

medullary region,differentiates into a plasma cell, and secretes immunoglobulin

into the efferent lymph.

When a T cell in the node encounters an antigen it recognizes,it proliferates

and joins the efferent lymph. The efferent lymph laden with antibodies and T cells specific for the inciting antigen passes through several nodes on its way

to the thoracic duct,which drains lymph from most of the body. From the

thoracic duct,lymph enters the bloodstream at the left subclavian vein. Lymph

from the head and neck and the right arm drain into the right subclavian vein.

From the bloodstream,the antibody and T cells localize to the site of infection.

Lymphadenopathy may be caused by infections,immunologic diseases, malignancies, lipid storage diseases, or a number of disorders of uncertain etiology

(e.g.,sarcoidosis, Castleman’s disease; Table 58-1). The two major mechanisms

of lymphadenopathy are hyperplasia,in response to immunologic or infectious

stimuli,and infiltration,by cancer cells or lipid- or glycoprotein-laden macrophages.

Approach to the Patient

History Age, occupation,animal exposures,sexual orientation, substance

abuse history,medication history, and concomitant symptoms influence diagnostic

workup. Adenopathy is more commonly malignant in origin in those over

age 40. Farmers have an increased incidence of brucellosis and lymphoma. Male

homosexuals may have AIDS-associated adenopathy. Alcohol and tobacco

abuse increase risk of malignancy. Phenytoin may induce adenopathy. The concomitant

presence of cervical adenopathy with sore throat or with fever,night

sweats,and weight loss suggests particular diagnoses (mononucleosis in the

former instance,Hodgkin’s disease in the latter).

Physical Examination Location of adenopathy,size, node texture, and

the presence of tenderness are important in differential diagnosis. Generalized

adenopathy (three or more anatomic regions) implies systemic infection or lymphoma. Subclavian or scalene adenopathy is always abnormal and should be

biopsied. Nodes _ 4 cm should be biopsied immediately. Rock hard nodes fixed

to surrounding soft tissue are usually a sign of metastatic carcinoma. Tender

nodes are most often benign.

Laboratory Tests Usually lab tests are not required in the setting of localized

adenopathy. If generalized adenopathy is noted,an excisional node biopsy

should be performed for diagnosis,rather than a panoply of laboratory

tests.

TREATMENT

Pts over age 40,those with scalene or supraclavicular adenopathy, those with

lymph nodes _ 4 cm in diameter,and those with hard nontender nodes should

undergo immediate excisional biopsy. In younger patients with smaller nodes

that are rubbery in consistency or tender,a period of observation for 7–14

days is reasonable. Empirical antibiotics are not indicated. If the nodes shrink,

no further evaluation is necessary. If they enlarge,excisional biopsy is indicated.

SPLENOMEGALY

Just as the lymph nodes are specialized to fight pathogens in the tissues,the

spleen is the lymphoid organ specialized to fight bloodborne pathogens. It has

no afferent lymphatics. The spleen has specialized areas like the lymph node

for making antibodies (follicles) and amplifying antigen-specific T cells (periarteriolar lymphatic sheath,or PALS). In addition, it has a well-developed

reticuloendothelial system for removing particles and antibody-coated bacteria.

The flow of blood through the spleen permits it to filter pathogens from the

blood and to maintain quality control over erythrocytes (RBCs)—those that are old and nondeformable are destroyed,and intracellular inclusions (sometimes

including pathogens such as babesia and malaria) are culled from the cells in a

process called pitting. Under certain conditions,the spleen can generate hematopoietic cells in place of the marrow.

The normal spleen is about 12 cm in length and 7 cm in width and is not

normally palpable. Dullness from the spleen can be percussed between the ninth

and eleventh ribs with the pt lying on the right side. Palpation is best performed

with the pt supine with knees flexed. The spleen may be felt as it descends when

the pt inspires. Physical diagnosis is not sensitive. CT or ultrasound are superior

tests.

Spleen enlargement occurs by three basic mechanisms: (1) hyperplasia or

hypertrophy due to an increase in demand for splenic function (e.g.,hereditary

spherocytosis where demand for removal of defective RBCs is high or immune

hyperplasia in response to systemic infection or immune diseases); (2) passive

vascular congestion due to portal hypertension; and (3) infiltration with malignant

cells,lipid- or glycoprotein-laden macrophages, or amyloid (Table 58-2).

Massive enlargement,with spleen palpable _8 cm below the left costal margin,

usually signifies a lymphoproliferative or myeloproliferative disorder.

Peripheral blood RBC count,WBC count, and platelet count may be normal,

decreased,or increased depending on the underlying disorder. Decreases in one

or more cell lineages could indicate hypersplenism,increased destruction. In

cases with hypersplenism,the spleen is removed and the cytopenia is generally

reversed. In the absence of hypersplenism,most causes of splenomegaly are diagnosed on the basis of signs and symptoms and laboratory abnormalities

associated with the underlying disorder. Splenectomy is rarely performed for

diagnostic purposes.

Individuals who have had splenectomy are at increased risk of sepsis from

a variety of organisms including the pneumococcus and Haemophilus influenzae.

Vaccines for these agents should be given before splenectomy is performed.

Splenectomy compromises the immune response to these T-independent antigens.

Diseases Associated with Lymphadenopathy

1. Infectious diseases

a. Viral—infectious mononucleosis syndromes (EBV,CMV), infectious

hepatitis,herpes simplex, herpesvirus-6, varicella-zoster virus, rubella,

measles,adenovirus, HIV, epidemic keratoconjunctivitis, vaccinia, herpesvirus-

8

b. Bacterial—streptococci,staphylococci,cat-scratch disease, brucellosis,

tularemia, plague, chancroid,melioidosis,glanders, tuberculosis, atypical

mycobacterial infection,primary and secondary syphilis, diphtheria, leprosy

c. Fungal—histoplasmosis,coccidioidomycosis,paracoccidioidomycosis

d. Chlamydial—lymphogranuloma venereum,trachoma

e. Parasitic—toxoplasmosis, leishmaniasis,trypanosomiasis,filariasis

f. Rickettsial—scrub typhus,rickettsialpox

2. Immunologic diseases

a. Rheumatoid arthritis

b. Juvenile rheumatoid arthritis

c. Mixed connective tissue disease

d. Systemic lupus erythematosus

e. Dermatomyositis

f. Sjo¨gren’s syndrome

g. Serum sickness

h. Drug hypersensitivity—diphenylhydantoin,hydralazine, allopurinol,

primidone,gold, carbamazepine, etc.

i. Angioimmunoblastic lymphadenopathy

j. Primary biliary cirrhosis

k. Graft-vs.-host disease

l. Silicone-associated

3. Malignant diseases

a. Hematologic—Hodgkin’s disease,non-Hodgkin’s lymphomas,acute or

chronic lymphocytic leukemia,hairy cell leukemia, malignant histiocytosis,

amyloidosis

b. Metastatic—from numerous primary sites

4. Lipid storage diseases—Gaucher’s,Niemann-Pick, Fabry, Tangier

5. Endocrine diseases—hyperthyroidism

6. Other disorders

a. Castleman’s disease (giant lymph node hyperplasia)

b. Sarcoidosis

c. Dermatopathic lymphadenitis

d. Lymphomatoid granulomatosis

e. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease)

f. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease)

g. Mucocutaneous lymph node syndrome (Kawasaki’s disease)

h. Histiocytosis X

i. Familial mediterranean fever

j. Severe hypertriglyceridemia

k. Vascular transformation of sinuses

l. Inflammatory pseudotumor of lymph node

Diseases Associated with Splenomegaly Grouped by

Pathogenic Mechanism

INFILTRATION OF THE SPLEEN

Intracellular or extracellular depositions

Amyloidosis

Gaucher’s disease

Niemann-Pick disease

Tangier disease

Hurler’s syndrome and other mucopolysaccharidoses

Hyperlipidemias

Benign and malignant cellular infiltrations

Leukemias (acute,chronic,lymphoid, myeloid, monocytic)

Lymphomas

Hodgkin’s disease

Myeloproliferative syndromes (e.g.,polycythemia vera)

Angiosarcomas

Metastatic tumors (melanoma is most common)

Eosinophilic granuloma

Histiocytosis X

Hamartomas

Hemangiomas,fibromas,lymphangiomas

Splenic cysts

UNKNOWN ETIOLOGY

Idiopathic splenomegaly

Berylliosis

Iron-deficiency anemia

Anemia and Polycythemia

ANEMIA

According to WHO criteria,anemia is defined as blood hemoglobin (Hb) concentration

_ 130 g/L (_13 g/dL) or hematocrit (Hct) _ 39% in adult males;

Hb _ 120 g/L (_12 g/dL) or Hct _ 37% in adult females.

Signs and symptoms of anemia are varied,depending on the level of anemia

and the time course over which it developed. Acute anemia is nearly always

due to blood loss or hemolysis. In acute blood loss,hypovolemia dominates the

clinical picture; hypotension and decreased organ perfusion are the main issues.

Symptoms associated with more chronic onset vary with the age of the pt and

the adequacy of blood supply to critical organs. Moderate anemia is associated

with fatigue, loss of stamina,breathlessness,and tachycardia. The pt’s skin and

mucous membranes may appear pale. If the palmar creases are lighter in color

than the surrounding skin with the fingers extended,Hb level is often _80 g/L (8 g/dL). In pts with coronary artery disease,anginal episodes may appear or

increase in frequency and severity. In pts with carotid artery disease,lightheadedness or dizziness may develop.

A physiologic approach to anemia diagnosis is based on the understanding

that a decrease in circulating red blood cells (RBC) can be related to either

inadequate production of RBCs or increased RBC destruction or loss. Within

the category of inadequate production,erythropoiesis can be either ineffective,

due to an erythrocyte maturation defect (which usually results in RBCs that are

too small or too large),or hypoproliferative (which usually results in RBCs of

normal size,but too few of them).

Basic evaluations include: (1) reticulocyte index (RI),(2) review of blood

smear and RBC indices [particularly mean corpuscular volume (MCV)] (Fig.

57-1).

The RI is a measure of RBC production. The reticulocyte count is corrected

for the Hct level and for early release of marrow reticulocytes into the circulation,

which leads to an increase in the life span of the circulating reticulocyte

beyond the usual 1 day. Thus,RI _ (% reticulocytes _ pt Hct/45%) _ (1/shift

correction factor). The shift correction factor varies with the Hct: 1.5 for Hct _35%,2 for Hct _ 25%,2.5 for Hct _ 15%. RI _ 2–2.5% implies inadequate

RBC production for the particular level of anemia; RI _ 2.5% implies excessive

RBC destruction or loss.

If the anemia is associated with a low RI,RBC morphology helps distinguish

a maturation disorder from hypoproliferative marrow states. Cytoplasmic maturation defects such as iron deficiency or Hb synthesis problems produce smaller RBCs,MCV _ 80; nuclear maturation defects such as B12 and folate deficiency and drug effects produce larger RBCs,MCV _ 100. In hypoproliferative marrow states,RBCs are generally normal in morphology but too few are produced.

Bone marrow examination is often helpful in the evaluation of anemia but is

done most frequently to diagnose hypoproliferative marrow states.

Other laboratory tests indicated to evaluate particular forms of anemia depend

on the initial classification based on the pathophysiology of the defect.

These are discussed in more detail in Chap. 64.

POLYCYTHEMIA (ERYTHROCYTOSIS)

This is an increase above the normal range of RBCs in the circulation. Concern

that the Hb level may be abnormally high should be triggered at a level of 170

g/L (17 g/dL) in men and 150 g/L (15 g/dL) in women. Polycythemia is usually found incidentally at routine blood count. Relative erythrocytosis,due to plasma

volume loss (e.g.,severe dehydration, burns),does not represent a true increase

in total RBC mass. Absolute erythrocytosis is a true increase in total RBC mass.

CAUSES Polycythemia vera (a clonal myeloproliferative disorder),erythropoietin-

producing neoplasms (e.g.,renal cancer, cerebellar hemangioma),

chronic hypoxemia (e.g.,high altitude, pulmonary disease), carboxyhemoglobin

excess (e.g.,smokers),high-affinity hemoglobin variants, Cushing’s syndrome,

androgen excess. Polycythemia vera is distinguished from secondary polycythemia

by the presence of splenomegaly, leukocytosis,thrombocytosis,and elevated

vitamin B12 levels,and by decreased erythropoietin levels. An approach

to evaluate polycythemic pts is shown in Fig. 57-2.

COMPLICATIONS Hyperviscosity (with diminished O2 delivery) with

risk of ischemic organ injury and thrombosis (venous or arterial) are most common.

Azotemia and Urinary Abnormalities

ABNORMALITIES OF RENAL FUNCTION, AZOTEMIA

Azotemia is the retention of nitrogenous waste products excreted by the kidney.

Increased levels of blood urea nitrogen (BUN) [_10.7 mmol/L (_30 mg/dL)]

and creatinine [_133 _mol/L (_1.5 mg/dL)] are ordinarily indicative of impaired

renal function. Renal function can be estimated by determining the clearance

of creatinine (CLcr) (normal _ 100 mL/min). CLcr overestimates glomerular

filtration rate (GFR),particularly at lower levels. A formula that allows an

estimate of creatinine clearance in men that accounts for age-related decreases

in GFR,body weight,and sex has been derived by Cockcroft-Gault:

(140 _ age) _ lean body weight (kg)

Creatinine clearance (mL/min) _ plasma creatinine (mg/dL) _ 72

This value should be multiplied by 0.85 for women.

GFR may also be estimated using serum creatinine–based equations derived

from the Modification of Diet in Renal Disease Study. Isotopic markers (e.g.,

iothalamate) provide more accurate estimates of GFR.

Manifestations of impaired renal function include: volume overload,hypertension,

electrolyte abnormalities (e.g., hyperkalemia, hypocalcemia, hyperphosphatemia),

metabolic acidosis, hormonal disturbances (e.g., insulin resistance,

functional vitamin D deficiency, secondary hyperparathyroidism), and,

when severe,“uremia” (one or more of the following: anorexia, lethargy, confusion,

asterixis, pleuritis,pericarditis,enteritis,pruritus, sleep and taste disturbance,

nitrogenous fetor).

An approach to the patient with azotemia is shown in Fig. 56-1.

ABNORMALITIES OF URINE VOLUME

OLIGURIA This refers to sparse urine output,usually defined as _400

mL/d. Oligoanuria refers to a more marked reduction in urine output,i.e., _100

mL/d. Anuria indicates the absence of urine output. Oliguria most often occurs

in the setting of volume depletion and/or renal hypoperfusion,resulting in “prerenal

azotemia” and acute renal failure (Chap. 140). Anuria can be caused by

complete bilateral urinary tract obstruction; a vascular catastrophe (dissection

or arterial occlusion); renal vein thrombosis; and hypovolemic,cardiogenic, or

septic shock. Oliguria is never normal,since at least 400 mL of maximally

concentrated urine must be produced to excrete the obligate daily osmolar load.

POLYURIA Polyuria is defined as a urine output _3 L/d. It is often accompanied

by nocturia and urinary frequency and must be differentiated from other more common conditions associated with lower urinary tract pathology

and urinary urgency or frequency (e.g.,cystitis, prostatism). It is often accompanied

by hypernatremia (Chap. 3). Polyuria (Table 56-1) can occur as a response

to a solute load (e.g.,hyperglycemia) or to an abnormality in antidiuretic

hormone (ADH) action. Diabetes insipidus is termed central if due to the insufficient hypothalmic production of ADH and nephrogenic if the result of renal

insensitivity to the action of ADH. Excess fluid intake can lead to polyuria,but

primary polydipsia rarely results in changes in plasma osmolality unless urinary

diluting capacity is impaired,as with chronic renal failure. Tubulointerstitial

diseases and urinary tract obstruction can be associated with nephrogenic diabetes

insipidus. The approach to the pt with polyuria is shown in Fig. 56-2.

Major Causes of Hematuria

LOWER URINARY TRACT

Bacterial cystitis

Intestitial cystitis

Urethritis (infectious or inflammatory)

Passed or passing kidney stone

Transitional cell carcinoma of bladder or structures proximal to it

Squamous cell carcinoma of bladder (e.g.,following schistosomiasis)

UPPER URINARY TRACT

Renal cell carcinoma

Age-related renal cysts

Other neoplasms (e.g.,oncocytoma, hamartoma)

Acquired renal cystic disease

Congenital cystic disease,including autosomal dominant form

Glomerular diseases

Interstitial renal diseases

Nephrolithiasis

Pyelonephritis

Renal infarction

ABNORMALITIES OF URINE COMPOSITION

PROTEINURIA This is the hallmark of glomerular disease. Levels up to

150 mg/d are considered within normal limits. Typical measurements are semiquantitative, using a moderately sensitive dipstick that estimates protein concentration; therefore,the degree of hydration may influence the dipstick protein

determination. Most commercially available urine dipsticks detect albumin and

do not detect smaller proteins,such as light chains, that require testing with

sulfosalicylic acid. More sensitive assays can be used to detect microalbuminuria

in diabetes mellitus. A urine albumin to creatinine ratio _30 mg/g defines

the presence of micoalbuminuria.

Urinary protein excretion rates between 500 mg/d and 3 g/d are nonspecific

and can be seen in a variety of renal diseases (including hypertensive nephrosclerosis, interstitial nephritis,vascular disease,and other primary renal diseases with little or no glomerular involvement). Lesser degrees of proteinuria (500 mg/d to 1.5 g/d) may be seen after vigorous exercise,changes in body position, fever,or congestive heart failure. Protein excretion rates _3 g/d are termed

nephrotic range proteinuria and are accompanied by hypoalbuminemia, hypercholesterolemia, and edema in the nephrotic syndrome. Massive degrees of proteinuria (_10 g/d) can be seen with minimal change disease,primary focal

segmental sclerosis,membranous nephropathy, collapsing glomerulopathy, and

HIV-associated nephropathy and can be associated with a variety of extrarenal

complications (Chap. 144).

Pharmacologic inhibition of ACE or blockade of angiotensin II or aldosterone

receptors may reduce proteinuria in some pts,particularly those with diabetic

nephropathy. Specific therapy for a variety of causes of nephrotic syndrome

is discussed in Chap. 144.

HEMATURIA Gross hematuria refers to the presence of frank blood in

the urine and is more characteristic of lower urinary tract disease and/or bleeding

diatheses than intrinsic renal disease (Table 56-2). Cyst rupture in polycystic

kidney disease and flares of IgA nephropathy are exceptions. Microscopic hematuria (_1–2 RBC/high powered field) accompanied by proteinuria,hypertension, and an active urinary sediment (the “nephritic syndrome”) is most likely related to an inflammatory glomerulonephritis (Chap. 144). Free hemoglobin and myoglobin are detected by dipstick; a negative urinary

sediment with strongly heme-positive dipstick are characteristic of either hemolysis or rhabdomyolysis,which can be differentiated by clinical history and

laboratory testing. Red blood cell casts are not commonly seen but are highly

specific for glomerulonephritis.

The approach to the pt with hematuria is shown in Fig. 56-3.

PYURIA This may accompany hematuria in inflammatory glomerular diseases.

Isolated pyuria is most commonly observed in association with an infection

of the upper or lower urinary tract. Pyuria may also occur with allergic

interstitial nephritis (often with a preponderance of eosinophils),transplant rejection, and noninfectious,nonallergic tubulointerstitial diseases. The finding of

“sterile” pyuria (i.e.,urinary white blood cells without bacteria) in the appropriate

clinical setting should raise suspicion of renal tuberculosis.