The inter-rater reliability for 3 basic maneuvers of the Total Body Functional Profile is good among musculoskeletal health care providers of various disciplines, according to the results of a study conducted by Prather and associates

in the section of physical medicine and rehabilitation, department of orthopedic surgery, at Washington University School of Medicine in St Louis. In the prospective observational study, the authors measured 28 adult volunteers aged 18 to 51 years on both the left and right sides. Each examiner assessed the distance of frontal and sagittal plane lunge and angle of motion for transverse plane testing. All participants completed University of California Los Angeles (UCLA) and Harris hip questionnaires.

The UCLA and Harris hip scores showed no significant activity restrictions or pain limitations in all participants. The inter-rater reliability and rater reliability between disciplines for sagittal, frontal, and transverse plane matrix testing were good. The authors concluded that the maneuvers may be used consistently as part of a musculoskeletal examination.

 Prather H, Hunt D, Steger-May K, et al. Inter-rater reliability of three musculoskeletal physical examination techniques used to assess motion in three planes while standing. 

Articles

The inter-rater reliability for 3 basic maneuvers of the Total Body Functional Profile is good among musculoskeletal health care providers of various disciplines

Musculoskeletal physical examination motion assessment techniques

Hand edema, or “puffy hand syndrome,” is seen frequently in primary care practice, and

 given its broad differential diagnosis (

), presents physicians a significant diagnostic challenge. Causes range from iatrogenic ones to end-organ disease.

 Considering the “usual suspects” of edema, such as cardiac, liver, and renal disease, is important; also considering venous thrombosis and lymphedema resulting from breast cancer treatment is a must. In addition, the history can be instrumental in ruling out the more common rheumatologic causes, such as rheumatoid arthritis (RA), gout, and pseudogout.

A former heroin addict with hepatitis C virus infection has 

 bilateral “puffy hands.” The hand edema begins as pitting edema, followed by thickening and fibrosis of the subcutaneous tissue.

Another common but frequently overlooked diagnosis is hepatitis C virus (HCV) infection, which often is seen in former heroin addicts whose previous habit resulted in isolated hand edema (aka “hep C hands”) (Figure 1).

 HCV infection has the highest incidence in persons born between the 1940s and the 1960s,

 and the prevalence of symptomatic HCV infection is increasing as the disease is becoming more apparent in the aging baby boomer generation.

 The “maturing process” of this population segment, dating back to the 1960s and 1970s, included widespread experimentation with drugs that ranged from LSD and other hallucinogens to hardcore intravenous (IV) heroin use. The latter resulted in repeated exposure to HCV infection (and subsequent development of chronic liver disease). Now this is an essential diagnosis to consider in such patients who have unilateral or bilateral puffy hands.

In this article, we discuss the history taking and physical examination for patients who present with puffy hands. We also describe the main clinical factors in the more common diagnoses.


 A thorough patient history can be useful for suggesting the cause of puffy hands. Ascertaining a history of IV drug use and the location of injections is critical. Significant IV drug use resulting in chronically puffy hands strongly supports a diagnosis of HCV infection.

In addition to RA, gout, and pseudogout, the history may help rule out anasarca resulting from cardiac, renal, or liver disease. A history of infection or trauma would suggest an infectious cause or fracture; a history of autoimmune disease (eg, scleroderma or Sjgren syndrome) often is associated with hand edema.


 The physical examination should start with evaluation of the patient’s general appearance; the presence of scleral icterus, jaundice, and anasarca should be noted. On abdominal examination, tender hepatomegaly, splenomegaly, or lymphadenopathy may be elicited. Patients may have purpura resulting from coagulopathy or encephalopathy resulting from chronic hepatic disease. Patients also should be examined for cardiac murmurs or scars suggesting previous cardiac surgery. Renal disease may be suggested as the cause of edema by oliguria, hypertension, foamy urine, or hematuria.

Patients’ hands may suggest an association with RA with the appearance of symmetrical inflammation of the metacarpophalangeal and proximal interphalangeal joints and finger deformities, such as ulnar deviation. Erythematous, swollen, and tender joints may be related to gout or pseudogout. Evaluating whether upper extremity edema is unilateral or bilateral and whether the edema involves the whole arm or is isolated to the hand helps delineate the cause of the puffy hands.


 The differential diagnosis of puffy hands is quite extensive. Many of the possible diagnoses are the ones that are most often involved (eg, congestive heart failure, nephrotic syndrome, and liver disease).


 This is spread primarily through blood transmission, often via IV drug use (90% of cases) or blood transfusions.

 Eighty percent of HCV infection is chronic, often manifesting signs and symptoms of chronic liver disease.

 Signs include scleral icterus, jaundice, fatigue, ascites, coagulopathy, lymphadenopathy, and renal dysfunction. Portal hypertension ensues with liver failure, often resulting in encephalopathy, hepatosplenomegaly, and formation of varices because of collateral blood flow.

 Another common clinical feature of HVC infection is bilateral puffy hands.

The pathogenesis of hand edema in HVC infection has not been identified definitively. When first described by Abeles

 in 1965, this variation of hand edema was attributed to poor venous return because of thrombosis of antecubital veins after years of injected drug use. Recurrent infections at the injection site also were thought to contribute.

 suggested that the cause is lymphedema associated with the sclerosing properties of the drugs. Neviaser and colleagues

 suggested that lymphatic obstruction persists after injected drug use stops, along with scarring resulting from chronic inflammation. In addition, heroin often is diluted with quinine, which is notable for destroying lymphatics.

The hand edema begins as pitting edema, followed by thickening and fibrosis of the subcutaneous skin (see Figure 1). The lymphatics are destroyed; tissue protein increases, causing excessive connective tissue growth and resulting in fibrosis.

 stated that injected drugs cause a dermal inflammatory reaction, resulting in granuloma formation similar to a foreign body–type granuloma or nonspecific granulomatous reaction.

The prevalence of HCV infection is up to 75% in injected drug users; the majority manifest chronic disease.

 Risk factors for puffy hands among injection drug users with HCV infection are female sex, injection into the hands, and not using a tourniquet.

 They also may include vein trauma, skin ulcers, superficial and deep venous thrombosis (DVT), and lymphatic blockage with repeated infection.


 Thrombosis of the subclavian and axillary veins results from primary or secondary causes. Primary thrombosis, known as Paget-Schroetter syndrome, occurs in healthy, young adults with strenuous exercise. The condition results from microtrauma of blood vessel intima activating the coagulation cascade; it accounts for 20% of upper extremity DVT (UEDVT).

There often is an association with cervical rib abnormalities, such as thoracic outlet syndrome. This clinical syndrome causes extrinsic compression or trauma to the subclavian vein, resulting in vessel fibrosis.

 The other 80% of UEDVT cases result from secondary means, distruption of 1 or more of the components of Virchow triad: damage of blood vessel walls, hypercoagulability, and stasis.

Left subclavian-axillary vein thrombosis occurred in this patient after central line placement.

Thrombosis may occur in up to 72% of central venous catheter placements (Figure 2),

 although rates of thrombosis are rare in catheters kept in place less than 15 days.

 Hand or arm edema develops, with associated tenderness, erythema, and warmth. Pain occurs that is described as dull, constant aching; it can be disabling. Other signs include engorgement of the jugular veins and decreased shoulder joint range of motion.


 Lymphedema results from accumulation of proteinaceous fluid in interstitial tissue; with time, there is inflammation and fibrosis of subcutaneous tissue.

 Slowed lymphatic transit time induces lipogenesis and fat deposition. Fibrocytes are then activated and, with time, connective tissue overgrowth occurs as fibrosis ensues (Figure 3).

Right-arm lymphedema occurred in this patient after axillary lymph node dissection.

The cause of lymphedema can be primary or secondary. Primary conditions are differentiated by age and are hereditary or spontaneous disorders of lymphatic architecture.

 Secondary causes are responsible for most lymphedema.

Worldwide, the most common cause of lymphedema is filariasis caused by infection with 

 In the United States, lymphedema most often is related to malignancy or treatments of malignancy.

 There may be upper extremity lymphatic obstruction resulting from malignancies, such as breast cancer, melanoma, and lymphoma.

 Treatment for malignancy may result in lymphedema, such as with mastectomy (24% to 49% of cases) and axillary lymph node dissection or sentinel lymph node biopsy.

Fracture of the fifth metacarpal neck resulting from trauma with a closed fist caused edema in a boxer’s hands.

Risk factors for the development of edema resulting from lymphatic disruption include trauma from previous surgeries, infection, and obesity.

 In addition, there is risk associated with radiation therapy causing tissue fibrosis, which constricts lymphatic channels.

 The degree of risk varies with the dose of radiation, posterior axillary boost radiation, and overlapping technique.

Bilateral hand edema resulting from inflammation occurs in patients with rheumatoid arthritis.

Lymphedema often presents clinically as unilateral, soft, pitting edema that, over time, progresses to fibrosis. There may be pain in the affected limb with a feeling of heaviness and tightness.

 Skin manifestations include the appearance of peau d’orange (dimpling), hyperkeratosis, papillomatosis, and cellulites.

In this patient, lipoma caused enlargement of the hand.

The International Society of Lymphology has described the classification of lymphedema in the following stages

:
 •0: Latent or subclinical condition in which swelling is not evident despite impaired lymph transport. 
 •1: Mild, less than 20% increase in volume of the affected extremity; early accumulation of proteinaceous fluid subsides with limb elevation.
 •2: Moderate, 20% to 40% increase in volume occurs in affected limb; limb elevation alone rarely reduces tissue swelling; pitting manifests as a result of increasing fibrosis in late stage 2.
 •3: Severe, more than 40% increase in volume occurs, resulting in lymphostatic elephantiasis; there is an absence of pitting; trophic skin changes occur, including acanthosis, fat deposition, and warty overgrowth.

 Schneiderman H. Puffy hands from drug abuse. 

 Studdiford JS, Stonehouse AR, Anandanadesan R, Scott KC. Association between the “puffyhand sign” and chronic hepatitis C in a geriatric patient. 

 Armstrong GL. Injection drug users in the United States, 1979-2002: an aging population. 

 Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy. 

 Itskowitz MS. Hepatitis C: epidemiology, diagnosis and management. 

 Abeles H. Puffy-hand sign of drug addiction. 

 Neviaser RJ, Butterfield WC, Wieche DR. The puffy hand of drug addiction: a study of pathogenesis. 

Diseases of Lymphatics and Lymph Circulation.

 Springfield, IL: Charles C. Thomas; 1969;12:30.
  

 Del Giudice P, Durant J, Dellamonica P. Hand edema and acrocyanosis: “puffy hand syndrome.” 

 Andresz V, Marcantoni N, Binder F, et al. Puffy hand syndrome due to drug addiction: a case control study of the pathogenesis. 

 Shah MK, Burke DT, Shah SH. Upper-extremity deep vein thrombosis. 

 Joffe HV, Goldhaber SZ. Upper-extremity deep vein thrombosis. 

 Marinella MA, Kathula SK, Markert RJ. Spectrum of upper-extremity deep venous thrombosis in a community teaching hospital. 

. Martin C, Viviand X, Saux P, Gouin F. Upper-extremity deep vein thrombosis after central vein catheterization via the axillary vein. 

 Warren AG, Brorson H, Borud LJ, Slavin SA. Lymphedema: a comprehensive review. 

 Meneses KD, McNees MP. Upper extremity lymphedema after treatment for breast cancer: a review of the literature. 

 International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: consensus document of the International Society of Lymphology. 

 Hinrichs CS, Watroba NL, Rezaishiraz H, et al. Lymphedema secondary to postmastectomy radiation: incidence and risk factors. 

Hand edema, or “puffy hand syndrome,”is seen frequently in primary care practice, and given its broad differential diagnosis (Table), presents physicians a significant diagnostic challenge. Causes range from iatrogenic ones to end-organ disease.1

Evaluating edema of the hands

Soft tissue musculoskeletal conditions are common causes of pelvic and lower extremity pain. Injection therapy may provide relief in 2 of these conditions-piriformis syndrome and greater trochanteric pain syndrome (GTPS), or trochanteric bursitis-but a required step in the procedure for both conditions is identification of the greater trochanter of the femur. In this article, we describe the appropriate injection techniques.

 The piriformis muscle lies deep in the gluteal region. It originates from the anterior sacral surface and then passes through the greater sciatic notch to insert on the greater trochanter of the femur, aiding in external rotation of the hip. Closely proximate to the piriformis is the sciatic nerve, although its relative position varies: its 2 major divisions (portions destined to be the tibial and common peroneal nerves) may both pass anterior and inferior to the muscle (in 85% of cases), split with either one (10% of cases) or both (fewer than 1% of cases) branches passing through the muscle, or split and encircle the muscle (2% to 3% of cases).

 Contraction or compression of the piriformis muscle can lead to an entrapment neuropathy of the sciatic nerve (piriformis syndrome).

Patients with piriformis syndrome may note paralumbar, sacral, buttock, and leg pain. Pain may radiate down the leg, suggesting lumbar sciatica; this accounts for about 5% of sciatica presentations. The pain may be aggravated by lifting or stooping, direct muscle compression from prolonged sitting on a hard surface, or excessive leg activities that require rotation of the hip. Examination may reveal pain and tenderness to deep palpation in the midbuttock just lateral to the sciatic notch. Straight-leg raising test results may be positive. Pain may be exacerbated with forced-passive-internal or resisted-external hip rotation.

Injection of the piriformis muscle can be challenging because of its proximity to the sciatic nerve and its anatomical variations. These factors increase the risk of inducing a sciatic nerve block. The risk must be discussed with the patient during the informed consent process.

 There are 3 constant bursae surrounding portions of the anterior, lateral, and posterior regions of the greater trochanter; they serve to promote smooth gliding movements of the gluteal muscles and the tensor fascia lata. Pain in this region may arise from direct trauma or chronic pressure, from exaggerated movements of the gluteal muscles (especially the gluteus medius) and the tensor fascia lata over the trochanter, and from conditions that alter lower extremity biomechanics and thus gluteal muscle function. Radiographic evaluation of patients affected with trochanteric bursitis only rarely shows swelling of the bursae. MRI scans more frequently show degrees of gluteal muscular or insertion tears or tendinosis, hence the preferred term greater trochanteric pain syndrome.

GTPS is more common in women than in men and is the most common cause of "hip pain" in older patients. Patients complain of pain that is over the lateral aspect of the hip that may radiate toward but rarely below the knee. It may be aching, intermittent, or chronic, and it may be exacerbated by prolonged standing, direct pressure (such as during sleep), or activities that lead to hip external rotation or abduction (such as leg crossing). Symptoms may be perceived as pain in the lower back region in some patients and as a nondermatomal-like paresthesia and numbness in the upper thigh.

Examination elicits point tenderness over the greater trochanter with variable degrees of tenderness over the upper third of the lateral and posterior thigh. Palpable warmth, swelling, and erythema usually are not observed. Passive internal rotation or resisted external rotation or abduction of the hip may reproduce the pain. Passive hip flexion and extension usually is painless, but acute trochanteric bursitis may limit passive motion.


•Ethyl chloride spray (if preferred for superficial anesthesia).
•3-mL syringe with 2 to 3 mL of 1% lidocaine for local anesthetic.
•10-mL syringe with 5 to 7 mL of 1% lidocaine admixed with 20 to 40 mg (0.5 to 1 mL) of a nonfluorinated corticosteroid (eg, methylprednisolone, 40 mg/mL).
•1.5-inch, 25-gauge needles for injection of anesthetic and corticosteroid-anesthetic mixture. For patients of large body habitus, have 3.5-inch 22-gauge spinal needles available.
•Alcohol wipes, povidone-iodine, or chlorhexidine for sterilization.
•Sterile hemostat (optional).
•Nonsterile or sterile gloves.
•Gauze pads and adhesive bandage.

 The midbelly of the piriformis lies lateral to the sciatic notch, about halfway along a line that joins the posterior superior iliac spine and the greater trochanter of the femur.
•

 The insertion sites of the gluteal muscles and the trochanteric bursae lie along the lateral and posterior portions of the greater trochanter of the femur.

 Place the patient in a prone position and draw a line from the posterior superior iliac spine to the greater trochanteric prominence on the lateral hip. The midpoint of this line is the point of needle insertion.
•

 Place the patient in the lateral position, hips and knees slightly flexed, with the affected hip pointing upward. Palpating from the midthigh cephalad, insert the needle at the point of maximal tenderness over the bony trochanteric prominence.

 For all needle insertions, instruct the patient to tell you if you induce a radiating paresthesia down the leg. After proper skin sterilization, anesthetize the skin and needle tract using a 25-gauge, 1.5-inch needle. Direct the needle toward the umbilicus to its full depth, injecting lidocaine along the path. In very thin patients, the periosteum of the ilium may be reached and should be numbed. Preload the 10-mL syringe with the corticosteroid-anesthetic mixture.

If the periosteum was reached during anesthesia, then a 25-gauge needle also may be used for injecting the corticosteroid mixture: insert the needle into the periosteum, then withdraw it by 3 to 5 mm and inject the contents of the syringe. If the periosteum was not reached during anesthesia, then a spinal needle is used for injecting the corticosteroid mixture: with the stylet in, insert the needle to its full depth, withdraw the stylet and attach the syringe, then inject. If spinal needle contact is made with the periosteum, withdraw the stylet and attach the syringe, then withdraw the needle by 3 to 5 mm before injecting the syringe contents.

 After proper skin sterilization, anesthetize the skin and needle tract using a 25-gauge, 1.5-inch needle (Figure). In thin patients, the periosteum of the trochanter may be reached and should be numbed. Preload the 10-mL syringe with the corticosteroid-anesthetic mixture.

 Injection of the left trochanteric bursal region is shown in this cadaver photograph. In the lateral position with the patient’s hip and knee slightly flexed, the needle enters at the point of maximal tenderness over the bony trochanteric prominence (outlined in black) at a 90° angle to the skin. 

If the periosteum was reached during anesthesia, then a 25-gauge needle also may be used for injecting the corticosteroid mixture: insert the needle into the periosteum, then withdraw it by 2 to 3 mm and inject the contents of the syringe. If the periosteum was not reached during anesthesia, then a spinal needle is used for injecting the corticosteroid mixture: with the stylet in, insert the needle to make contact with the periosteum. Withdraw the stylet and attach the syringe, then withdraw the needle by 2 to 3 mm and inject the syringe contents. For patients with a history of lateral thigh radiation of pain, one-half to two-thirds of the syringe contents are injected at the trochanter and the remainder is distributed distally in a fan pattern into the deep lateral thigh without removing the needle from the skin.

 Travell JG, Simons DG. Piriformis and other short lateral rotators. In: Travell JG, Simons DG, eds. 

Myofascial Pain and Dysfunction: The Trigger Point Manual

. Vol 2. Baltimore: Williams and Wilkins; 1992:201.
  

 Shbeeb MI, Matteson EL. Trochanteric bursitis (greater trochanteric pain syndrome). 

 Alvarez-Nemegyei J, Canoso JJ. Evidence-based soft tissue rheumatology: III: trochanteric bursitis. 

Soft tissue musculoskeletal conditions are common causes of pelvic and lower extremity pain.

Injection therapy for pelvic soft tissue conditions

Hemochromatosis is a disorder of iron metabolism that may lead to abnormalities in multiple organ systems. It is characterized by excessive body iron stores and deposition of hemosiderin, which can cause tissue damage and organ dysfunction. The diagnosis is often delayed, sometimes for decades, because a period of silent iron deposition occurs before symptoms are manifest. Diagnosis is difficult even in symptomatic patients, because the signs and symptoms are nonspecific and overlap with those of many other conditions.

Joint abnormalities are common and often lead to morbidity and loss of quality of life. Joint disease often is an early manifestation of hemochromatosis and may be the symptom complex that leads to hemochromatosis diagnosis; however, a high index of suspicion must be maintained because the joint findings mimic those seen in other common rheumatologic conditions.

In this article, we briefly describe the diagnosis and management of hemochromatosis. Then we focus on the findings in hemochromatosis arthropathy and those of several conditions with similar symptoms involved in the differential diagnosis, including rheumatoid arthritis (RA), osteoarthritis (OA), and calcium pyrophosphate dihydrate (CPPD) crystal deposition disease.


 After elucidation of the genetics of hemochromatosis, the disorder is now best defined as the presence of 2 mutations of the hemochromatosis (

 Subsequent development of iron overload, which is variable among persons with the mutations, can cause complications in multiple organ systems.

 gene have been defined. In the United States, homozygosity for the C282Y mutation accounts for most clinical cases of iron overload

 This mutation may have arisen from a single progenitor in northwestern Europe.

 H63D is the next most common mutation, followed by S65C. Compound heterozygosity of C282Y and H63D accounts for a very few additional cases.

 The C282Y mutation results in abnormal binding of the 

-microglobulin, leading to excessive iron absorption.

Hemochromatosis type 1 is the common adult type of hemochromatosis (mutations of 

). Hemochromatosis type 2 (juvenile hemochromatosis) is divided into type 2A (mutations of the hemojuvelin gene, 

) and type 2B (mutations of the hepcidin antimicrobial peptide gene, 

). Hemochromatosis types 3 through 5 are associated with mutations that inactivate transferrin receptor 2 (TfR2), mutations of the ferroportin gene (

), and mutations of the H ferritin gene, respectively. Intensive investigation is under way to determine the role of each of these genes and their mutations and also of the iron-regulated gene 1, the duodenal cytochrome 

 (DCYTB, CYBYRD1), and others in iron accumulation.


 Symptoms of hemochromatosis result from damage to various organs caused by iron overloading. Symptoms tend to appear earlier in affected men than in women.

 Patients whose hemochromatosis is diagnosed on the basis of symptoms have evidence

 of iron overload and end-organ damage; those with hemochromatosis diagnosed by screening manifest fewer symptoms, if any (

 Because of a trend of earlier diagnosis, the classic symptoms of cirrhosis, diabetes mellitus (DM), and bronze skin are seen infrequently; the most common presenting symptoms are fatigue, malaise, and joint symptoms.

Many organs may be affected by iron overload. Eventually, overload in the liver may lead to cirrhosis and hepatocellular carcinoma. Cardiac iron deposition may lead to cardiomyopathy, with arrhythmia and congestive heart failure. Deposition of iron in the pituitary gland can lead to hypogonadrotropic hypogonadism, hypothyroidism or, rarely, panhypopituitarism. Deposition of iron in the islet cells of the pancreas may lead to DM. The skin may take on a bronze hue (Figure 1). Joint manifestations are common.

The skin of this patient with hemochromatosis exhibits the bronze pigmentation characteristic of the disease (compare with the skin of the unaffected person's hand in the foreground). The patient also demonstrates abdominal distention and an everted umbilicus resulting from tense ascites; this complicates cirrhosis caused by hepatic iron deposition.


 The most common laboratory abnormalities in hemochromatosis are elevations of serum iron concentration, percent saturation of transferrin, and serum ferritin concentration.

 Often, transferrin saturation is the first laboratory abnormality observed; it may be detected in some children and teenagers with the disease.

 Values for ferritin concentration and transferrin saturation in patients with clinical hemochromatosis compared with asymptomatic persons who were identified by screening are shown in 

 A transferrin saturation of 60% or more in

 symptomatic men or 50% or more in symptomatic women is highly sensitive for the diagnosis.

There is debate about the advisability of screening the general population for hemochromatosis. In 2006, the US Preventive Service Task Force recommended against routine genetic screening for hemochromatosis in asymptomatic persons.

 An NIH-sponsored screening study was performed and reported recently.

 In this study (Hemochromatosis and Iron Overload Screening [HEIRS]), 100,000 persons in North America were screened for hemochromatosis in a primary care setting. Very few newly diagnosed C282Y homozygotes had any symptoms of illness.

It seems prudent to evaluate the siblings of hemochromatosis homozygotes for the presence of 2 mutations of 

-C282Y and H63D. Siblings who are homozygous for the C282Y mutation should be evaluated for iron overload, employing transferrin saturation and serum ferritin concentration. Siblings who are not homozygous for the C282Y mutation do not need to undergo further evaluation or follow-up for hemochromatosis. Compound heterozygotes usually do not become iron-loaded.

Other common laboratory findings reflect sequelae of damage to organs from iron overload. These include elevated alanine aminotransferase and aspartate aminotransferase levels (usually to 2 to 5 times the upper limit of normal), abnormalities of serum glucose or thyroid-stimulating hormone, and hypogonadotropic hypogonadism. An ECG may show arrhythmia, and decreased ejection fraction may be present on an echocardiogram.

Liver biopsy is very informative in selected patients, but many persons do not need to undergo the procedure. In young homozygotes whose serum ferritin level is normal, liver histology is expected to be unaffected by iron overload and should not show fibrosis or cirrhosis in the absence of another liver disease. Liver biopsy is not needed in such persons, because it will not provide important information or change therapy and it poses risk and expense. Cirrhosis is not likely to be present in patients whose serum ferritin level is lower than 1000 ng/mL or whose hepatic iron concentration is below 22,000 μg/g of liver wet weight.

 In patients with high levels of serum ferritin, liver biopsy with quantitation of hepatic iron concentration can be helpful in planning iron depletion therapy. Patients who have massive hepatic iron overload may be served best by phlebotomy of 2 units of whole blood each week until iron depletion is accomplished.


 Phlebotomy is the mainstay of treatment, both for initial depletion of excess iron stores and for subsequent maintenance of normal total body iron. During initial iron depletion therapy, scheduled phlebotomy generally consists of removal of 500 mL of whole blood weekly until the hematocrit falls 2 to 4 mL/dL below baseline. Smaller volumes (eg, 250 mL) may be removed in fragile patients. Twice-weekly phlebotomy may be considered in those who have very severe iron overload noted on liver biopsy (Figure 2) or in patients who have liver failure or heart failure.

The liver biopsy specimen seen here shows severe (grade 4) hepatic iron deposition.   


Initial iron depletion is followed by lifelong phlebotomy to maintain normal total-body iron. Maintenance phlebotomy involves removal of 500 mL of whole blood every 2 to 4 months in men or every 3 to 12 months in women before menopause. The intent of lifelong maintenance phlebotomy therapy is to allow persons to maintain a normal hematocrit level with a serum ferritin concentration of about 50 ng/mL. A ferritin concentration that rises to greater than 100 ng/mL suggests inadequate iron removal and the need for more frequent phlebotomy therapy.

Patients with hemochromatosis should avoid ingestion of hepatotoxins, such as alcohol. Alcohol can increase iron absorption, and some red wines have a high iron content.

 There are some data indicating that ingestion of more than 30 g of ethanol per day may worsen the hepatic injury that is caused by iron overload   

    and may increase the risk of hepatocellular carcinoma in patients who have cirrhosis.

Patients with hemochromatosis should not eat raw oysters because of the risk of septicemia and death from 

 Iron-rich foods need not be restricted from the diet, because phlebotomy therapy is a much more efficient process than dietary limitations. Restriction of vitamin C is suggested by some authors, advice most applicable to patients with hemochromatosis cardiomyopathy, in whom vitamin C ingestion can increase iron absorption as well as the tendency toward ventricular arrhythmia.

 Medicinal iron supplementation should be discouraged.

Some patients experience improvement in joint symptoms after iron depletion therapy, but the majority do not. In some patients, the first onset of arthralgia occurs after phlebotomy therapy is initiated.

 Currently, predicting which persons will experience improvement or worsening of joint pain after iron depletion is not possible.

NSAIDs and acetaminophen are useful for relief of arthralgia in hemochromatosis, but they should not be used in patients who have cirrhosis or renal failure. Older persons may be more sensitive to the hepatotoxic and nephrotoxic effects of nonsteroidal medications than younger patients.


 An arthropathy associated with hemochromatosis was first described by Schumacher in 1964.

 The rate of occurrence of arthritis in persons with hemochromatosis has been variously estimated depending on the design of the study. Rates of about 50% have been reported when rigorous criteria are used to define arthritis,

 and rates have varied in other survey-based studies.

A survey of C282Y homozygotes compared with controls in whom the same survey instrument was administered (to reduce ascertainment bias) showed no statistically significant difference in the prevalence of joint complaints-82% of C282Y homozygotes answered "yes" to the question, "Do you have chronic pain in any of your joints?" compared with 62% of the controls. Homozygotes were more likely than controls to report symptoms in the fingers or hands (50% vs 34%), hips (31% vs 21%), and knees (71% vs 52%). Although none of these differences reached statistical significance, the small sample size of the homozygous population limited the study's power.

In the HEIRS study, the complaint of arthralgia was not more common among C282Y homozygotes compared with normal study participants.

 Because the symptoms and signs of hemochromatosis arthritis can overlap with those of other common joint disorders, the diagnosis can be overlooked.


 Iron overload is postulated to be the cause of joint damage in patients who have hemochromatosis arthropathy, but the mechanism remains unclear. Iron or ferritin may be found in synovial type A and type B cells and macrophages within joints, but this also may be true in other types of arthritis.

Apatite and CPPD crystals are found in some patients who have hemochromatosis arthropathy. In fact, the pattern of arthritis often can imitate pseudogout.

 In animal models, intra-articular iron has been shown to reduce CPPD crystal clearance from joints.

 However, hemochromatosis arthropathy often is observed without associated crystals. When found, crystals are not morphologically associated with iron or ferritin deposits.

Note the prominent enlargement of the second and third metacarpophalangeal joints (arrows) in the fingers of this patient with hemochromatosis arthritis who is making the "victory sign" while attempting to fully approximate the second and third fingers (A). The loss of depressions between knuckle ridges of these joints (arrows) is notable when the same patient's closed fists are viewed (B).


 Most patients with symptomatic arthropathy of hemochromatosis present with chronic, indolent pain and joint stiffness; bony enlargement; and minimal signs of inflammation.

 Hemochromatosis may involve the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints, wrists, knees, hips, feet, and shoulders. The distribution of affected joints combined with the character of the arthritis offers important clues to the diagnosis. The arthropathy is generally symmetrical and polyarticular. A predilection for disease in the second and third MCP joints is notable, and enlargement of these joints is readily seen in the fingers when they are extended to form a V, as in the "victory" sign (Figure 3).

Acute episodes of inflammatory arthritis also may occur, and they may be associated with recovery of CPPD crystals from joint fluid aspiration. A rare syndrome of septicemia accompanied by monoarticular or oligoarticular septic arthritis caused by 

 species has been described in patients who have hemochromatosis.

 Prosthetic joints seem especially susceptible to this infection.

Results from case reports have suggested that joint destruction related to repetitive motion or exercise may be particularly prominent in hemochromatosis arthropathy.

 It also has been suggested that the diagnosis of hemochromatosis should be entertained when younger patients present with symptoms suggestive of early, severe OA, such as the need for arthroplasty in the fifth decade of life or earlier.


 The radiographic findings in hemochromatosis are those of a degenerative arthritis with the joint distribution noted above. Early lesions consist of subchondral cysts with sclerotic margins; they may be especially notable at the metacarpal heads. Generalized osteoporosis appears to be common in patients with hemochromatosis.

 Joint-space narrowing occurs as arthritis progresses and generally is asymmetrical with cartilage loss most pronounced near subchondral cysts.

Subchondral cysts and sclerosis are less common in the knees than in other affected joints. In the hips, cartilage narrowing and marginal osteophytes are common and may be indistinguishable from the radiographic features of OA.

In this x-ray film, prominent osteophytes can be seen in the second through fifth metacarpophalangeal (MCP) joints (solid arrows). Note the hook shape of the osteophyte in the proximal fifth MCP joint (dashed arrow). Also seen are a marked loss of joint space and partial subluxation of the MCP joints.

Osteophyte formation is common. The hook or beak shape of osteophytes in the MCP joints may help distinguish hemochromatosis from other conditions (Figure 4).

Chondrocalcinosis affecting the triangular fibrocartilage above the ulnar styloid, the knees (Figure 5), or the MCP joints is common. Occasionally, chondrocalcinosis in the shoulders, elbows, and other joints may be seen.

 Not all joints affected by hemochromatosis exhibit chondrocalcinosis, and many joints affected by hemochromatosis arthritis do not have CPPD crystals detected in synovial fluid.

 Profound joint destruction may be visualized in radiographs of the knees and hips. Hemochromatosis arthropathy can result in the need for joint replacement.

This x-ray film of the right knee demonstrates chondrocalcinosis (arrow).

Hemochromatosis is a disorder of iron metabolism that may lead to abnormalities in multiple organ systems.

Identifying and managing hemochromatosis arthropathy

Not all patients with symptoms suggestive of a rheumatologic disease leave their doctor's office with a firm diagnosis in hand. Although disease classification and diagnosis guidelines are available to help physicians evaluate their patients, a rheumatologic disorder can present atypically, or the patient might not have all of the criteria needed to unequivocally support a given diagnosis. Also, the clinical picture may change as the disease progresses from early to middle and late stages. Consider, too, that many physicians practice in areas where specialists are not available to consult on cases that are especially challenging or questionable.

Thus, the process of arriving at an accurate diagnosis often is an imprecise art. The physician may revisit evidence, assess the patient at intervals, test response to treatment, consult with colleagues, and rely on past experiences rather than primarily on a published list of diagnostic criteria to confirm his or her clinical suspicions.

Scleroderma (systemic sclerosis) is a rheumatologic disorder that can be mistaken for rheumatoid arthritis (RA) or mixed connective tissue disease. Accurate diagnosis influences assessment of the patient's prognosis as well as the choice of management. In this article, we use a scleroderma case study to highlight the potential for misdiagnosis of a rheumatologic condition and demonstrate potential pitfalls the physician might encounter when evaluating patients.


 MJ is a 62-year-old man with pulmonary fibrosis. In 2006, he was referred by his primary care physician to the rheumatology clinic with a provisional diagnosis of mixed connective tissue disease and RA. The patient had a 30-year history of the following rheumatologic symptoms: diffuse skin tightness; general fatigue; sicca syndrome; Raynaud phenomenon; and constant, moderately severe bilateral hand pain. The hand pain worsens in the mornings, when MJ's hands are also stiff for about an hour.


 On examination, the patient had no skin tightness. However, Velcro rales were audible at the lung bases. MJ exhibited contractures of his fingers, primarily at the level of the proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints. His fingertips had pitting scars, and his distal finger pads lacked substance.

Laboratory test results completed at this visit were as follows: antiscleroderma (Scl) 70 antibody, 684 U/mL (normal range, 0 to 99 U/mL); white blood cell count, 5000/μL; erythrocyte sedimentation rate, 110 mm/h; C-reactive protein level, 38 mg/L (normal range, less than 5 mg/L); blood urea nitrogen level, 14 mg/dL; creatinine level, 1 mg/dL; rheumatoid factor (RF), positive; and antiribonucleoprotein (RNP) antibody, negative.

A radiograph of the right hand of a 67-year-old man with possible scleroderma shows erosive osteoarthritis with degenerative changes in the distal interphalangeal joints and resorption of distal phalangeal tufts, which is highly suggestive of scleroderma and typically not seen in rheumatoid arthritis without an overlap.

Chest radiographs showed a diffuse interstitial pattern predominantly involving the lung bases. Radiographs of the hands showed erosive osteoarthritis; degenerative changes were seen in the DIP joints along with resorption of distal phalangeal tufts, which is highly suggestive of scleroderma. There were no erosive changes to suggest RA (Figure 1). CT of the chest revealed bibasilar parenchymal opacities (Figure 2). It is important to note that the neither the x-ray film nor the CT scan findings are specific for scleroderma. Results of repeat RF testing performed on the day of evaluation were negative.

 A CT scan of the patient's chest shows alveolar opacities within the lung bases on both sides, which is not specific for scleroderma or any other rheumatologic disease that could affect the lungs.

The patient's physician made a diagnosis of scleroderma with positive anti-Scl 70 antibody based on the following findings from the history and physical examination: the presence of diffuse cutaneous scleroderma in the early stages; nonerosive arthritis with tendinopathy and contractures; severe Raynaud phenomenon, with fingertip ulcerations, pitting scars, and substance atrophy in the distal finger pads; sicca syndrome; and pulmonary fibrosis. The patient was taking prednisone, 20 mg/d, and oral methotrexate (MTX), 10 mg/wk, a regimen he had followed for the past 5 years. Because the arthritis appeared to be degenerative and MJ's pulmonary fibrosis was stable, medications were discontinued according to standard protocol (eg, MTX was stopped and prednisone was tapered).

It is possible that MJ had an active alveolitis or inflammatory nonerosive arthritis in the earlier stages of his disease and fulfilled, at least partially, the diagnostic criteria for RA or mixed connective tissue disease. He also might have benefited clinically from the previously prescribed therapies. However, an overlap syndrome-when a patient has a diagnosis of more than 1 rheumatologic disease at the same time-is considered rare.


 As this case exemplifies, diagnosis of rheumatologic disorders is not always accurate. These conditions can present a confusing picture-especially to physicians who might be practicing in a community setting and lack access to rheumatologists, rheumatology clinics, or other specialized resources.

The American College of Rheumatology (ACR) has established criteria for classifying RA.

 Although these criteria were developed to ensure that the diagnosis of RA is made according to standardized guidelines in research participants rather than in clinical patients, clinicians now use these criteria widely to make a diagnosis in individual patients. Keep in mind, however, that these criteria are empiric and are not meant to include or exclude a particular diagnosis in any given patient.

According to the ACR criteria, a person is considered to have RA if he has satisfied at least 4 of the following 7 findings (criteria 1 through 4 must have been present for at least 6 weeks)

:
 •Morning stiffness for at least 1 hour.
 •Arthritis of at least 3 joints occurring simultaneously, with swelling or fluid accumulation (not bony overgrowth alone) observed by a physician. Areas of involvement are right or left PIP, metacarpophalangeal (MCP), wrist, elbow, knee, ankle, and metatarsophalangeal joints.
 •Arthritis of the hand joints, with swelling in at least 1 of these areas: wrist, MCP joint, or PIP joints.
 •Symmetrical arthritis, with simultaneous involvement of the same joint areas (see second bullet) on both sides of the body.
 •Subcutaneous nodules present over bony prominences or extensor surfaces or in areas near the involved joints and observed by a physician.
 •Positive RF, demonstrable by any method showing a positive result in fewer than 5% of controls.
 •Radiographic features typical of RA on posteroanterior hand and wrist x-ray films. Films must show erosions or unequivocal bony decalcification localized in or most evident in areas adjacent to the involved joints.

MJ met only 3 of the 7 diagnostic criteria. Therefore, he did not qualify for a diagnosis of RA.

Not all patients with symptoms suggestive of a rheumatologic disease leave their doctor's office with a firm diagnosis in hand.

The Journal of Musculoskeletal Medicine Vol 26 No 1

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Evaluating edema of the hands

Injection therapy for pelvic soft tissue conditions

Identifying and managing hemochromatosis arthropathy

When diagnosis of rheumatologic disease does not "follow the book"

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