Deep vein thrombosis and pulmonary embolism are collectively referred to as venous thromboembolic (VTE) disease. They affect approximately 100,000 to 300,000 patients per year in the United States.¹ Although patients with deep vein thrombosis can be treated as outpatients, many are admitted for the initiation of anticoagulation. Initial anticoagulation usually requires the overlap of a parenteral anticoagulant (unfractionated heparin, low-molecular-weight heparin [LMWH] or fondaparinux) with warfarin for a minimum of 5 days and until the international normalized ratio (INR) of the prothrombin time is above 2.0 for at least 24 hours.²

Three clinical issues need to be addressed after the initiation of anticoagulation for VTE:

• Determination of the length of anticoagulation with the correct anticoagulant
• Prevention of postthrombotic syndrome
• Appropriate screening for occult malignancy.

HOW LONG SHOULD VTE BE TREATED?

The duration of anticoagulation has been a matter of debate.

The risk of recurrent VTE appears related to clinical risk factors that a patient has at the time of the initial thrombotic event. An epidemiologic study³ found that patients with VTE treated for approximately 6 months had a low rate of recurrence (0% at 2 years of follow-up) if surgery was the risk factor. The risk climbed to 9% if the risk factor was nonsurgical and to 19% if there were no provoking risk factors.

The likelihood of VTE recurrence and therefore the recommended duration of treatment depend on whether the VTE event was provoked, cancer-related, recurrent, thrombophilia-related, or idiopathic. We address each of these scenarios below.

HOW LONG TO TREAT PROVOKED VTE

A VTE event is considered provoked if the patient had a clear inciting risk factor. As defined in various clinical trials, these risk factors include:

• Hospitalization with confinement to bed for 3 or more consecutive days in the last 3 months
• Surgery or general anesthesia in the last 3 months
• Immobilization for more than 7 days, regardless of the cause
• Trauma in the last 3 months
• Pregnancy
• Use of an oral contraceptive, regardless of which estrogen or progesterone analogue it contains
• Travel for more than 4 hours
• Recent childbirth.

However, the trials that tested different lengths of anticoagulation have varied markedly in how they defined provoked deep vein thrombosis.^4–7

A systematic review⁸ showed that patients who developed VTE after surgery had a lower rate of recurrent VTE at 12 and 24 months than patients with a nonsurgical provoking risk factor, and patients with nonprovoked (idiopathic) VTE had the highest risk of recurrence (Table 1).

Recommendation: Warfarin or equivalent for 3 months

The American College of Chest Physicians (ACCP) recommends 3 months of anticoagulation with warfarin or another vitamin K antagonist for patients with VTE secondary to a transient (reversible) risk factor,² and we agree.

HOW LONG TO TREAT CANCER-RELATED VTE

Patients with cancer are at higher risk of developing VTE. Furthermore, in one study,⁹ compared with other patients with VTE, patients with cancer were three times more likely to have another episode of VTE, with a cumulative rate of recurrence at 1 year of 21% vs 7%. Cancer patients were also twice as likely to suffer major bleeding complications while on anticoagulation.⁹

Warfarin is a difficult drug to manage because it has many interactions with foods, diseases, and other drugs. These difficulties are amplified in many cancer patients during chemotherapy.

Warfarin was compared with a LMWH in four randomized trials in cancer patients, and a meta-analysis¹⁰ found a 50% relative reduction in the rates of recurrent deep vein thrombosis and pulmonary embolism with LMWH treatment. These results were driven primarily by the CLOT trial (Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer),¹¹ which showed an 8% absolute risk reduction (number needed to treat 13) without an increase in major bleeding when cancer-related VTE was treated with an LMWH—ie, dalteparin (Fragmin)—for 6 months compared with warfarin.

Current thinking suggests that VTE should be treated until the cancer is resolved. However, this hypothesis has not been adequately tested, and consequently, the ACCP gives it only a level 1C recommendation.² The largest of the four trials comparing warfarin and an LMWH lasted only 6 months. The safety of extending LMWH treatment beyond 6 months is currently unknown but is under investigation (clinicaltrials.gov identifier NCT00942968).

 

 

Recommendation: LMWH therapy for at least 6 months

The ACCP guidelines recommend LMWH therapy for 3 to 6 months, followed by warfarin or another vitamin K antagonist or continued LMWH treatment until the cancer is resolved.²

The National Comprehensive Cancer Network guidelines recommend an LMWH for 6 months as monotherapy and indefinite anticoagulation if the cancer is still active.¹²

The American Society of Clinical Oncology guidelines recommend an LMWH for at least 6 months and indefinite anticoagulant therapy for selected patients with active cancer.¹³

We agree that patients with active cancer should receive an LMWH for at least 6 months and indefinite anticoagulation until the cancer is resolved.

In our experience, many patients are reluctant to give themselves the daily injections that LMWH therapy requires, and so they need to be well-informed about the marked decrease in VTE recurrence with this less-convenient and more-expensive therapy. Many patients face insurance barriers to cover the cost of LMWH therapy; however, careful attention to preauthorization can usually overcome this obstacle.

HOW LONG TO TREAT RECURRENT VTE

It makes clinical sense that patients who have a second VTE event should be treated indefinitely. This theory was tested in a randomized clinical trial¹⁴ in which patients with provoked or unprovoked VTE were randomized after their second event to receive anticoagulation for 6 months vs indefinitely.

After 4 years of follow-up, the recurrence rate was 21% in patients assigned to 6 months of treatment and only 3% in patients who continued anticoagulation throughout the trial. On the other hand, major hemorrhage occurred in 3% of patients treated for 6 months and in 9% in patients who continued anticoagulation indefinitely.

Of note, most of the patients in this trial had unprovoked (idiopathic) VTE, so the results should not be extrapolated to patients with provoked VTE, who accounted for only 20% of the study population.¹⁴

Recommendation: Long-term anticoagulation

We agree with the ACCP recommendation² that patients who have had a second episode of unprovoked VTE should receive long-term anticoagulation. Because of a lack of data, the duration of therapy for patients with a second episode of provoked VTE should be individualized.

HOW LONG TO TREAT THROMBOPHILIA-RELATED VTE

Inherited thrombophilias

Patients with VTE that is not related to a clear provoking risk factor or cancer frequently have testing to evaluate for a hypercoagulable state. This workup traditionally includes the most common inherited thrombophilias for gene mutations for factor V and prothrombin as well as for deficiencies in protein C, protein S, antithrombin and the acquired antiphospholipid syndrome.

The key questions that should be asked prior to embarking on this workup are:

• Will the results change the length of therapy for the patient?
• Will testing the patient help with genetic counseling and possible testing of family members?
• Will the results change the targeted INR range for warfarin or other vitamin K antagonist therapy?

Patients with inherited thrombophilia have a greater risk of developing an initial VTE event; however, these tests do not help predict the recurrence of VTE in patients with established disease more than clinical risk factors do. A prospective study demonstrated this by looking at the effect of thrombophilia and clinical factors on the recurrence of venous thrombosis and found that inherited prothrombotic abnormalities do not appear to play an important role in the risk of a recurrent event.¹⁵ On the other hand, clinical factors, such as whether the first event was idiopathic or provoked, appear more important in determining the duration of anticoagulation therapy.¹⁵ A systematic review of the common inherited thrombophilias showed the VTE recurrence rate of patients with factor V Leiden was higher than in patients without the mutation; however, the absolute rates of recurrence were not much different than what would be expected in patients with idiopathic VTE.¹⁶

A retrospective study involving a large cohort of families of patients who already had experienced a first episode of either idiopathic or provoked VTE showed high annual risks of recurrent VTE associated with hereditary deficiencies of protein S (8.4%), protein C (6.0%), and antithrombin (10%).¹⁷ However, for the more commonly occurring genetic thrombophilias, the factor V Leiden and prothrombin G20210A mutations, family members with either gene abnormality had low rates of VTE, suggesting that testing of relatives of probands is not clinically useful.¹⁶

Antiphospholipid syndrome

Antiphospholipid syndrome is an acquired thrombophilia. A patient has thrombotic antiphospholipid syndrome when there is a history of vascular thrombosis in the presence of persistently positive tests (at least 12 weeks apart) for lupus anticoagulants, anticardiolipin antibodies, or anti-beta-2 glycoprotein I. A prospective study of 412 patients with a first episode of VTE found that 15% were positive for anticardiolipin antibody at the end of 6 months of anticoagulation. The risk of recurrent VTE after 4 years was 29% in patients with antibodies and 14% in those without antibodies (relative risk 2.1; 95% confidence interval [CI] 1.3–3.3; P =.0013).¹⁸

Recent reviews advise indefinite warfarin anticoagulation in patients with VTE and persistence of antiphospholipid antibodies.¹⁹ However, the optimal duration of anticoagulation is uncertain. Until well-designed clinical trials are done, the current general consensus is to anticoagulate these patients indefinitely.^20,21 Retrospective studies had suggested that patients with antiphospholipid antibodies required a higher therapeutic INR range; however, this observation was tested in two trials that found no difference in thromboembolic rates when patients were randomized to an INR of 2.0–3.0 vs 3.1–4.0,²² or 2.0–3.0 vs 3.0–4.5.²³

No formal recommendations

In the absence of strong evidence, the ACCP guidelines do not include a recommendation on the duration of anticoagulation treatment specific to inherited thrombophilias. We believe that clinical factors are more important than inherited thrombophilias for deciding the duration of anticoagulation, and that testing is almost never indicated or useful. However, patients with antiphospholipid syndrome are at high risk of recurrence, and it is our practice to anticoagulate these patients indefinitely.

 

HOW LONG TO TREAT UNPROVOKED (IDIOPATHIC) VTE

A VTE event is thought to be idiopathic if it occurs without a clearly identified provoking factor.

Commonly accepted risk factors for VTE are recent surgery, hospitalization for an acute medical illness, active cancer, and some inherited thrombophilias. Less clear is whether immobilization, pregnancy, use of female hormones, and long-distance travel should also be considered as provoking conditions. Various trials have used different combinations of risk factors as exclusion criteria to define idiopathic (unprovoked) VTE when assessing the length or intensity of anticoagulation (Table 2).^24–29 The ACCP guidelines² cite estrogen therapy, pregnancy, and travel longer than 8 hours as minor risk factors for VTE.

In an observational study,³ patients with oral contraceptive use, transient illness, immobilization, or a history of travel had an 8.8% risk of recurrence vs 19.4% in patients with unprovoked VTE. The meta-analysis discussed above (Table 1)⁸ also shows that patients with these nonsurgical risk factors have a lower rate of recurrence than patients with idiopathic VTE.

The high rate of recurrence of idiopathic VTE (4% to 27% after 3 months of anticoagulation^24–26) suggests that a longer duration of treatment is reasonable. However, increasing the length of therapy from 3 to 12 months delays but does not prevent recurrence, the risk of which begins to accumulate once anticoagulation is stopped.^24,25

Three promising strategies to identify subgroups of patients with idiopathic VTE who are at highest risk of recurrence and who would benefit the most from prolonged anticoagulation are d-dimer testing, evaluation for residual vein thrombosis in patients who present with a deep vein thrombosis, and clinical prediction rules.

d-dimer testing

d-dimer is a degradation product of fibrin and is an indirect marker of residual thrombosis.³⁰

In a systematic review of patients with a first episode of unprovoked VTE,³¹ a normal d-dimer concentration at the end of at least 3 months of anticoagulation was associated with a 3.5% annual risk of recurrence, whereas an elevated d-dimer level at that time was associated with an annual risk of 8.9%. These results were confirmed in a systematic review of individual patient data.³²

In a randomized trial,²⁸ patients with an idiopathic VTE event who received anticoagulation for at least 3 months had their d-dimer level measured 1 month after cessation of treatment. Those with an elevated level were randomized to either resume anticoagulation or not. Patients who resumed anticoagulation had an annual recurrence rate of 2%; however, those who were allocated not to restart anticoagulation had a recurrence rate of 10.9% per year. There was no difference in the rate of major bleeding between the two groups. Patients in this clinical trial who had a normal d-dimer level did not restart anticoagulation and had an annual recurrence rate of 4.4%.

Evaluation for residual thrombosis

Patients who have residual deep vein thrombosis after treatment have been shown to have higher rates of recurrent VTE.³³ Therefore, repeating Doppler ultrasonography is another clinical consideration that may help establish the optimal duration of anticoagulation.

A randomized trial³⁴ in patients with both provoked and idiopathic deep vein thrombosis showed a reduction in recurrence when those who had residual vein thrombosis were given extended anticoagulation. In the subset of patients whose deep vein thrombosis was idiopathic, the recurrence rate was 17% per year when treatment lasted only 3 months and 10% when it was extended for up to 1 year.

Another trial³⁵ randomized patients with provoked and idiopathic deep vein thrombosis to receive anticoagulation for the usual duration or to continue treatment until recanalization of the residual thrombus was demonstrated on follow-up Doppler ultrasonography. Patients who received this ultrasonography-tailored treatment had a lower rate of recurrence of VTE; however, the absolute reductions in recurrence rates cannot be calculated from this report for patients with idiopathic deep vein thrombosis.

A prospective observational study³⁶ of the predictive value of d-dimer status and residual vein thrombus found that only d-dimer was an independent risk factor for recurrent VTE after vitamin K antagonist withdrawal.

A clinical prediction rule: ‘Men and HERDOO₂’

A promising tool for predicting if a patient is at low risk of recurrent VTE after the first episode of proximal deep vein thrombosis or pulmonary embolism is known by the mnemonic device “Men and HERDOO₂.” It is based on data prospectively derived by Rodger et al³⁷ to identify patients with less than a 3% annual risk of recurrent VTE after their first event of idiopathic proximal deep vein thrombosis or pulmonary embolism. Risk factors for recurrent VTE were male sex (the “men” of “Men and HERDOO₂”), signs of postthrombotic syndrome, including hyperpigmentation of the lower extremities, edema or redness of either leg, a d-dimer level > 250 μg/L, obesity (body mass index > 30 kg/m², and older age (> 65 years).

Overall, one-fourth of the population were women with no risk factors or one risk factor, and their risk of recurrence was 1.6% per year. Men and women who had two or more risk factors for postthrombotic syndrome (hyperpigmentation, edema, or redness), elevated d-dimer, obesity, or older age were predicted to be at higher risk of recurrent VTE. Patients such as this should be considered for indefinite anticoagulation.

Ideally, clinical prediction rules should be validated in a separate group of patients before they are used routinely in practice,³⁸ and this clinical prediction rule is currently being tested in the REVERSE II study. If the results are consistent, this will be an easy-to-use tool to help identify patients who likely can safely stop anticoagulation therapy after 3 to 6 months (clinicaltrials.gov Identifier: NCT00967304).

The location of the thrombosis also influences the likelihood of recurrence. Patients with isolated distal (calf) deep vein thrombosis are less likely to suffer recurrent VTE than those who present with proximal deep vein thrombosis. However, trials focusing specifically on the precise subset of idiopathic isolated distal deep vein thrombosis are lacking. In a randomized trial³⁹ comparing 6 vs 12 weeks of anticoagulation for isolated distal deep vein thrombosis and 12 vs 24 weeks for proximal deep vein thrombosis, the annual rates of recurrence after 12 weeks of treatment were approximately 3.4% for isolated distal and 8.1% for proximal deep vein thrombosis.³⁹

 

 

Recommendation: At least 3 months of warfarin or equivalent

We agree with the ACCP recommendation² that patients with unprovoked VTE should receive at least 3 months of anticoagulation with a vitamin K antagonist.

If the patient has no risk factors for bleeding and good anticoagulant monitoring is achievable, we agree with long-term anticoagulation for proximal unprovoked deep vein thrombosis or pulmonary embolism, and 3 months of therapy for isolated distal unprovoked deep vein thrombosis.

Patient preferences and the risk of recurrence vs the risk of bleeding should be discussed with patients when contemplating indefinite anticoagulation.

If testing is being considered to assist in the decision to prescribe indefinite anticoagulation, we prefer using d-dimer levels rather than ultrasonography to detect residual venous thrombosis because of its ease of use and the strength of the current evidence.

PREVENTING POSTTHROMBOTIC SYNDROME

The postthrombotic (postphlebitic) syndrome is a chronic and burdensome consequence of deep vein thrombosis that occurs despite anticoagulation therapy. It is estimated to affect 23% to 60% of patients and typically manifests in the first 2 years.⁴⁰ It is not only costly in clinical terms, with decreased quality of life for the patient, but health care expenditures have been estimated to range from $400 per year in a Brazilian study to $7,000 per year in a US study.⁴⁰

Typical symptoms include leg pain, heaviness, swelling, and cramping. In severe cases, chronic venous ulcers can occur and are difficult to treat.⁴¹

The definition of postthrombotic syndrome has been unclear over the years, and six different scales that measure signs and symptoms have been reported.⁴²

The Villalta scale has been proposed by the International Society of Thrombosis and Hemostasis as a diagnostic standard to define postthrombotic syndrome.⁴² This validated scale is based on five clinical symptoms, six clinical signs, and the presence or absence of venous ulcers. Each clinical symptom and sign is scored as mild (1 point), moderate (2 points), or severe (3 points). Symptoms include pain, cramps, heaviness, paresthesia, and pruritus; the six clinical signs are pretibial edema, skin induration, hyperpigmentation, redness, venous ectasia, and pain on calf compression.

According to the International Society of Thrombosis and Hemostasis, postthrombotic syndrome is present if the Villalta score is 5 or greater or if a venous ulcer is present in a leg with previous deep vein thrombosis. Further, using the Villalta scale, postthrombotic syndrome can be categorized as mild (score 5–9), moderate (10–14), or severe (≥ 15).

A limitation of the Villalta scale is that the presence or absence of a venous ulcer has not been assigned a score. Since a venous ulcer requires more aggressive measures, the society defines postthrombotic syndrome as severe if venous ulcers are present.⁴²

Acute symptoms of deep vein thrombosis may take months to resolve and, indeed, acute symptoms may transition to chronic symptoms without a symptom-free interval. It is recommended that postthrombotic syndrome not be diagnosed before 3 months to avoid inappropriately attributing acute symptoms and signs of deep vein thrombosis to the postthrombotic syndrome.⁴²

Studies of stockings

A systematic review of three randomized trials⁴⁴ concluded that elastic compression stockings reduce the risk of postthrombotic syndrome (any severity) from 43% to 20% and severe postthrombotic syndrome from 15% to 7%.⁴³

The first of these trials⁴⁴ randomized patients soon after the diagnosis of deep vein thrombosis to receive made-to-order compression stockings that were rated at 30 to 40 mm Hg or to be in a control group that did not receive stockings. The second trial⁴⁵ randomized patients 1 year after the index event of deep vein thrombosis to receive 20- to 30-mm Hg stockings or stockings that were two sizes too large (the control group). The third study⁴⁶ randomly allocated patients to receive “off-the-shelf” stockings (30–40 mm Hg) or no stockings. Each study used its own definition of postthrombotic syndrome.

Although these studies strongly suggest compression stockings prevent postthrombotic syndrome, several methodologic issues remain:

• A standard definition of postthrombotic syndrome was not used
• The amount of compression varied between studies
• The studies were not blinded.

Lack of blinding becomes most significant when an outcome is based on subjective findings, like the symptoms that make up a large part of the diagnosis of postthrombotic syndrome.

The SOX trial, currently under way, is designed to address these methodologic issues and should be completed in 2012 (clinicaltrials.gov Identifier: NCT00143598).

Recommendation: Stockings for at least 2 years

We agree with the ACCP recommendation that a patient who has had a symptomatic proximal deep vein thrombosis should wear an elastic compression stocking with an ankle pressure gradient of 30 to 40 mm Hg as soon as possible after starting anticoagulant therapy and continuing for a minimum of 2 years.²

 

SCREENING FOR OCCULT MALIGNANCY

VTE can be the first manifestation of cancer.

French physician Armand Trousseau, in the 1860s, was the first to describe disseminated intravascular coagulation closely associated with adenocarcinoma. Ironically, several years later, after suffering for weeks from abdominal pain, he declared to one of his students that he had developed thrombosis, and he died of gastric cancer shortly thereafter.⁴⁷

Since cancer is a well-known risk factor for VTE, it is logical to screen for cancer as an explanation for an idiopathic VTE event.⁴⁸ To make an informed decision, one needs to understand the rate of occult cancer at the time VTE is diagnosed, the risk of future development of cancer, and the utility of extensive cancer screening.

The clinical efficacy, side effects, and cost-effectiveness of cancer screening in patients with idiopathic VTE are unknown. However, a systematic review⁴⁷ of 34 studies found that, in patients with idiopathic VTE, cancer was diagnosed within 1 month in 6.1%, within 6 months in 8.6%, and within 1 year in 10.0% (95% CI 8.6–11.3).

A subset of studies compared two strategies for screening soon after the diagnosis of idiopathic VTE: a strategy limited to the history, physical examination, basic blood work, and chest radiography vs an extensive screening strategy that also included serum tumor markers or abdominal ultrasonography or computed tomography. Limited screening detected 49% of the prevalent cancers; extensive screening increased this rate to 70%. Stated another way, the detection rate for prevalent cancers was 5% with limited screening and 7% with extensive screening soon after the diagnosis of idiopathic VTE.⁴⁷

Patients with idiopathic VTE had higher rates of cancer within 1 month of diagnosis than patients with provoked VTE (6.1% vs 1.9%), and this difference persisted at 1 year (10.0% vs 2.6%).⁴⁷

Recommendation: Individualized cancer screening

Patients with idiopathic VTE have a significant risk of occult cancer within the first year after diagnosis, and cancer screening should be considered. Our practice for patients with idiopathic VTE is to perform a history and physical examination and ensure that the patient is up to date on age- and sex-specific cancer screening.

The use of additional imaging or biomarkers should be discussed with patients so they can balance the risks (radiation and potential false-positive results with their downstream consequences), costs, and potential benefits, given the lack of proven survival benefit or cost-effectiveness.

ORAL ANTICOAGULANT MANAGEMENT

Warfarin’s multiple interactions, along with the need for INR monitoring, make it a difficult medication to manage.

The Joint Commission, the US organization for health service accreditation and certification, has defined National Patient Safety Goals and quality measures for the management of anticoagulation.⁴⁹ Organized anticoagulation management services, dosing algorithms, and patient self-testing using capillary INR meters or patient self-management of warfarin were recommended as tools to improve the time patients spend in the therapeutic INR range.⁵⁰

Two new oral anticoagulants

The limitations of warfarin have stimulated the search for newer oral anticoagulants that do not require laboratory monitoring or have as many diet and drug interactions.

Two trials have been published with experimental oral anticoagulants that had similar efficacy and safety as warfarin in the treatment of VTE.

The study of dabigatran (Pradaxa) vs warfarin in the treatment of acute VTE (the RECOVER trial)⁵¹ randomized 2,539 patients with acute VTE to receive the oral direct thrombin inhibitor dabigatran or warfarin for approximately 6 months. Of note, each treatment group received a median of 6 days of heparin, LMWH, or fondaparinux at the beginning of blinded therapy. The rates of recurrent VTE and major bleeding were similar between the treatment arms, and overall bleeding was less with dabigatran. Dabigatran was approved in the United States in October 2010 for stroke prevention in atrial fibrillation but has yet to be approved for the treatment of VTE pending further study (clinicaltrials.gov Identifier: NCT00680186).

A study of oral rivaroxaban (Xarelto) for symptomatic VTE (the EINSTEIN-DVT trial) ⁵² randomized 3,449 patients with acute deep vein thrombosis to rivaroxaban or enoxaparin (Lovenox) overlapped with warfarin or another vitamin K antagonist in the usual manner. No difference was noted between the treatments in the rate of recurrence of VTE or of major bleeding. Of note, patients randomized to rivaroxaban received 15 mg twice a day for the first 3 weeks of treatment and then 20 mg per day for the remainder of their therapy and did not require parenteral anticoagulant overlap.

The long-awaited promise of easier-to-use oral anticoagulants for the treatment of VTE is drawing near and has the potential to revolutionize the treatment of this common disorder. In the meantime, close monitoring of warfarin and careful patient education regarding its use are essential. And even with the development of new drugs in the future, it is still imperative that patients with acute VTE receive the correct length of anticoagulation treatment, are prescribed stockings to prevent postthrombotic syndrome, and are updated on routine cancer screening.

Deep vein thrombosis and pulmonary embolism are collectively referred to as venous thromboembolic (VTE) disease. They affect approximately 100,000 to 300,000 patients per year in the United States.¹ Although patients with deep vein thrombosis can be treated as outpatients, many are admitted for the initiation of anticoagulation. Initial anticoagulation usually requires the overlap of a parenteral anticoagulant (unfractionated heparin, low-molecular-weight heparin [LMWH] or fondaparinux) with warfarin for a minimum of 5 days and until the international normalized ratio (INR) of the prothrombin time is above 2.0 for at least 24 hours.²

Three clinical issues need to be addressed after the initiation of anticoagulation for VTE:

• Determination of the length of anticoagulation with the correct anticoagulant
• Prevention of postthrombotic syndrome
• Appropriate screening for occult malignancy.

HOW LONG SHOULD VTE BE TREATED?

The duration of anticoagulation has been a matter of debate.

The risk of recurrent VTE appears related to clinical risk factors that a patient has at the time of the initial thrombotic event. An epidemiologic study³ found that patients with VTE treated for approximately 6 months had a low rate of recurrence (0% at 2 years of follow-up) if surgery was the risk factor. The risk climbed to 9% if the risk factor was nonsurgical and to 19% if there were no provoking risk factors.

The likelihood of VTE recurrence and therefore the recommended duration of treatment depend on whether the VTE event was provoked, cancer-related, recurrent, thrombophilia-related, or idiopathic. We address each of these scenarios below.

HOW LONG TO TREAT PROVOKED VTE

A VTE event is considered provoked if the patient had a clear inciting risk factor. As defined in various clinical trials, these risk factors include:

• Hospitalization with confinement to bed for 3 or more consecutive days in the last 3 months
• Surgery or general anesthesia in the last 3 months
• Immobilization for more than 7 days, regardless of the cause
• Trauma in the last 3 months
• Pregnancy
• Use of an oral contraceptive, regardless of which estrogen or progesterone analogue it contains
• Travel for more than 4 hours
• Recent childbirth.

However, the trials that tested different lengths of anticoagulation have varied markedly in how they defined provoked deep vein thrombosis.^4–7

A systematic review⁸ showed that patients who developed VTE after surgery had a lower rate of recurrent VTE at 12 and 24 months than patients with a nonsurgical provoking risk factor, and patients with nonprovoked (idiopathic) VTE had the highest risk of recurrence (Table 1).

Recommendation: Warfarin or equivalent for 3 months

The American College of Chest Physicians (ACCP) recommends 3 months of anticoagulation with warfarin or another vitamin K antagonist for patients with VTE secondary to a transient (reversible) risk factor,² and we agree.

HOW LONG TO TREAT CANCER-RELATED VTE

Patients with cancer are at higher risk of developing VTE. Furthermore, in one study,⁹ compared with other patients with VTE, patients with cancer were three times more likely to have another episode of VTE, with a cumulative rate of recurrence at 1 year of 21% vs 7%. Cancer patients were also twice as likely to suffer major bleeding complications while on anticoagulation.⁹

Warfarin is a difficult drug to manage because it has many interactions with foods, diseases, and other drugs. These difficulties are amplified in many cancer patients during chemotherapy.

Warfarin was compared with a LMWH in four randomized trials in cancer patients, and a meta-analysis¹⁰ found a 50% relative reduction in the rates of recurrent deep vein thrombosis and pulmonary embolism with LMWH treatment. These results were driven primarily by the CLOT trial (Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer),¹¹ which showed an 8% absolute risk reduction (number needed to treat 13) without an increase in major bleeding when cancer-related VTE was treated with an LMWH—ie, dalteparin (Fragmin)—for 6 months compared with warfarin.

Current thinking suggests that VTE should be treated until the cancer is resolved. However, this hypothesis has not been adequately tested, and consequently, the ACCP gives it only a level 1C recommendation.² The largest of the four trials comparing warfarin and an LMWH lasted only 6 months. The safety of extending LMWH treatment beyond 6 months is currently unknown but is under investigation (clinicaltrials.gov identifier NCT00942968).

 

 

Recommendation: LMWH therapy for at least 6 months

The ACCP guidelines recommend LMWH therapy for 3 to 6 months, followed by warfarin or another vitamin K antagonist or continued LMWH treatment until the cancer is resolved.²

The National Comprehensive Cancer Network guidelines recommend an LMWH for 6 months as monotherapy and indefinite anticoagulation if the cancer is still active.¹²

The American Society of Clinical Oncology guidelines recommend an LMWH for at least 6 months and indefinite anticoagulant therapy for selected patients with active cancer.¹³

We agree that patients with active cancer should receive an LMWH for at least 6 months and indefinite anticoagulation until the cancer is resolved.

In our experience, many patients are reluctant to give themselves the daily injections that LMWH therapy requires, and so they need to be well-informed about the marked decrease in VTE recurrence with this less-convenient and more-expensive therapy. Many patients face insurance barriers to cover the cost of LMWH therapy; however, careful attention to preauthorization can usually overcome this obstacle.

HOW LONG TO TREAT RECURRENT VTE

It makes clinical sense that patients who have a second VTE event should be treated indefinitely. This theory was tested in a randomized clinical trial¹⁴ in which patients with provoked or unprovoked VTE were randomized after their second event to receive anticoagulation for 6 months vs indefinitely.

After 4 years of follow-up, the recurrence rate was 21% in patients assigned to 6 months of treatment and only 3% in patients who continued anticoagulation throughout the trial. On the other hand, major hemorrhage occurred in 3% of patients treated for 6 months and in 9% in patients who continued anticoagulation indefinitely.

Of note, most of the patients in this trial had unprovoked (idiopathic) VTE, so the results should not be extrapolated to patients with provoked VTE, who accounted for only 20% of the study population.¹⁴

Recommendation: Long-term anticoagulation

We agree with the ACCP recommendation² that patients who have had a second episode of unprovoked VTE should receive long-term anticoagulation. Because of a lack of data, the duration of therapy for patients with a second episode of provoked VTE should be individualized.

HOW LONG TO TREAT THROMBOPHILIA-RELATED VTE

Inherited thrombophilias

Patients with VTE that is not related to a clear provoking risk factor or cancer frequently have testing to evaluate for a hypercoagulable state. This workup traditionally includes the most common inherited thrombophilias for gene mutations for factor V and prothrombin as well as for deficiencies in protein C, protein S, antithrombin and the acquired antiphospholipid syndrome.

The key questions that should be asked prior to embarking on this workup are:

• Will the results change the length of therapy for the patient?
• Will testing the patient help with genetic counseling and possible testing of family members?
• Will the results change the targeted INR range for warfarin or other vitamin K antagonist therapy?

Patients with inherited thrombophilia have a greater risk of developing an initial VTE event; however, these tests do not help predict the recurrence of VTE in patients with established disease more than clinical risk factors do. A prospective study demonstrated this by looking at the effect of thrombophilia and clinical factors on the recurrence of venous thrombosis and found that inherited prothrombotic abnormalities do not appear to play an important role in the risk of a recurrent event.¹⁵ On the other hand, clinical factors, such as whether the first event was idiopathic or provoked, appear more important in determining the duration of anticoagulation therapy.¹⁵ A systematic review of the common inherited thrombophilias showed the VTE recurrence rate of patients with factor V Leiden was higher than in patients without the mutation; however, the absolute rates of recurrence were not much different than what would be expected in patients with idiopathic VTE.¹⁶

A retrospective study involving a large cohort of families of patients who already had experienced a first episode of either idiopathic or provoked VTE showed high annual risks of recurrent VTE associated with hereditary deficiencies of protein S (8.4%), protein C (6.0%), and antithrombin (10%).¹⁷ However, for the more commonly occurring genetic thrombophilias, the factor V Leiden and prothrombin G20210A mutations, family members with either gene abnormality had low rates of VTE, suggesting that testing of relatives of probands is not clinically useful.¹⁶

Antiphospholipid syndrome

Antiphospholipid syndrome is an acquired thrombophilia. A patient has thrombotic antiphospholipid syndrome when there is a history of vascular thrombosis in the presence of persistently positive tests (at least 12 weeks apart) for lupus anticoagulants, anticardiolipin antibodies, or anti-beta-2 glycoprotein I. A prospective study of 412 patients with a first episode of VTE found that 15% were positive for anticardiolipin antibody at the end of 6 months of anticoagulation. The risk of recurrent VTE after 4 years was 29% in patients with antibodies and 14% in those without antibodies (relative risk 2.1; 95% confidence interval [CI] 1.3–3.3; P =.0013).¹⁸

Recent reviews advise indefinite warfarin anticoagulation in patients with VTE and persistence of antiphospholipid antibodies.¹⁹ However, the optimal duration of anticoagulation is uncertain. Until well-designed clinical trials are done, the current general consensus is to anticoagulate these patients indefinitely.^20,21 Retrospective studies had suggested that patients with antiphospholipid antibodies required a higher therapeutic INR range; however, this observation was tested in two trials that found no difference in thromboembolic rates when patients were randomized to an INR of 2.0–3.0 vs 3.1–4.0,²² or 2.0–3.0 vs 3.0–4.5.²³

No formal recommendations

In the absence of strong evidence, the ACCP guidelines do not include a recommendation on the duration of anticoagulation treatment specific to inherited thrombophilias. We believe that clinical factors are more important than inherited thrombophilias for deciding the duration of anticoagulation, and that testing is almost never indicated or useful. However, patients with antiphospholipid syndrome are at high risk of recurrence, and it is our practice to anticoagulate these patients indefinitely.

 

HOW LONG TO TREAT UNPROVOKED (IDIOPATHIC) VTE

A VTE event is thought to be idiopathic if it occurs without a clearly identified provoking factor.

Commonly accepted risk factors for VTE are recent surgery, hospitalization for an acute medical illness, active cancer, and some inherited thrombophilias. Less clear is whether immobilization, pregnancy, use of female hormones, and long-distance travel should also be considered as provoking conditions. Various trials have used different combinations of risk factors as exclusion criteria to define idiopathic (unprovoked) VTE when assessing the length or intensity of anticoagulation (Table 2).^24–29 The ACCP guidelines² cite estrogen therapy, pregnancy, and travel longer than 8 hours as minor risk factors for VTE.

In an observational study,³ patients with oral contraceptive use, transient illness, immobilization, or a history of travel had an 8.8% risk of recurrence vs 19.4% in patients with unprovoked VTE. The meta-analysis discussed above (Table 1)⁸ also shows that patients with these nonsurgical risk factors have a lower rate of recurrence than patients with idiopathic VTE.

The high rate of recurrence of idiopathic VTE (4% to 27% after 3 months of anticoagulation^24–26) suggests that a longer duration of treatment is reasonable. However, increasing the length of therapy from 3 to 12 months delays but does not prevent recurrence, the risk of which begins to accumulate once anticoagulation is stopped.^24,25

Three promising strategies to identify subgroups of patients with idiopathic VTE who are at highest risk of recurrence and who would benefit the most from prolonged anticoagulation are d-dimer testing, evaluation for residual vein thrombosis in patients who present with a deep vein thrombosis, and clinical prediction rules.

d-dimer testing

d-dimer is a degradation product of fibrin and is an indirect marker of residual thrombosis.³⁰

In a systematic review of patients with a first episode of unprovoked VTE,³¹ a normal d-dimer concentration at the end of at least 3 months of anticoagulation was associated with a 3.5% annual risk of recurrence, whereas an elevated d-dimer level at that time was associated with an annual risk of 8.9%. These results were confirmed in a systematic review of individual patient data.³²

In a randomized trial,²⁸ patients with an idiopathic VTE event who received anticoagulation for at least 3 months had their d-dimer level measured 1 month after cessation of treatment. Those with an elevated level were randomized to either resume anticoagulation or not. Patients who resumed anticoagulation had an annual recurrence rate of 2%; however, those who were allocated not to restart anticoagulation had a recurrence rate of 10.9% per year. There was no difference in the rate of major bleeding between the two groups. Patients in this clinical trial who had a normal d-dimer level did not restart anticoagulation and had an annual recurrence rate of 4.4%.

Evaluation for residual thrombosis

Patients who have residual deep vein thrombosis after treatment have been shown to have higher rates of recurrent VTE.³³ Therefore, repeating Doppler ultrasonography is another clinical consideration that may help establish the optimal duration of anticoagulation.

A randomized trial³⁴ in patients with both provoked and idiopathic deep vein thrombosis showed a reduction in recurrence when those who had residual vein thrombosis were given extended anticoagulation. In the subset of patients whose deep vein thrombosis was idiopathic, the recurrence rate was 17% per year when treatment lasted only 3 months and 10% when it was extended for up to 1 year.

Another trial³⁵ randomized patients with provoked and idiopathic deep vein thrombosis to receive anticoagulation for the usual duration or to continue treatment until recanalization of the residual thrombus was demonstrated on follow-up Doppler ultrasonography. Patients who received this ultrasonography-tailored treatment had a lower rate of recurrence of VTE; however, the absolute reductions in recurrence rates cannot be calculated from this report for patients with idiopathic deep vein thrombosis.

A prospective observational study³⁶ of the predictive value of d-dimer status and residual vein thrombus found that only d-dimer was an independent risk factor for recurrent VTE after vitamin K antagonist withdrawal.

A clinical prediction rule: ‘Men and HERDOO₂’

A promising tool for predicting if a patient is at low risk of recurrent VTE after the first episode of proximal deep vein thrombosis or pulmonary embolism is known by the mnemonic device “Men and HERDOO₂.” It is based on data prospectively derived by Rodger et al³⁷ to identify patients with less than a 3% annual risk of recurrent VTE after their first event of idiopathic proximal deep vein thrombosis or pulmonary embolism. Risk factors for recurrent VTE were male sex (the “men” of “Men and HERDOO₂”), signs of postthrombotic syndrome, including hyperpigmentation of the lower extremities, edema or redness of either leg, a d-dimer level > 250 μg/L, obesity (body mass index > 30 kg/m², and older age (> 65 years).

Overall, one-fourth of the population were women with no risk factors or one risk factor, and their risk of recurrence was 1.6% per year. Men and women who had two or more risk factors for postthrombotic syndrome (hyperpigmentation, edema, or redness), elevated d-dimer, obesity, or older age were predicted to be at higher risk of recurrent VTE. Patients such as this should be considered for indefinite anticoagulation.

Ideally, clinical prediction rules should be validated in a separate group of patients before they are used routinely in practice,³⁸ and this clinical prediction rule is currently being tested in the REVERSE II study. If the results are consistent, this will be an easy-to-use tool to help identify patients who likely can safely stop anticoagulation therapy after 3 to 6 months (clinicaltrials.gov Identifier: NCT00967304).

The location of the thrombosis also influences the likelihood of recurrence. Patients with isolated distal (calf) deep vein thrombosis are less likely to suffer recurrent VTE than those who present with proximal deep vein thrombosis. However, trials focusing specifically on the precise subset of idiopathic isolated distal deep vein thrombosis are lacking. In a randomized trial³⁹ comparing 6 vs 12 weeks of anticoagulation for isolated distal deep vein thrombosis and 12 vs 24 weeks for proximal deep vein thrombosis, the annual rates of recurrence after 12 weeks of treatment were approximately 3.4% for isolated distal and 8.1% for proximal deep vein thrombosis.³⁹

 

 

Recommendation: At least 3 months of warfarin or equivalent

We agree with the ACCP recommendation² that patients with unprovoked VTE should receive at least 3 months of anticoagulation with a vitamin K antagonist.

If the patient has no risk factors for bleeding and good anticoagulant monitoring is achievable, we agree with long-term anticoagulation for proximal unprovoked deep vein thrombosis or pulmonary embolism, and 3 months of therapy for isolated distal unprovoked deep vein thrombosis.

Patient preferences and the risk of recurrence vs the risk of bleeding should be discussed with patients when contemplating indefinite anticoagulation.

If testing is being considered to assist in the decision to prescribe indefinite anticoagulation, we prefer using d-dimer levels rather than ultrasonography to detect residual venous thrombosis because of its ease of use and the strength of the current evidence.

PREVENTING POSTTHROMBOTIC SYNDROME

The postthrombotic (postphlebitic) syndrome is a chronic and burdensome consequence of deep vein thrombosis that occurs despite anticoagulation therapy. It is estimated to affect 23% to 60% of patients and typically manifests in the first 2 years.⁴⁰ It is not only costly in clinical terms, with decreased quality of life for the patient, but health care expenditures have been estimated to range from $400 per year in a Brazilian study to $7,000 per year in a US study.⁴⁰

Typical symptoms include leg pain, heaviness, swelling, and cramping. In severe cases, chronic venous ulcers can occur and are difficult to treat.⁴¹

The definition of postthrombotic syndrome has been unclear over the years, and six different scales that measure signs and symptoms have been reported.⁴²

The Villalta scale has been proposed by the International Society of Thrombosis and Hemostasis as a diagnostic standard to define postthrombotic syndrome.⁴² This validated scale is based on five clinical symptoms, six clinical signs, and the presence or absence of venous ulcers. Each clinical symptom and sign is scored as mild (1 point), moderate (2 points), or severe (3 points). Symptoms include pain, cramps, heaviness, paresthesia, and pruritus; the six clinical signs are pretibial edema, skin induration, hyperpigmentation, redness, venous ectasia, and pain on calf compression.

According to the International Society of Thrombosis and Hemostasis, postthrombotic syndrome is present if the Villalta score is 5 or greater or if a venous ulcer is present in a leg with previous deep vein thrombosis. Further, using the Villalta scale, postthrombotic syndrome can be categorized as mild (score 5–9), moderate (10–14), or severe (≥ 15).

A limitation of the Villalta scale is that the presence or absence of a venous ulcer has not been assigned a score. Since a venous ulcer requires more aggressive measures, the society defines postthrombotic syndrome as severe if venous ulcers are present.⁴²

Acute symptoms of deep vein thrombosis may take months to resolve and, indeed, acute symptoms may transition to chronic symptoms without a symptom-free interval. It is recommended that postthrombotic syndrome not be diagnosed before 3 months to avoid inappropriately attributing acute symptoms and signs of deep vein thrombosis to the postthrombotic syndrome.⁴²

Studies of stockings

A systematic review of three randomized trials⁴⁴ concluded that elastic compression stockings reduce the risk of postthrombotic syndrome (any severity) from 43% to 20% and severe postthrombotic syndrome from 15% to 7%.⁴³

The first of these trials⁴⁴ randomized patients soon after the diagnosis of deep vein thrombosis to receive made-to-order compression stockings that were rated at 30 to 40 mm Hg or to be in a control group that did not receive stockings. The second trial⁴⁵ randomized patients 1 year after the index event of deep vein thrombosis to receive 20- to 30-mm Hg stockings or stockings that were two sizes too large (the control group). The third study⁴⁶ randomly allocated patients to receive “off-the-shelf” stockings (30–40 mm Hg) or no stockings. Each study used its own definition of postthrombotic syndrome.

Although these studies strongly suggest compression stockings prevent postthrombotic syndrome, several methodologic issues remain:

• A standard definition of postthrombotic syndrome was not used
• The amount of compression varied between studies
• The studies were not blinded.

Lack of blinding becomes most significant when an outcome is based on subjective findings, like the symptoms that make up a large part of the diagnosis of postthrombotic syndrome.

The SOX trial, currently under way, is designed to address these methodologic issues and should be completed in 2012 (clinicaltrials.gov Identifier: NCT00143598).

Recommendation: Stockings for at least 2 years

We agree with the ACCP recommendation that a patient who has had a symptomatic proximal deep vein thrombosis should wear an elastic compression stocking with an ankle pressure gradient of 30 to 40 mm Hg as soon as possible after starting anticoagulant therapy and continuing for a minimum of 2 years.²

 

SCREENING FOR OCCULT MALIGNANCY

VTE can be the first manifestation of cancer.

French physician Armand Trousseau, in the 1860s, was the first to describe disseminated intravascular coagulation closely associated with adenocarcinoma. Ironically, several years later, after suffering for weeks from abdominal pain, he declared to one of his students that he had developed thrombosis, and he died of gastric cancer shortly thereafter.⁴⁷

Since cancer is a well-known risk factor for VTE, it is logical to screen for cancer as an explanation for an idiopathic VTE event.⁴⁸ To make an informed decision, one needs to understand the rate of occult cancer at the time VTE is diagnosed, the risk of future development of cancer, and the utility of extensive cancer screening.

The clinical efficacy, side effects, and cost-effectiveness of cancer screening in patients with idiopathic VTE are unknown. However, a systematic review⁴⁷ of 34 studies found that, in patients with idiopathic VTE, cancer was diagnosed within 1 month in 6.1%, within 6 months in 8.6%, and within 1 year in 10.0% (95% CI 8.6–11.3).

A subset of studies compared two strategies for screening soon after the diagnosis of idiopathic VTE: a strategy limited to the history, physical examination, basic blood work, and chest radiography vs an extensive screening strategy that also included serum tumor markers or abdominal ultrasonography or computed tomography. Limited screening detected 49% of the prevalent cancers; extensive screening increased this rate to 70%. Stated another way, the detection rate for prevalent cancers was 5% with limited screening and 7% with extensive screening soon after the diagnosis of idiopathic VTE.⁴⁷

Patients with idiopathic VTE had higher rates of cancer within 1 month of diagnosis than patients with provoked VTE (6.1% vs 1.9%), and this difference persisted at 1 year (10.0% vs 2.6%).⁴⁷

Recommendation: Individualized cancer screening

Patients with idiopathic VTE have a significant risk of occult cancer within the first year after diagnosis, and cancer screening should be considered. Our practice for patients with idiopathic VTE is to perform a history and physical examination and ensure that the patient is up to date on age- and sex-specific cancer screening.

The use of additional imaging or biomarkers should be discussed with patients so they can balance the risks (radiation and potential false-positive results with their downstream consequences), costs, and potential benefits, given the lack of proven survival benefit or cost-effectiveness.

ORAL ANTICOAGULANT MANAGEMENT

Warfarin’s multiple interactions, along with the need for INR monitoring, make it a difficult medication to manage.

The Joint Commission, the US organization for health service accreditation and certification, has defined National Patient Safety Goals and quality measures for the management of anticoagulation.⁴⁹ Organized anticoagulation management services, dosing algorithms, and patient self-testing using capillary INR meters or patient self-management of warfarin were recommended as tools to improve the time patients spend in the therapeutic INR range.⁵⁰

Two new oral anticoagulants

The limitations of warfarin have stimulated the search for newer oral anticoagulants that do not require laboratory monitoring or have as many diet and drug interactions.

Two trials have been published with experimental oral anticoagulants that had similar efficacy and safety as warfarin in the treatment of VTE.

The study of dabigatran (Pradaxa) vs warfarin in the treatment of acute VTE (the RECOVER trial)⁵¹ randomized 2,539 patients with acute VTE to receive the oral direct thrombin inhibitor dabigatran or warfarin for approximately 6 months. Of note, each treatment group received a median of 6 days of heparin, LMWH, or fondaparinux at the beginning of blinded therapy. The rates of recurrent VTE and major bleeding were similar between the treatment arms, and overall bleeding was less with dabigatran. Dabigatran was approved in the United States in October 2010 for stroke prevention in atrial fibrillation but has yet to be approved for the treatment of VTE pending further study (clinicaltrials.gov Identifier: NCT00680186).

A study of oral rivaroxaban (Xarelto) for symptomatic VTE (the EINSTEIN-DVT trial) ⁵² randomized 3,449 patients with acute deep vein thrombosis to rivaroxaban or enoxaparin (Lovenox) overlapped with warfarin or another vitamin K antagonist in the usual manner. No difference was noted between the treatments in the rate of recurrence of VTE or of major bleeding. Of note, patients randomized to rivaroxaban received 15 mg twice a day for the first 3 weeks of treatment and then 20 mg per day for the remainder of their therapy and did not require parenteral anticoagulant overlap.

The long-awaited promise of easier-to-use oral anticoagulants for the treatment of VTE is drawing near and has the potential to revolutionize the treatment of this common disorder. In the meantime, close monitoring of warfarin and careful patient education regarding its use are essential. And even with the development of new drugs in the future, it is still imperative that patients with acute VTE receive the correct length of anticoagulation treatment, are prescribed stockings to prevent postthrombotic syndrome, and are updated on routine cancer screening.

Deep vein thrombosis and pulmonary embolism are collectively referred to as venous thromboembolic (VTE) disease. They affect approximately 100,000 to 300,000 patients per year in the United States.¹ Although patients with deep vein thrombosis can be treated as outpatients, many are admitted for the initiation of anticoagulation. Initial anticoagulation usually requires the overlap of a parenteral anticoagulant (unfractionated heparin, low-molecular-weight heparin [LMWH] or fondaparinux) with warfarin for a minimum of 5 days and until the international normalized ratio (INR) of the prothrombin time is above 2.0 for at least 24 hours.²

Three clinical issues need to be addressed after the initiation of anticoagulation for VTE:

• Determination of the length of anticoagulation with the correct anticoagulant
• Prevention of postthrombotic syndrome
• Appropriate screening for occult malignancy.

HOW LONG SHOULD VTE BE TREATED?

The duration of anticoagulation has been a matter of debate.

The risk of recurrent VTE appears related to clinical risk factors that a patient has at the time of the initial thrombotic event. An epidemiologic study³ found that patients with VTE treated for approximately 6 months had a low rate of recurrence (0% at 2 years of follow-up) if surgery was the risk factor. The risk climbed to 9% if the risk factor was nonsurgical and to 19% if there were no provoking risk factors.

The likelihood of VTE recurrence and therefore the recommended duration of treatment depend on whether the VTE event was provoked, cancer-related, recurrent, thrombophilia-related, or idiopathic. We address each of these scenarios below.

HOW LONG TO TREAT PROVOKED VTE

A VTE event is considered provoked if the patient had a clear inciting risk factor. As defined in various clinical trials, these risk factors include:

• Hospitalization with confinement to bed for 3 or more consecutive days in the last 3 months
• Surgery or general anesthesia in the last 3 months
• Immobilization for more than 7 days, regardless of the cause
• Trauma in the last 3 months
• Pregnancy
• Use of an oral contraceptive, regardless of which estrogen or progesterone analogue it contains
• Travel for more than 4 hours
• Recent childbirth.

However, the trials that tested different lengths of anticoagulation have varied markedly in how they defined provoked deep vein thrombosis.^4–7

A systematic review⁸ showed that patients who developed VTE after surgery had a lower rate of recurrent VTE at 12 and 24 months than patients with a nonsurgical provoking risk factor, and patients with nonprovoked (idiopathic) VTE had the highest risk of recurrence (Table 1).

Recommendation: Warfarin or equivalent for 3 months

The American College of Chest Physicians (ACCP) recommends 3 months of anticoagulation with warfarin or another vitamin K antagonist for patients with VTE secondary to a transient (reversible) risk factor,² and we agree.

HOW LONG TO TREAT CANCER-RELATED VTE

Patients with cancer are at higher risk of developing VTE. Furthermore, in one study,⁹ compared with other patients with VTE, patients with cancer were three times more likely to have another episode of VTE, with a cumulative rate of recurrence at 1 year of 21% vs 7%. Cancer patients were also twice as likely to suffer major bleeding complications while on anticoagulation.⁹

Warfarin is a difficult drug to manage because it has many interactions with foods, diseases, and other drugs. These difficulties are amplified in many cancer patients during chemotherapy.

Warfarin was compared with a LMWH in four randomized trials in cancer patients, and a meta-analysis¹⁰ found a 50% relative reduction in the rates of recurrent deep vein thrombosis and pulmonary embolism with LMWH treatment. These results were driven primarily by the CLOT trial (Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer),¹¹ which showed an 8% absolute risk reduction (number needed to treat 13) without an increase in major bleeding when cancer-related VTE was treated with an LMWH—ie, dalteparin (Fragmin)—for 6 months compared with warfarin.

Current thinking suggests that VTE should be treated until the cancer is resolved. However, this hypothesis has not been adequately tested, and consequently, the ACCP gives it only a level 1C recommendation.² The largest of the four trials comparing warfarin and an LMWH lasted only 6 months. The safety of extending LMWH treatment beyond 6 months is currently unknown but is under investigation (clinicaltrials.gov identifier NCT00942968).

 

 

Recommendation: LMWH therapy for at least 6 months

The ACCP guidelines recommend LMWH therapy for 3 to 6 months, followed by warfarin or another vitamin K antagonist or continued LMWH treatment until the cancer is resolved.²

The National Comprehensive Cancer Network guidelines recommend an LMWH for 6 months as monotherapy and indefinite anticoagulation if the cancer is still active.¹²

The American Society of Clinical Oncology guidelines recommend an LMWH for at least 6 months and indefinite anticoagulant therapy for selected patients with active cancer.¹³

We agree that patients with active cancer should receive an LMWH for at least 6 months and indefinite anticoagulation until the cancer is resolved.

In our experience, many patients are reluctant to give themselves the daily injections that LMWH therapy requires, and so they need to be well-informed about the marked decrease in VTE recurrence with this less-convenient and more-expensive therapy. Many patients face insurance barriers to cover the cost of LMWH therapy; however, careful attention to preauthorization can usually overcome this obstacle.

HOW LONG TO TREAT RECURRENT VTE

It makes clinical sense that patients who have a second VTE event should be treated indefinitely. This theory was tested in a randomized clinical trial¹⁴ in which patients with provoked or unprovoked VTE were randomized after their second event to receive anticoagulation for 6 months vs indefinitely.

After 4 years of follow-up, the recurrence rate was 21% in patients assigned to 6 months of treatment and only 3% in patients who continued anticoagulation throughout the trial. On the other hand, major hemorrhage occurred in 3% of patients treated for 6 months and in 9% in patients who continued anticoagulation indefinitely.

Of note, most of the patients in this trial had unprovoked (idiopathic) VTE, so the results should not be extrapolated to patients with provoked VTE, who accounted for only 20% of the study population.¹⁴

Recommendation: Long-term anticoagulation

We agree with the ACCP recommendation² that patients who have had a second episode of unprovoked VTE should receive long-term anticoagulation. Because of a lack of data, the duration of therapy for patients with a second episode of provoked VTE should be individualized.

HOW LONG TO TREAT THROMBOPHILIA-RELATED VTE

Inherited thrombophilias

Patients with VTE that is not related to a clear provoking risk factor or cancer frequently have testing to evaluate for a hypercoagulable state. This workup traditionally includes the most common inherited thrombophilias for gene mutations for factor V and prothrombin as well as for deficiencies in protein C, protein S, antithrombin and the acquired antiphospholipid syndrome.

The key questions that should be asked prior to embarking on this workup are:

• Will the results change the length of therapy for the patient?
• Will testing the patient help with genetic counseling and possible testing of family members?
• Will the results change the targeted INR range for warfarin or other vitamin K antagonist therapy?

Patients with inherited thrombophilia have a greater risk of developing an initial VTE event; however, these tests do not help predict the recurrence of VTE in patients with established disease more than clinical risk factors do. A prospective study demonstrated this by looking at the effect of thrombophilia and clinical factors on the recurrence of venous thrombosis and found that inherited prothrombotic abnormalities do not appear to play an important role in the risk of a recurrent event.¹⁵ On the other hand, clinical factors, such as whether the first event was idiopathic or provoked, appear more important in determining the duration of anticoagulation therapy.¹⁵ A systematic review of the common inherited thrombophilias showed the VTE recurrence rate of patients with factor V Leiden was higher than in patients without the mutation; however, the absolute rates of recurrence were not much different than what would be expected in patients with idiopathic VTE.¹⁶

A retrospective study involving a large cohort of families of patients who already had experienced a first episode of either idiopathic or provoked VTE showed high annual risks of recurrent VTE associated with hereditary deficiencies of protein S (8.4%), protein C (6.0%), and antithrombin (10%).¹⁷ However, for the more commonly occurring genetic thrombophilias, the factor V Leiden and prothrombin G20210A mutations, family members with either gene abnormality had low rates of VTE, suggesting that testing of relatives of probands is not clinically useful.¹⁶

Antiphospholipid syndrome

Antiphospholipid syndrome is an acquired thrombophilia. A patient has thrombotic antiphospholipid syndrome when there is a history of vascular thrombosis in the presence of persistently positive tests (at least 12 weeks apart) for lupus anticoagulants, anticardiolipin antibodies, or anti-beta-2 glycoprotein I. A prospective study of 412 patients with a first episode of VTE found that 15% were positive for anticardiolipin antibody at the end of 6 months of anticoagulation. The risk of recurrent VTE after 4 years was 29% in patients with antibodies and 14% in those without antibodies (relative risk 2.1; 95% confidence interval [CI] 1.3–3.3; P =.0013).¹⁸

Recent reviews advise indefinite warfarin anticoagulation in patients with VTE and persistence of antiphospholipid antibodies.¹⁹ However, the optimal duration of anticoagulation is uncertain. Until well-designed clinical trials are done, the current general consensus is to anticoagulate these patients indefinitely.^20,21 Retrospective studies had suggested that patients with antiphospholipid antibodies required a higher therapeutic INR range; however, this observation was tested in two trials that found no difference in thromboembolic rates when patients were randomized to an INR of 2.0–3.0 vs 3.1–4.0,²² or 2.0–3.0 vs 3.0–4.5.²³

No formal recommendations

In the absence of strong evidence, the ACCP guidelines do not include a recommendation on the duration of anticoagulation treatment specific to inherited thrombophilias. We believe that clinical factors are more important than inherited thrombophilias for deciding the duration of anticoagulation, and that testing is almost never indicated or useful. However, patients with antiphospholipid syndrome are at high risk of recurrence, and it is our practice to anticoagulate these patients indefinitely.

 

HOW LONG TO TREAT UNPROVOKED (IDIOPATHIC) VTE

A VTE event is thought to be idiopathic if it occurs without a clearly identified provoking factor.

Commonly accepted risk factors for VTE are recent surgery, hospitalization for an acute medical illness, active cancer, and some inherited thrombophilias. Less clear is whether immobilization, pregnancy, use of female hormones, and long-distance travel should also be considered as provoking conditions. Various trials have used different combinations of risk factors as exclusion criteria to define idiopathic (unprovoked) VTE when assessing the length or intensity of anticoagulation (Table 2).^24–29 The ACCP guidelines² cite estrogen therapy, pregnancy, and travel longer than 8 hours as minor risk factors for VTE.

In an observational study,³ patients with oral contraceptive use, transient illness, immobilization, or a history of travel had an 8.8% risk of recurrence vs 19.4% in patients with unprovoked VTE. The meta-analysis discussed above (Table 1)⁸ also shows that patients with these nonsurgical risk factors have a lower rate of recurrence than patients with idiopathic VTE.

The high rate of recurrence of idiopathic VTE (4% to 27% after 3 months of anticoagulation^24–26) suggests that a longer duration of treatment is reasonable. However, increasing the length of therapy from 3 to 12 months delays but does not prevent recurrence, the risk of which begins to accumulate once anticoagulation is stopped.^24,25

Three promising strategies to identify subgroups of patients with idiopathic VTE who are at highest risk of recurrence and who would benefit the most from prolonged anticoagulation are d-dimer testing, evaluation for residual vein thrombosis in patients who present with a deep vein thrombosis, and clinical prediction rules.

d-dimer testing

d-dimer is a degradation product of fibrin and is an indirect marker of residual thrombosis.³⁰

In a systematic review of patients with a first episode of unprovoked VTE,³¹ a normal d-dimer concentration at the end of at least 3 months of anticoagulation was associated with a 3.5% annual risk of recurrence, whereas an elevated d-dimer level at that time was associated with an annual risk of 8.9%. These results were confirmed in a systematic review of individual patient data.³²

In a randomized trial,²⁸ patients with an idiopathic VTE event who received anticoagulation for at least 3 months had their d-dimer level measured 1 month after cessation of treatment. Those with an elevated level were randomized to either resume anticoagulation or not. Patients who resumed anticoagulation had an annual recurrence rate of 2%; however, those who were allocated not to restart anticoagulation had a recurrence rate of 10.9% per year. There was no difference in the rate of major bleeding between the two groups. Patients in this clinical trial who had a normal d-dimer level did not restart anticoagulation and had an annual recurrence rate of 4.4%.

Evaluation for residual thrombosis

Patients who have residual deep vein thrombosis after treatment have been shown to have higher rates of recurrent VTE.³³ Therefore, repeating Doppler ultrasonography is another clinical consideration that may help establish the optimal duration of anticoagulation.

A randomized trial³⁴ in patients with both provoked and idiopathic deep vein thrombosis showed a reduction in recurrence when those who had residual vein thrombosis were given extended anticoagulation. In the subset of patients whose deep vein thrombosis was idiopathic, the recurrence rate was 17% per year when treatment lasted only 3 months and 10% when it was extended for up to 1 year.

Another trial³⁵ randomized patients with provoked and idiopathic deep vein thrombosis to receive anticoagulation for the usual duration or to continue treatment until recanalization of the residual thrombus was demonstrated on follow-up Doppler ultrasonography. Patients who received this ultrasonography-tailored treatment had a lower rate of recurrence of VTE; however, the absolute reductions in recurrence rates cannot be calculated from this report for patients with idiopathic deep vein thrombosis.

A prospective observational study³⁶ of the predictive value of d-dimer status and residual vein thrombus found that only d-dimer was an independent risk factor for recurrent VTE after vitamin K antagonist withdrawal.

A clinical prediction rule: ‘Men and HERDOO₂’

A promising tool for predicting if a patient is at low risk of recurrent VTE after the first episode of proximal deep vein thrombosis or pulmonary embolism is known by the mnemonic device “Men and HERDOO₂.” It is based on data prospectively derived by Rodger et al³⁷ to identify patients with less than a 3% annual risk of recurrent VTE after their first event of idiopathic proximal deep vein thrombosis or pulmonary embolism. Risk factors for recurrent VTE were male sex (the “men” of “Men and HERDOO₂”), signs of postthrombotic syndrome, including hyperpigmentation of the lower extremities, edema or redness of either leg, a d-dimer level > 250 μg/L, obesity (body mass index > 30 kg/m², and older age (> 65 years).

Overall, one-fourth of the population were women with no risk factors or one risk factor, and their risk of recurrence was 1.6% per year. Men and women who had two or more risk factors for postthrombotic syndrome (hyperpigmentation, edema, or redness), elevated d-dimer, obesity, or older age were predicted to be at higher risk of recurrent VTE. Patients such as this should be considered for indefinite anticoagulation.

Ideally, clinical prediction rules should be validated in a separate group of patients before they are used routinely in practice,³⁸ and this clinical prediction rule is currently being tested in the REVERSE II study. If the results are consistent, this will be an easy-to-use tool to help identify patients who likely can safely stop anticoagulation therapy after 3 to 6 months (clinicaltrials.gov Identifier: NCT00967304).

The location of the thrombosis also influences the likelihood of recurrence. Patients with isolated distal (calf) deep vein thrombosis are less likely to suffer recurrent VTE than those who present with proximal deep vein thrombosis. However, trials focusing specifically on the precise subset of idiopathic isolated distal deep vein thrombosis are lacking. In a randomized trial³⁹ comparing 6 vs 12 weeks of anticoagulation for isolated distal deep vein thrombosis and 12 vs 24 weeks for proximal deep vein thrombosis, the annual rates of recurrence after 12 weeks of treatment were approximately 3.4% for isolated distal and 8.1% for proximal deep vein thrombosis.³⁹

 

 

Recommendation: At least 3 months of warfarin or equivalent

We agree with the ACCP recommendation² that patients with unprovoked VTE should receive at least 3 months of anticoagulation with a vitamin K antagonist.

If the patient has no risk factors for bleeding and good anticoagulant monitoring is achievable, we agree with long-term anticoagulation for proximal unprovoked deep vein thrombosis or pulmonary embolism, and 3 months of therapy for isolated distal unprovoked deep vein thrombosis.

Patient preferences and the risk of recurrence vs the risk of bleeding should be discussed with patients when contemplating indefinite anticoagulation.

If testing is being considered to assist in the decision to prescribe indefinite anticoagulation, we prefer using d-dimer levels rather than ultrasonography to detect residual venous thrombosis because of its ease of use and the strength of the current evidence.

PREVENTING POSTTHROMBOTIC SYNDROME

The postthrombotic (postphlebitic) syndrome is a chronic and burdensome consequence of deep vein thrombosis that occurs despite anticoagulation therapy. It is estimated to affect 23% to 60% of patients and typically manifests in the first 2 years.⁴⁰ It is not only costly in clinical terms, with decreased quality of life for the patient, but health care expenditures have been estimated to range from $400 per year in a Brazilian study to $7,000 per year in a US study.⁴⁰

Typical symptoms include leg pain, heaviness, swelling, and cramping. In severe cases, chronic venous ulcers can occur and are difficult to treat.⁴¹

The definition of postthrombotic syndrome has been unclear over the years, and six different scales that measure signs and symptoms have been reported.⁴²

The Villalta scale has been proposed by the International Society of Thrombosis and Hemostasis as a diagnostic standard to define postthrombotic syndrome.⁴² This validated scale is based on five clinical symptoms, six clinical signs, and the presence or absence of venous ulcers. Each clinical symptom and sign is scored as mild (1 point), moderate (2 points), or severe (3 points). Symptoms include pain, cramps, heaviness, paresthesia, and pruritus; the six clinical signs are pretibial edema, skin induration, hyperpigmentation, redness, venous ectasia, and pain on calf compression.

According to the International Society of Thrombosis and Hemostasis, postthrombotic syndrome is present if the Villalta score is 5 or greater or if a venous ulcer is present in a leg with previous deep vein thrombosis. Further, using the Villalta scale, postthrombotic syndrome can be categorized as mild (score 5–9), moderate (10–14), or severe (≥ 15).

A limitation of the Villalta scale is that the presence or absence of a venous ulcer has not been assigned a score. Since a venous ulcer requires more aggressive measures, the society defines postthrombotic syndrome as severe if venous ulcers are present.⁴²

Acute symptoms of deep vein thrombosis may take months to resolve and, indeed, acute symptoms may transition to chronic symptoms without a symptom-free interval. It is recommended that postthrombotic syndrome not be diagnosed before 3 months to avoid inappropriately attributing acute symptoms and signs of deep vein thrombosis to the postthrombotic syndrome.⁴²

Studies of stockings

A systematic review of three randomized trials⁴⁴ concluded that elastic compression stockings reduce the risk of postthrombotic syndrome (any severity) from 43% to 20% and severe postthrombotic syndrome from 15% to 7%.⁴³

The first of these trials⁴⁴ randomized patients soon after the diagnosis of deep vein thrombosis to receive made-to-order compression stockings that were rated at 30 to 40 mm Hg or to be in a control group that did not receive stockings. The second trial⁴⁵ randomized patients 1 year after the index event of deep vein thrombosis to receive 20- to 30-mm Hg stockings or stockings that were two sizes too large (the control group). The third study⁴⁶ randomly allocated patients to receive “off-the-shelf” stockings (30–40 mm Hg) or no stockings. Each study used its own definition of postthrombotic syndrome.

Although these studies strongly suggest compression stockings prevent postthrombotic syndrome, several methodologic issues remain:

• A standard definition of postthrombotic syndrome was not used
• The amount of compression varied between studies
• The studies were not blinded.

Lack of blinding becomes most significant when an outcome is based on subjective findings, like the symptoms that make up a large part of the diagnosis of postthrombotic syndrome.

The SOX trial, currently under way, is designed to address these methodologic issues and should be completed in 2012 (clinicaltrials.gov Identifier: NCT00143598).

Recommendation: Stockings for at least 2 years

We agree with the ACCP recommendation that a patient who has had a symptomatic proximal deep vein thrombosis should wear an elastic compression stocking with an ankle pressure gradient of 30 to 40 mm Hg as soon as possible after starting anticoagulant therapy and continuing for a minimum of 2 years.²

 

SCREENING FOR OCCULT MALIGNANCY

VTE can be the first manifestation of cancer.

French physician Armand Trousseau, in the 1860s, was the first to describe disseminated intravascular coagulation closely associated with adenocarcinoma. Ironically, several years later, after suffering for weeks from abdominal pain, he declared to one of his students that he had developed thrombosis, and he died of gastric cancer shortly thereafter.⁴⁷

Since cancer is a well-known risk factor for VTE, it is logical to screen for cancer as an explanation for an idiopathic VTE event.⁴⁸ To make an informed decision, one needs to understand the rate of occult cancer at the time VTE is diagnosed, the risk of future development of cancer, and the utility of extensive cancer screening.

The clinical efficacy, side effects, and cost-effectiveness of cancer screening in patients with idiopathic VTE are unknown. However, a systematic review⁴⁷ of 34 studies found that, in patients with idiopathic VTE, cancer was diagnosed within 1 month in 6.1%, within 6 months in 8.6%, and within 1 year in 10.0% (95% CI 8.6–11.3).

A subset of studies compared two strategies for screening soon after the diagnosis of idiopathic VTE: a strategy limited to the history, physical examination, basic blood work, and chest radiography vs an extensive screening strategy that also included serum tumor markers or abdominal ultrasonography or computed tomography. Limited screening detected 49% of the prevalent cancers; extensive screening increased this rate to 70%. Stated another way, the detection rate for prevalent cancers was 5% with limited screening and 7% with extensive screening soon after the diagnosis of idiopathic VTE.⁴⁷

Patients with idiopathic VTE had higher rates of cancer within 1 month of diagnosis than patients with provoked VTE (6.1% vs 1.9%), and this difference persisted at 1 year (10.0% vs 2.6%).⁴⁷

Recommendation: Individualized cancer screening

Patients with idiopathic VTE have a significant risk of occult cancer within the first year after diagnosis, and cancer screening should be considered. Our practice for patients with idiopathic VTE is to perform a history and physical examination and ensure that the patient is up to date on age- and sex-specific cancer screening.

The use of additional imaging or biomarkers should be discussed with patients so they can balance the risks (radiation and potential false-positive results with their downstream consequences), costs, and potential benefits, given the lack of proven survival benefit or cost-effectiveness.

ORAL ANTICOAGULANT MANAGEMENT

Warfarin’s multiple interactions, along with the need for INR monitoring, make it a difficult medication to manage.

The Joint Commission, the US organization for health service accreditation and certification, has defined National Patient Safety Goals and quality measures for the management of anticoagulation.⁴⁹ Organized anticoagulation management services, dosing algorithms, and patient self-testing using capillary INR meters or patient self-management of warfarin were recommended as tools to improve the time patients spend in the therapeutic INR range.⁵⁰

Two new oral anticoagulants

The limitations of warfarin have stimulated the search for newer oral anticoagulants that do not require laboratory monitoring or have as many diet and drug interactions.

Two trials have been published with experimental oral anticoagulants that had similar efficacy and safety as warfarin in the treatment of VTE.

The study of dabigatran (Pradaxa) vs warfarin in the treatment of acute VTE (the RECOVER trial)⁵¹ randomized 2,539 patients with acute VTE to receive the oral direct thrombin inhibitor dabigatran or warfarin for approximately 6 months. Of note, each treatment group received a median of 6 days of heparin, LMWH, or fondaparinux at the beginning of blinded therapy. The rates of recurrent VTE and major bleeding were similar between the treatment arms, and overall bleeding was less with dabigatran. Dabigatran was approved in the United States in October 2010 for stroke prevention in atrial fibrillation but has yet to be approved for the treatment of VTE pending further study (clinicaltrials.gov Identifier: NCT00680186).

A study of oral rivaroxaban (Xarelto) for symptomatic VTE (the EINSTEIN-DVT trial) ⁵² randomized 3,449 patients with acute deep vein thrombosis to rivaroxaban or enoxaparin (Lovenox) overlapped with warfarin or another vitamin K antagonist in the usual manner. No difference was noted between the treatments in the rate of recurrence of VTE or of major bleeding. Of note, patients randomized to rivaroxaban received 15 mg twice a day for the first 3 weeks of treatment and then 20 mg per day for the remainder of their therapy and did not require parenteral anticoagulant overlap.

The long-awaited promise of easier-to-use oral anticoagulants for the treatment of VTE is drawing near and has the potential to revolutionize the treatment of this common disorder. In the meantime, close monitoring of warfarin and careful patient education regarding its use are essential. And even with the development of new drugs in the future, it is still imperative that patients with acute VTE receive the correct length of anticoagulation treatment, are prescribed stockings to prevent postthrombotic syndrome, and are updated on routine cancer screening.

A 50-year-old male Japanese immigrant with a history of smoking and occasional untreated heartburn presented with the recent onset of flank pain, weight loss, headache, syncope, and blurred vision.

Previously healthy, he began feeling moderate pain in his left flank 1 month ago; it was diagnosed as kidney stones and was treated conservatively. Two weeks later he had an episode of syncope and soon after developed blurred vision, mainly in his left eye, along with severe bifrontal headache. An eye examination and magnetic resonance imaging of the brain indicated optic neuritis, for which he was given glucocorticoids intravenously for 3 days, with moderate improvement.

As his symptoms continued over the next 2 weeks, he lost 20 lb (9.1 kg) due to the pain, loss of appetite, nausea, and occasional vomiting.

Computed tomography (CT) at our clinic revealed an extensive heterogeneous ill-defined infiltrative process in the retroperitoneum extending into the left pelvis, invading the left psoas, left hemidiaphragm, and left adrenal gland (Figure 1A). Also noted were left hydronephrosis, related to compression of the left ureter, and stomach-wall thickening, most marked near the cardia (Figure 1B).

Positron emission tomography showed the retroperitoneal infiltrative process and the thickened gastric cardia to be hypermetabolic (Figure 1C).

The area of retroperitoneal infiltration was biopsied under CT guidance, and pathologic study showed poorly differentiated carcinoma with signet-ring cells, a feature of gastric cancer.

The patient underwent lumbar puncture. His cerebrospinal fluid had 206 white blood cells/μL (reference range 0–5) and large numbers of poorly differentiated malignant cells, most consistent with adenocarcinoma on cytologic study.

Esophagogastro-
duodenoscopy (EGD) revealed a large, ulcerated, submucosal, nodular mass in the cardia of the stomach extending to the gastroesophageal junction (Figure 2A). Biopsy of the mass again revealed poorly differentiated adenocarcinoma with scattered signet-ring cells undermining the gastric mucosa, favoring a gastric origin (Figure 2B).

THREE SUBTYPES OF GASTRIC CANCER

Worldwide, gastric cancer is the third most common type of cancer and the second most common cause of cancer-related deaths.¹ In the United States, blacks and people of Asian ancestry have almost twice the risk of death, with the highest incidence and mortality rates.^2,3

Most cases of gastric adenocarcinoma can be categorized as either intestinal or diffuse, but a new proximal subtype is emerging.⁴

Intestinal-type gastric adenocarcinoma is the most common subtype and accounts for almost all the ethnic and geographic variation in incidence.² The lesions are often ulcerative and distal; the pathogenesis is stepwise and is initiated by chronic inflammation. Risk factors include old age, Helicobacter pylori infection, tobacco smoking, family history, and high salt intake, with an observed risk-reduction with the use of nonsteroidal anti-inflammatory drugs and with a high intake of fruits and vegetables.³

Diffuse gastric adenocarcinoma, on the other hand, has a uniform distribution worldwide, and its incidence is increasing. It typically carries a poor prognosis. Evidence thus far has shown its pathogenesis to be independent of chronic inflammation, but it has a strong tendency to be hereditary.³

Proximal gastric adenocarcinoma is observed in the gastric cardia and near the gastroesophageal junction. It is often grouped with the distal esophageal adenocarcinomas and has similar risk factors, including reflux disease, obesity, alcohol abuse, and tobacco smoking. Interestingly, however, H pylori infection does not contribute to the pathogenesis of this type, and it may even have a protective role.³

DIFFICULT TO DETECT EARLY

Gastric cancer is difficult to detect early enough in its course to be cured. Understanding its risk factors, recognizing its common symptoms, and regarding its uncommon symptoms with suspicion may lead to earlier diagnosis and more effective treatment.

Our patient’s proximal gastric cancer was diagnosed late even though he had several risk factors for it (he was Japanese, he was a smoker, and he had gastroesophageal reflux disease) because of a late and atypical presentation with misleading paraneoplastic symptoms.

Early diagnosis is difficult because most patients have no symptoms in the early stage; weight loss and abdominal pain are often late signs of tumor progression.

Screening may be justified in high-risk groups in the United States, although the issue is debatable. Diagnostic imaging is the only effective method for screening,⁵ with EGD considered the first-line targeted evaluation should there be suspicion of gastric cancer either from the clinical presentation or from barium swallow.⁶ Candidates for screening may include elderly patients with atrophic gastritis or pernicious anemia, immigrants from countries with high rates of gastric carcinoma, and people with a family history of gastrointestinal cancer.⁷

A 50-year-old male Japanese immigrant with a history of smoking and occasional untreated heartburn presented with the recent onset of flank pain, weight loss, headache, syncope, and blurred vision.

Previously healthy, he began feeling moderate pain in his left flank 1 month ago; it was diagnosed as kidney stones and was treated conservatively. Two weeks later he had an episode of syncope and soon after developed blurred vision, mainly in his left eye, along with severe bifrontal headache. An eye examination and magnetic resonance imaging of the brain indicated optic neuritis, for which he was given glucocorticoids intravenously for 3 days, with moderate improvement.

As his symptoms continued over the next 2 weeks, he lost 20 lb (9.1 kg) due to the pain, loss of appetite, nausea, and occasional vomiting.

Computed tomography (CT) at our clinic revealed an extensive heterogeneous ill-defined infiltrative process in the retroperitoneum extending into the left pelvis, invading the left psoas, left hemidiaphragm, and left adrenal gland (Figure 1A). Also noted were left hydronephrosis, related to compression of the left ureter, and stomach-wall thickening, most marked near the cardia (Figure 1B).

Positron emission tomography showed the retroperitoneal infiltrative process and the thickened gastric cardia to be hypermetabolic (Figure 1C).

The area of retroperitoneal infiltration was biopsied under CT guidance, and pathologic study showed poorly differentiated carcinoma with signet-ring cells, a feature of gastric cancer.

The patient underwent lumbar puncture. His cerebrospinal fluid had 206 white blood cells/μL (reference range 0–5) and large numbers of poorly differentiated malignant cells, most consistent with adenocarcinoma on cytologic study.

Esophagogastro-
duodenoscopy (EGD) revealed a large, ulcerated, submucosal, nodular mass in the cardia of the stomach extending to the gastroesophageal junction (Figure 2A). Biopsy of the mass again revealed poorly differentiated adenocarcinoma with scattered signet-ring cells undermining the gastric mucosa, favoring a gastric origin (Figure 2B).

THREE SUBTYPES OF GASTRIC CANCER

Worldwide, gastric cancer is the third most common type of cancer and the second most common cause of cancer-related deaths.¹ In the United States, blacks and people of Asian ancestry have almost twice the risk of death, with the highest incidence and mortality rates.^2,3

Most cases of gastric adenocarcinoma can be categorized as either intestinal or diffuse, but a new proximal subtype is emerging.⁴

Intestinal-type gastric adenocarcinoma is the most common subtype and accounts for almost all the ethnic and geographic variation in incidence.² The lesions are often ulcerative and distal; the pathogenesis is stepwise and is initiated by chronic inflammation. Risk factors include old age, Helicobacter pylori infection, tobacco smoking, family history, and high salt intake, with an observed risk-reduction with the use of nonsteroidal anti-inflammatory drugs and with a high intake of fruits and vegetables.³

Diffuse gastric adenocarcinoma, on the other hand, has a uniform distribution worldwide, and its incidence is increasing. It typically carries a poor prognosis. Evidence thus far has shown its pathogenesis to be independent of chronic inflammation, but it has a strong tendency to be hereditary.³

Proximal gastric adenocarcinoma is observed in the gastric cardia and near the gastroesophageal junction. It is often grouped with the distal esophageal adenocarcinomas and has similar risk factors, including reflux disease, obesity, alcohol abuse, and tobacco smoking. Interestingly, however, H pylori infection does not contribute to the pathogenesis of this type, and it may even have a protective role.³

DIFFICULT TO DETECT EARLY

Gastric cancer is difficult to detect early enough in its course to be cured. Understanding its risk factors, recognizing its common symptoms, and regarding its uncommon symptoms with suspicion may lead to earlier diagnosis and more effective treatment.

Our patient’s proximal gastric cancer was diagnosed late even though he had several risk factors for it (he was Japanese, he was a smoker, and he had gastroesophageal reflux disease) because of a late and atypical presentation with misleading paraneoplastic symptoms.

Early diagnosis is difficult because most patients have no symptoms in the early stage; weight loss and abdominal pain are often late signs of tumor progression.

Screening may be justified in high-risk groups in the United States, although the issue is debatable. Diagnostic imaging is the only effective method for screening,⁵ with EGD considered the first-line targeted evaluation should there be suspicion of gastric cancer either from the clinical presentation or from barium swallow.⁶ Candidates for screening may include elderly patients with atrophic gastritis or pernicious anemia, immigrants from countries with high rates of gastric carcinoma, and people with a family history of gastrointestinal cancer.⁷

A 50-year-old male Japanese immigrant with a history of smoking and occasional untreated heartburn presented with the recent onset of flank pain, weight loss, headache, syncope, and blurred vision.

Previously healthy, he began feeling moderate pain in his left flank 1 month ago; it was diagnosed as kidney stones and was treated conservatively. Two weeks later he had an episode of syncope and soon after developed blurred vision, mainly in his left eye, along with severe bifrontal headache. An eye examination and magnetic resonance imaging of the brain indicated optic neuritis, for which he was given glucocorticoids intravenously for 3 days, with moderate improvement.

As his symptoms continued over the next 2 weeks, he lost 20 lb (9.1 kg) due to the pain, loss of appetite, nausea, and occasional vomiting.

Computed tomography (CT) at our clinic revealed an extensive heterogeneous ill-defined infiltrative process in the retroperitoneum extending into the left pelvis, invading the left psoas, left hemidiaphragm, and left adrenal gland (Figure 1A). Also noted were left hydronephrosis, related to compression of the left ureter, and stomach-wall thickening, most marked near the cardia (Figure 1B).

Positron emission tomography showed the retroperitoneal infiltrative process and the thickened gastric cardia to be hypermetabolic (Figure 1C).

The area of retroperitoneal infiltration was biopsied under CT guidance, and pathologic study showed poorly differentiated carcinoma with signet-ring cells, a feature of gastric cancer.

The patient underwent lumbar puncture. His cerebrospinal fluid had 206 white blood cells/μL (reference range 0–5) and large numbers of poorly differentiated malignant cells, most consistent with adenocarcinoma on cytologic study.

Esophagogastro-
duodenoscopy (EGD) revealed a large, ulcerated, submucosal, nodular mass in the cardia of the stomach extending to the gastroesophageal junction (Figure 2A). Biopsy of the mass again revealed poorly differentiated adenocarcinoma with scattered signet-ring cells undermining the gastric mucosa, favoring a gastric origin (Figure 2B).

THREE SUBTYPES OF GASTRIC CANCER

Worldwide, gastric cancer is the third most common type of cancer and the second most common cause of cancer-related deaths.¹ In the United States, blacks and people of Asian ancestry have almost twice the risk of death, with the highest incidence and mortality rates.^2,3

Most cases of gastric adenocarcinoma can be categorized as either intestinal or diffuse, but a new proximal subtype is emerging.⁴

Intestinal-type gastric adenocarcinoma is the most common subtype and accounts for almost all the ethnic and geographic variation in incidence.² The lesions are often ulcerative and distal; the pathogenesis is stepwise and is initiated by chronic inflammation. Risk factors include old age, Helicobacter pylori infection, tobacco smoking, family history, and high salt intake, with an observed risk-reduction with the use of nonsteroidal anti-inflammatory drugs and with a high intake of fruits and vegetables.³

Diffuse gastric adenocarcinoma, on the other hand, has a uniform distribution worldwide, and its incidence is increasing. It typically carries a poor prognosis. Evidence thus far has shown its pathogenesis to be independent of chronic inflammation, but it has a strong tendency to be hereditary.³

Proximal gastric adenocarcinoma is observed in the gastric cardia and near the gastroesophageal junction. It is often grouped with the distal esophageal adenocarcinomas and has similar risk factors, including reflux disease, obesity, alcohol abuse, and tobacco smoking. Interestingly, however, H pylori infection does not contribute to the pathogenesis of this type, and it may even have a protective role.³

DIFFICULT TO DETECT EARLY

Gastric cancer is difficult to detect early enough in its course to be cured. Understanding its risk factors, recognizing its common symptoms, and regarding its uncommon symptoms with suspicion may lead to earlier diagnosis and more effective treatment.

Our patient’s proximal gastric cancer was diagnosed late even though he had several risk factors for it (he was Japanese, he was a smoker, and he had gastroesophageal reflux disease) because of a late and atypical presentation with misleading paraneoplastic symptoms.

Early diagnosis is difficult because most patients have no symptoms in the early stage; weight loss and abdominal pain are often late signs of tumor progression.

Screening may be justified in high-risk groups in the United States, although the issue is debatable. Diagnostic imaging is the only effective method for screening,⁵ with EGD considered the first-line targeted evaluation should there be suspicion of gastric cancer either from the clinical presentation or from barium swallow.⁶ Candidates for screening may include elderly patients with atrophic gastritis or pernicious anemia, immigrants from countries with high rates of gastric carcinoma, and people with a family history of gastrointestinal cancer.⁷

Hepatic encephalopathy is a serious but often reversible complication that arises when the liver cannot detoxify the portal venous blood (Table 1).¹

Prompt identification and treatment are essential, because once overt encephalopathy develops the prognosis worsens rapidly. Thus, internists and other primary care physicians who care for patients with severe liver disease play a key role in identifying the condition. They will often see the patients when hepatic encephalopathy is in its early stages and its neuropsychiatric manifestations—reduced attention, diminishing fine motor skills, or impaired communication—are subtle. Since primary care physicians see patients over a longer span of time, they are more likely to recognize these subtle changes.

PROPOSED PATHOGENETIC FACTORS

About 5.5 million cases of chronic liver disease and cirrhosis were reported in the United States in 2001. Hepatic encephalopathy is becoming more common as the prevalence of cirrhosis increases,² and this will have important economic repercussions; in 2001, charges from hospitalizations because of hepatic encephalopathy were estimated at $932 million.³

Hepatic encephalopathy develops as cirrhosis progresses or as a result of portosystemic shunting, so that the liver cannot detoxify the portal venous blood. Several neurotoxins (notably ammonia) and inflammatory mediators play key roles in its pathogenesis, inducing low-grade brain edema and producing a wide spectrum of neuropsychiatric manifestations.⁴ Yet its pathogenesis is not entirely understood, impeding advances in its diagnosis and therapy.

Several hypotheses about the pathogenesis of hepatic encephalopathy have emerged in the last few years, and a number of factors are reported to directly or indirectly affect brain function in this condition. Ammonia and glutamine are the neurotoxins most often implicated in this syndrome⁵; others include inflammatory mediators, certain amino acids, and manganese.^5,6

Ammonia causes brain swelling

Ammonia is primarily the byproduct of bacterial metabolism of protein and nitrogenous compounds in the colon and of glutamine metabolism in enterocytes.⁷

Normally, gut-absorbed ammonia is delivered via the portal vein to the liver, where most of it is metabolized into urea, leaving a small amount to be metabolized in the muscles, heart, brain, and kidneys. In cirrhosis and other conditions associated with hepatic encephalopathy, less ammonia is metabolized into urea and more of it reaches the astrocytes in the brain. The brain lacks a urea cycle but metabolizes ammonia to glutamine via glutamine synthase, an enzyme unique to astrocytes.

Ammonia causes swelling of astrocytes and brain edema via generation of glutamine, an osmotically active substance.

Glutamine causes swelling, oxidative stress

Glutamine draws water into astrocytes and induces changes of type II astrocytosis (also called Alzheimer type II astrocytosis)⁵ characterized by swelling, enlarged and pale nuclei, and displacement of chromatin to the periphery of the cell. Inhibition of glutamine synthase prevents astrocyte swelling in animals.⁸

Glutamine also enhances the activation of several receptors, including N-methyl-d-aspartate (NMDA) receptors,^9,10 gammaaminobutyric acid (GABA) receptors, and peripheral-type benzodiazepine receptors on the mitochondrial membrane.^10–12 A state of oxidative stress ensues, and this affects oxidation of protein and RNA, neurotransmitter synthesis, and neurotransmission at the neuronal junction.¹³ Reactive nitrogen and oxide radicals induce the release of inflammatory mediators such as interleukins 1 and 6, tumor necrosis factor, interferons, and neurosteroids, and contribute to edema and neurotoxicity.^6,10 Neurosteroids are byproducts of mitochondrial metabolism of steroid hormones in the astrocyte.

Manganese enhances neurosteroid synthesis

Manganese enhances neurosteroid synthesis via activation of translocator proteins on the astrocyte membrane. It was first recognized as a factor in hepatic encephalopathy when cirrhotic patients experiencing extrapyramidal symptoms were found to have deposits of manganese in the caudate nucleus and in the globus pallidus on magnetic resonance imaging (MRI). Such deposits were also seen in specimens of brain tissue on autopsy of these patients. When the encephalopathy resolved, so did the abnormalities on MRI.^14,15

Changes in the blood-brain barrier

Astrocytes contribute to the selective permeability of the blood-brain barrier. Disruptions in the permeability of the blood-brain barrier underlie hepatic encephalopathy, with poor diffusion of molecules out of astrocytes.

For instance, zinc, which plays a regulatory role in gene transcription and synaptic plasticity, accumulates in the astrocytes, causing relative zinc deficiency and further affecting neurotransmitter synthesis and neurotransmission at the neuronal synapse.^6,16

 

 

Hyponatremia

Hyponatremia (a serum sodium concentration < 130 mmol/L) is increasingly being recognized as an independent predictor of overt hepatic encephalopathy and is reported to increase the risk by a factor of eight.¹⁷

Neuronal dysfunction

Astrocytes are integral to the physiologic functioning of the neurons, and it is becoming clear that both neurons and astrocytes are affected in hepatic encephalopathy.

Additionally, neuroinflammation and a decrease in energy metabolism by the brain are described during episodes of hepatic encephalopathy.¹⁸

Amino acid imbalance

An imbalance between aromatic amino acids (ie, high levels of tyrosine and phenylalanine) and branched-chain amino acids (leucine, isoleucine, and valine) has been linked with encephalopathy in patients with liver disease, ^19–21 but it is not totally clear whether this imbalance contributes to hepatic encephalopathy or is a consequence of it.

Low-grade brain edema

Edema of the brain occurs in all forms of hepatic encephalopathy, but in cirrhosis it is characteristically of low grade. The mechanism behind this low-grade edema is not clear. Studies have shown that swelling of astrocytes is not global but involves certain areas of the brain and is associated with compensatory extrusion of intracellular myoinositol.²² This, in combination with a mild degree of brain atrophy²³ observed in patients with chronic liver disease, is thought to keep the brain from extreme swelling and herniation, a phenomenon usually seen in acute hepatic failure.^24,25

Transjugular intrahepatic portosystemic shunting and encephalopathy

The incidence rate of hepatic encephalopathy after placement of a portosystemic shunt to treat portal hypertension ranges from 30% to 55% and is similar to the rate in cirrhotic patients without a shunt.²⁶ In 5% to 8% of patients, the hepatic encephalopathy is refractory and requires intentional occlusion of the shunt.^26,27 An elevated serum creatinine level appears to be a risk factor for refractory hepatic encephalopathy in patients with a portosystemic shunt.²⁶

In one study,²⁸ when transjugular intrahepatic portosystemic shunting was done early in the treatment of cirrhotic patients with acute variceal bleeding, the rates of treatment failure and death were significantly less than in a control group that received endoscopic therapy, and no significant difference was noted in the rate of encephalopathy or of serious adverse effects between the groups.

Whether to place a portosystemic shunt in a patient with cirrhosis and a history of hepatic encephalopathy depends on the possible underlying causes of the encephalopathy. For example, if encephalopathy was precipitated by variceal bleeding, shunt placement will prevent further bleeding and will make a recurrence of encephalopathy less likely. However, if the encephalopathy is persistent and uncontrollable, then shunt placement is contraindicated.²⁷

A SPECTRUM OF SYMPTOMS

The spectrum of symptoms extends from a subclinical syndrome that may not be clinically apparent (early-stage or “minimal” hepatic encephalopathy) to full-blown neuropsychiatric manifestations such as cognitive impairment, confusion, slow speech, loss of fine motor skills, asterixis, peripheral neuropathy, clonus, the Babinski sign, decerebrate and decorticate posturing, seizures, extrapyramidal symptoms, and coma.⁴ The clinical manifestations are usually reversible with prompt treatment, but recurrence is common, typically induced by an event such as gastrointestinal bleeding or an infection.

Minimal hepatic encephalopathy is important to recognize

Although this subclinical syndrome is a very early stage, it is nevertheless associated with higher rates of morbidity and can affect quality of life, including the patient’s ability to drive a car.^29,30

Abnormal changes in the brain begin at this stage and eventually progress to more damage and to the development of overt clinical symptoms.

The exact prevalence of minimal hepatic encephalopathy is not known because it is difficult to diagnose, but reported rates range between 30% and 84% of patients with cirrhosis.³¹ Progression from minimal to overt hepatic encephalopathy is 3.7 times more likely than in patients without the diagnosis of minimal hepatic encephalopathy.³²

Thus, minimal hepatic encephalopathy is important to identify,²⁹ so that treatment can be started.

Overt encephalopathy and survival

The prevalence of overt encephalopathy in cirrhosis ranges from 30% to 40% and is even higher in the advanced stages. Once encephalopathy develops, the prognosis worsens rapidly. In patients who do not undergo liver transplantation, the survival rate at 1 year is 42%, and the survival rate at 3 years is 23%.³³

These rates are worse than those after liver transplantation, and the American Association for the Study of Liver Diseases recommends that patients with cirrhosis who develop a first episode of encephalopathy be considered for liver transplantation and be referred to a transplantation center.³⁴

CHALLENGES IN DIAGNOSIS

Since the symptoms of hepatic encephalopathy are not specific and can be subtle in the early stage, its diagnosis may be a challenge. It is important to recognize that this neuropsychiatric complication occurs in people with severe comorbidities and requires dedicated time for evaluation and management.

 

 

Special tests may be needed to detect subclinical hepatic encephalopathy

In subclinical hepatic encephalopathy, the apparent lack of manifestations poses a great diagnostic challenge, but a thorough history may uncover poor social interaction, personality changes, poor performance at work, and recent traffic violations or motor vehicle accidents. Primary care physicians are usually the first to suspect the condition because they are familiar with the patient’s baseline mental and physical conditions.

For example, the primary care physician may notice decreased attention and worsening memory during a follow-up visit, or the physician may ask whether the patient has difficulty with work performance and handwork (psychomotor and fine motor skills), and whether there have been traffic violations or car accidents (visuospatial skills). Such clues, although not restrictive, may help identify patients with minimal hepatic encephalopathy and prompt referral for neuropsychiatric testing.

Neurologic deficits described in the subclinical form are in the domains of attention and concentration, working memory, visuospatial ability, and fine motor skills; communication skills remain intact.³⁵ These deficits are not reliably detected on standard clinical evaluation but can be detected by neuropsychiatric and neurophysiologic testing.

While several tests for minimal hepatic encephalopathy have been developed, they need to be validated in large trials in the United States.

Neurophysiologic tests include electroencephalography and auditory or visual event-related P300 (evoked potential) testing.

Neuropsychiatric tests traditionally involved several batteries administered and interpreted by specialized personnel. They were time-consuming and were not practical in a typical office setting. They were later refined into the Psychometric Hepatic Encephalopathy Score test (ie, the PSE syndrome test).³⁶ This combines a digit symbol test, a serial dotting test, a line-tracing test, and a number-connection or figure-connection test. An abnormal result in at least three of the four subtests constitutes an overall abnormal PSE syndrome test.

The PSE syndrome test has been validated for standard use in Germany, Spain, Italy, the United Kingdom, and India.³⁵ In 1999, the Working Group on Hepatic Encephalopathy designated it as the official test for minimal hepatic encephalopathy.¹ But the test has not been validated for use in the United States. Other tests have been developed, but their use is also limited by a lack of validation and by copyright laws. These factors constitute major obstacles to the diagnosis of subclinical hepatic encephalopathy in the United States. Nonetheless, physicians who suspect minimal hepatic encephalopathy may start lactulose therapy³⁷ and schedule frequent follow-up visits to address and manage potential precipitating factors for overt hepatic encephalopathy.

Staging the severity of the encephalopathy

When symptoms are overt, staging should be done to define the severity of the disease. The most commonly used staging scales are the West Haven Grading System (Table 2)³⁸ and the Glasgow Coma Scale (Table 3).³⁹

It is essential to exclude stroke, cerebral bleeding, and brain tumor before making a diagnosis of a first episode of hepatic encephalopathy. Thereafter, such exclusion must be guided by whether the patient has risk factors for these conditions or persistent symptoms of encephalopathy that do not respond to medical therapy.

Symptoms often resolve if precipitating factors are treated (Table 4). The most common precipitating factors include infections, dehydration, drug toxicity, and variceal bleeding.

Laboratory tests can identify metabolic derangements

Although laboratory tests are not diagnostic for hepatic encephalopathy, they can identify metabolic derangements that could contribute to it.

Blood ammonia levels are often measured in cirrhotic patients suspected of having hepatic encephalopathy, but this is not a reliable indicator, since many conditions and even prolonged tourniquet application during blood-drawing can raise blood ammonia levels (Table 5).

Imaging can help exclude other diagnoses

Conventional imaging studies of the brain, ie, computed tomography and MRI, are useful only to exclude a stroke, a brain tumor, or an intracranial or subdural hematoma. They may identify changes in the white matter and deposits of manganese in the basal ganglia in patients with cirrhosis with or without subclinical hepatic encephalopathy, but they are not likely to show low-grade brain edema.⁴⁰

Neurophysiologic imaging studies such as magnetic resonance spectroscopy, magnetic transfer imaging, and water-mapping techniques have helped elucidate pathologic mechanisms of hepatic encephalopathy and are available in research centers, but they are not currently considered for diagnosis.

SEVERAL LINES OF TREATMENT

Treatment of hepatic encephalopathy involves a preemptive approach to address potential precipitating factors, medical therapy to reduce the production and absorption of ammonia from the gut, and surgical or interventional therapies. A multidisciplinary approach for testing the severity of neurologic impairment and response to therapy is needed to help determine if and when liver transplantation is required.

Prevent potential precipitating factors

An important concept in managing hepatic encephalopathy is to recognize that every cirrhotic patient is at risk and to make an effort to address potential precipitating factors during regular clinic visits. This includes reviewing medication dosing and adverse effects, emphasizing abstinence from alcohol and other toxic substances, and preventing bleeding from esophageal varices with endoscopic band ligation.

 

 

Diet therapy

The prevalence of malnutrition in cirrhosis may be as high as 100%. Vitamin and nutritional deficiencies should be evaluated by a nutrition specialist, and nutritional needs should be reassessed on a regular basis. Protein restriction is no longer recommended and may even be harmful.

Guidelines of the European Society of Parenteral and Enteric Nutrition in 2006 recommended that patients with liver disease should have an energy intake of 35 to 40 kcal/kg of body weight daily, with a total daily protein intake of 1.2 to 1.5 mg/kg of body weight.⁴¹ Frequent meals and bedtime snacks are encouraged to avoid periods of prolonged fasting and catabolism of muscle protein and to improve nitrogen balance. Branched-chain amino acids and vegetable protein supplements are suggested to help meet the daily requirements.⁴²

Drug therapy to reduce neurotoxins

Drug treatment is directed at reducing the neurotoxins that accumulate in cirrhosis. A variety of agents have been used.

Lactulose (Kristalose) is approved by the US Food and Drug Administration (FDA) as a first-line treatment. It has been shown to improve quality of life and cognitive function in patients with cirrhosis and minimal hepatic encephalopathy, although it has failed to improve mortality rates.³⁷

Lactulose, a cathartic disaccharide, is metabolized by colonic bacteria into short-chain fatty acids. The acidic microenvironment has three major effects:

• It aids the transformation of ammonia to ammonium (NH4⁺), which is then trapped in the stool, leaving less ammonia to be absorbed
• It has a cathartic effect
• It reduces the breakdown of nitrogenous compounds into ammonia.⁴³

Lactulose has an excessively sweet taste. Its side effects include flatulence, abdominal discomfort, and diarrhea. The usual oral dose is 15 to 45 mL/day given in multiple doses to induce two to three soft bowel movements daily. At this dosage, the monthly cost varies between $60 and $120.

Lactilol, a nonabsorbable disaccharide, is as effective as lactulose but with fewer side effects. It is not available in the United States.

Rifaximin (Xifaxan), a derivative of rifamycin, is FDA-approved for the maintenance of remission of hepatic encephalopathy but is not recommended as a first-line agent. It inhibits bacterial RNA synthesis in the gut. Less than 0.4% of an oral dose is absorbed.⁴⁴

In a randomized, double-blind, placebo-controlled trial in patients who had had at least two episodes of hepatic encephalopathy while on lactulose therapy, taking rifaximin 550 mg twice a day for 6 months provided a prolonged remission from recurrences of encephalopathy compared with placebo.⁴⁵ Side effects included nausea, vomiting, abdominal pain, weight loss, and Clostridium difficile colitis, which was reported in two cases in the study.⁴⁵

Unfortunately, the effects of this drug beyond 6 months of therapy have not been studied. In addition, the drug is expensive: 1 month of treatment with rifaximin can cost between $700 and $1,500. Combining lactulose and rifaximin adds to the costs and the side effects, and contributes to poor adherence to therapy.

Other antibiotics such as metronidazole (Flagyl), vancomycin, and neomycin have been used as alternatives to lactulose, based on the principle that they reduce ammonia-producing bacteria in the gut. However, their efficacy in hepatic encephalopathy remains to be determined.

In controlled trials, neomycin combined with sorbitol, magnesium sulfate, or lactulose was as effective as lactulose, but when used alone, neomycin was no better than placebo.^46,47 Neomycin was approved many years ago as an adjunct in the management of hepatic coma, but it has since fallen out of favor in the management of hepatic encephalopathy because of poor trial results and because of neurotoxicity and ototoxicity.

Branched-chain amino acids (leucine, isoleucine, and valine)⁴⁸ are reported to increase ammonia intake in muscle and to improve cognitive functions on the PSE scale in minimal hepatic encephalopathy,^49,50 but they did not decrease the rate of recurrence of hepatic encephalopathy.⁵¹ While debate continues over their efficacy in the management of hepatic encephalopathy, branched-chain amino acids may be used to improve nutritional status and muscle mass of patients with cirrhosis. However, the dosing is not standardized, and long-term compliance may be problematic.

Other medical therapies include zinc,¹⁶ sodium benzoate,⁵⁰ and l-ornithine-l-aspartate^52,53 to stimulate residual urea cycle activities; probiotics (which pose a risk of sepsis from fungi and lactobacilli); and laxatives.

Liver dialysis

Adsorbing toxins from the blood via liver dialysis or using a non-cell-based liver support system such as MARS (Molecular Adsorbent Recirculating System, Gambro, Inc.) appears to improve the amino acid profile in hepatic encephalopathy, but its role has not been clarified, and its use is limited to clinical trials.^54,55

Transjugular intrahepatic shunts and large portosystemic shunts may need to be closed in order to reverse encephalopathy refractory to drug therapy.^26,27,56

Liver transplantation

The current scoring system for end-stage liver disease does not include hepatic encephalopathy as a criterion for prioritizing patients on the transplantation list because it was originally developed to assess short-term prognosis in patients undergoing transjugular intrahepatic shunting. As a consequence, patients with end-stage liver disease are at increased risk of repeated episodes of encephalopathy, hospital readmission, and death. Therefore, the American Association for the Study of Liver Diseases recommends referral to a transplantation center when the patient experiences a first episode of overt hepatic encephalopathy to initiate a workup for liver transplantation.³⁴

Liver transplantation improves survival in patients with severe hepatic dysfunction, but the presence of neurologic deficits may result in significant morbidity and in death.^57,58 After transplantation, resolution of cognitive dysfunction, brain edema, and white-matter changes have been reported,⁵⁹ but neuronal cell death and persistent cognitive impairment after resolution of overt hepatic encephalopathy are also described.^60–63

Whether neurologic impairment will resolve after liver transplantation depends on a number of factors: the severity of encephalopathy before transplantation; the nature of the neurologic deficits; advanced age; history of alcohol abuse and the presence of alcoholic brain damage; persistence of portosystemic shunts after transplant; emergency transplantation; complications during surgery; and side effects of immunosuppressive drugs.^57,58,64

The optimal timing of liver transplantation is not clearly defined for patients who have had bouts of hepatic encephalopathy, and more study is needed to determine the reversibility of clinical symptoms and brain damage. It is in these situations that neuropsychiatric testing and advanced neuroimaging can help determine the efficacy of therapeutic interventions, and it should be considered part of the pretransplantation evaluation.

Managing sleep disturbances

Insomnia and other changes in sleep-wake patterns are common in patients with cirrhosis, especially advanced cirrhosis.⁶⁵ It is not known whether these changes represent early stages of hepatic encephalopathy.⁶⁶ Patients often complain of fatigue, the need for frequent naps, and lethargy during the day and restlessness and inability to sleep at night. This affects the patient’s behavior and daytime functioning, and it also burdens household members and caregivers.

Long-acting benzodiazepines should be avoided when treating sleep disorders in cirrhosis because they may precipitate the encephalopathy. In a randomized controlled trial, hydroxyzine (Vistaril) at a dose of 25 mg at bedtime improved sleep behavior in 40% of patients with cirrhosis and subclinical hepatic encephalopathy, but 1 of 17 patients developed acute encephalopathy, which reversed with cessation of the hydroxyzine.⁶⁶ Clearly, caution and close monitoring are required when giving hydroxyzine for sleep disorders in cirrhotic patients.

Hepatic encephalopathy is a serious but often reversible complication that arises when the liver cannot detoxify the portal venous blood (Table 1).¹

Prompt identification and treatment are essential, because once overt encephalopathy develops the prognosis worsens rapidly. Thus, internists and other primary care physicians who care for patients with severe liver disease play a key role in identifying the condition. They will often see the patients when hepatic encephalopathy is in its early stages and its neuropsychiatric manifestations—reduced attention, diminishing fine motor skills, or impaired communication—are subtle. Since primary care physicians see patients over a longer span of time, they are more likely to recognize these subtle changes.

PROPOSED PATHOGENETIC FACTORS

About 5.5 million cases of chronic liver disease and cirrhosis were reported in the United States in 2001. Hepatic encephalopathy is becoming more common as the prevalence of cirrhosis increases,² and this will have important economic repercussions; in 2001, charges from hospitalizations because of hepatic encephalopathy were estimated at $932 million.³

Hepatic encephalopathy develops as cirrhosis progresses or as a result of portosystemic shunting, so that the liver cannot detoxify the portal venous blood. Several neurotoxins (notably ammonia) and inflammatory mediators play key roles in its pathogenesis, inducing low-grade brain edema and producing a wide spectrum of neuropsychiatric manifestations.⁴ Yet its pathogenesis is not entirely understood, impeding advances in its diagnosis and therapy.

Several hypotheses about the pathogenesis of hepatic encephalopathy have emerged in the last few years, and a number of factors are reported to directly or indirectly affect brain function in this condition. Ammonia and glutamine are the neurotoxins most often implicated in this syndrome⁵; others include inflammatory mediators, certain amino acids, and manganese.^5,6

Ammonia causes brain swelling

Ammonia is primarily the byproduct of bacterial metabolism of protein and nitrogenous compounds in the colon and of glutamine metabolism in enterocytes.⁷

Normally, gut-absorbed ammonia is delivered via the portal vein to the liver, where most of it is metabolized into urea, leaving a small amount to be metabolized in the muscles, heart, brain, and kidneys. In cirrhosis and other conditions associated with hepatic encephalopathy, less ammonia is metabolized into urea and more of it reaches the astrocytes in the brain. The brain lacks a urea cycle but metabolizes ammonia to glutamine via glutamine synthase, an enzyme unique to astrocytes.

Ammonia causes swelling of astrocytes and brain edema via generation of glutamine, an osmotically active substance.

Glutamine causes swelling, oxidative stress

Glutamine draws water into astrocytes and induces changes of type II astrocytosis (also called Alzheimer type II astrocytosis)⁵ characterized by swelling, enlarged and pale nuclei, and displacement of chromatin to the periphery of the cell. Inhibition of glutamine synthase prevents astrocyte swelling in animals.⁸

Glutamine also enhances the activation of several receptors, including N-methyl-d-aspartate (NMDA) receptors,^9,10 gammaaminobutyric acid (GABA) receptors, and peripheral-type benzodiazepine receptors on the mitochondrial membrane.^10–12 A state of oxidative stress ensues, and this affects oxidation of protein and RNA, neurotransmitter synthesis, and neurotransmission at the neuronal junction.¹³ Reactive nitrogen and oxide radicals induce the release of inflammatory mediators such as interleukins 1 and 6, tumor necrosis factor, interferons, and neurosteroids, and contribute to edema and neurotoxicity.^6,10 Neurosteroids are byproducts of mitochondrial metabolism of steroid hormones in the astrocyte.

Manganese enhances neurosteroid synthesis

Manganese enhances neurosteroid synthesis via activation of translocator proteins on the astrocyte membrane. It was first recognized as a factor in hepatic encephalopathy when cirrhotic patients experiencing extrapyramidal symptoms were found to have deposits of manganese in the caudate nucleus and in the globus pallidus on magnetic resonance imaging (MRI). Such deposits were also seen in specimens of brain tissue on autopsy of these patients. When the encephalopathy resolved, so did the abnormalities on MRI.^14,15

Changes in the blood-brain barrier

Astrocytes contribute to the selective permeability of the blood-brain barrier. Disruptions in the permeability of the blood-brain barrier underlie hepatic encephalopathy, with poor diffusion of molecules out of astrocytes.

For instance, zinc, which plays a regulatory role in gene transcription and synaptic plasticity, accumulates in the astrocytes, causing relative zinc deficiency and further affecting neurotransmitter synthesis and neurotransmission at the neuronal synapse.^6,16

 

 

Hyponatremia

Hyponatremia (a serum sodium concentration < 130 mmol/L) is increasingly being recognized as an independent predictor of overt hepatic encephalopathy and is reported to increase the risk by a factor of eight.¹⁷

Neuronal dysfunction

Astrocytes are integral to the physiologic functioning of the neurons, and it is becoming clear that both neurons and astrocytes are affected in hepatic encephalopathy.

Additionally, neuroinflammation and a decrease in energy metabolism by the brain are described during episodes of hepatic encephalopathy.¹⁸

Amino acid imbalance

An imbalance between aromatic amino acids (ie, high levels of tyrosine and phenylalanine) and branched-chain amino acids (leucine, isoleucine, and valine) has been linked with encephalopathy in patients with liver disease, ^19–21 but it is not totally clear whether this imbalance contributes to hepatic encephalopathy or is a consequence of it.

Low-grade brain edema

Edema of the brain occurs in all forms of hepatic encephalopathy, but in cirrhosis it is characteristically of low grade. The mechanism behind this low-grade edema is not clear. Studies have shown that swelling of astrocytes is not global but involves certain areas of the brain and is associated with compensatory extrusion of intracellular myoinositol.²² This, in combination with a mild degree of brain atrophy²³ observed in patients with chronic liver disease, is thought to keep the brain from extreme swelling and herniation, a phenomenon usually seen in acute hepatic failure.^24,25

Transjugular intrahepatic portosystemic shunting and encephalopathy

The incidence rate of hepatic encephalopathy after placement of a portosystemic shunt to treat portal hypertension ranges from 30% to 55% and is similar to the rate in cirrhotic patients without a shunt.²⁶ In 5% to 8% of patients, the hepatic encephalopathy is refractory and requires intentional occlusion of the shunt.^26,27 An elevated serum creatinine level appears to be a risk factor for refractory hepatic encephalopathy in patients with a portosystemic shunt.²⁶

In one study,²⁸ when transjugular intrahepatic portosystemic shunting was done early in the treatment of cirrhotic patients with acute variceal bleeding, the rates of treatment failure and death were significantly less than in a control group that received endoscopic therapy, and no significant difference was noted in the rate of encephalopathy or of serious adverse effects between the groups.

Whether to place a portosystemic shunt in a patient with cirrhosis and a history of hepatic encephalopathy depends on the possible underlying causes of the encephalopathy. For example, if encephalopathy was precipitated by variceal bleeding, shunt placement will prevent further bleeding and will make a recurrence of encephalopathy less likely. However, if the encephalopathy is persistent and uncontrollable, then shunt placement is contraindicated.²⁷

A SPECTRUM OF SYMPTOMS

The spectrum of symptoms extends from a subclinical syndrome that may not be clinically apparent (early-stage or “minimal” hepatic encephalopathy) to full-blown neuropsychiatric manifestations such as cognitive impairment, confusion, slow speech, loss of fine motor skills, asterixis, peripheral neuropathy, clonus, the Babinski sign, decerebrate and decorticate posturing, seizures, extrapyramidal symptoms, and coma.⁴ The clinical manifestations are usually reversible with prompt treatment, but recurrence is common, typically induced by an event such as gastrointestinal bleeding or an infection.

Minimal hepatic encephalopathy is important to recognize

Although this subclinical syndrome is a very early stage, it is nevertheless associated with higher rates of morbidity and can affect quality of life, including the patient’s ability to drive a car.^29,30

Abnormal changes in the brain begin at this stage and eventually progress to more damage and to the development of overt clinical symptoms.

The exact prevalence of minimal hepatic encephalopathy is not known because it is difficult to diagnose, but reported rates range between 30% and 84% of patients with cirrhosis.³¹ Progression from minimal to overt hepatic encephalopathy is 3.7 times more likely than in patients without the diagnosis of minimal hepatic encephalopathy.³²

Thus, minimal hepatic encephalopathy is important to identify,²⁹ so that treatment can be started.

Overt encephalopathy and survival

The prevalence of overt encephalopathy in cirrhosis ranges from 30% to 40% and is even higher in the advanced stages. Once encephalopathy develops, the prognosis worsens rapidly. In patients who do not undergo liver transplantation, the survival rate at 1 year is 42%, and the survival rate at 3 years is 23%.³³

These rates are worse than those after liver transplantation, and the American Association for the Study of Liver Diseases recommends that patients with cirrhosis who develop a first episode of encephalopathy be considered for liver transplantation and be referred to a transplantation center.³⁴

CHALLENGES IN DIAGNOSIS

Since the symptoms of hepatic encephalopathy are not specific and can be subtle in the early stage, its diagnosis may be a challenge. It is important to recognize that this neuropsychiatric complication occurs in people with severe comorbidities and requires dedicated time for evaluation and management.

 

 

Special tests may be needed to detect subclinical hepatic encephalopathy

In subclinical hepatic encephalopathy, the apparent lack of manifestations poses a great diagnostic challenge, but a thorough history may uncover poor social interaction, personality changes, poor performance at work, and recent traffic violations or motor vehicle accidents. Primary care physicians are usually the first to suspect the condition because they are familiar with the patient’s baseline mental and physical conditions.

For example, the primary care physician may notice decreased attention and worsening memory during a follow-up visit, or the physician may ask whether the patient has difficulty with work performance and handwork (psychomotor and fine motor skills), and whether there have been traffic violations or car accidents (visuospatial skills). Such clues, although not restrictive, may help identify patients with minimal hepatic encephalopathy and prompt referral for neuropsychiatric testing.

Neurologic deficits described in the subclinical form are in the domains of attention and concentration, working memory, visuospatial ability, and fine motor skills; communication skills remain intact.³⁵ These deficits are not reliably detected on standard clinical evaluation but can be detected by neuropsychiatric and neurophysiologic testing.

While several tests for minimal hepatic encephalopathy have been developed, they need to be validated in large trials in the United States.

Neurophysiologic tests include electroencephalography and auditory or visual event-related P300 (evoked potential) testing.

Neuropsychiatric tests traditionally involved several batteries administered and interpreted by specialized personnel. They were time-consuming and were not practical in a typical office setting. They were later refined into the Psychometric Hepatic Encephalopathy Score test (ie, the PSE syndrome test).³⁶ This combines a digit symbol test, a serial dotting test, a line-tracing test, and a number-connection or figure-connection test. An abnormal result in at least three of the four subtests constitutes an overall abnormal PSE syndrome test.

The PSE syndrome test has been validated for standard use in Germany, Spain, Italy, the United Kingdom, and India.³⁵ In 1999, the Working Group on Hepatic Encephalopathy designated it as the official test for minimal hepatic encephalopathy.¹ But the test has not been validated for use in the United States. Other tests have been developed, but their use is also limited by a lack of validation and by copyright laws. These factors constitute major obstacles to the diagnosis of subclinical hepatic encephalopathy in the United States. Nonetheless, physicians who suspect minimal hepatic encephalopathy may start lactulose therapy³⁷ and schedule frequent follow-up visits to address and manage potential precipitating factors for overt hepatic encephalopathy.

Staging the severity of the encephalopathy

When symptoms are overt, staging should be done to define the severity of the disease. The most commonly used staging scales are the West Haven Grading System (Table 2)³⁸ and the Glasgow Coma Scale (Table 3).³⁹

It is essential to exclude stroke, cerebral bleeding, and brain tumor before making a diagnosis of a first episode of hepatic encephalopathy. Thereafter, such exclusion must be guided by whether the patient has risk factors for these conditions or persistent symptoms of encephalopathy that do not respond to medical therapy.

Symptoms often resolve if precipitating factors are treated (Table 4). The most common precipitating factors include infections, dehydration, drug toxicity, and variceal bleeding.

Laboratory tests can identify metabolic derangements

Although laboratory tests are not diagnostic for hepatic encephalopathy, they can identify metabolic derangements that could contribute to it.

Blood ammonia levels are often measured in cirrhotic patients suspected of having hepatic encephalopathy, but this is not a reliable indicator, since many conditions and even prolonged tourniquet application during blood-drawing can raise blood ammonia levels (Table 5).

Imaging can help exclude other diagnoses

Conventional imaging studies of the brain, ie, computed tomography and MRI, are useful only to exclude a stroke, a brain tumor, or an intracranial or subdural hematoma. They may identify changes in the white matter and deposits of manganese in the basal ganglia in patients with cirrhosis with or without subclinical hepatic encephalopathy, but they are not likely to show low-grade brain edema.⁴⁰

Neurophysiologic imaging studies such as magnetic resonance spectroscopy, magnetic transfer imaging, and water-mapping techniques have helped elucidate pathologic mechanisms of hepatic encephalopathy and are available in research centers, but they are not currently considered for diagnosis.

SEVERAL LINES OF TREATMENT

Treatment of hepatic encephalopathy involves a preemptive approach to address potential precipitating factors, medical therapy to reduce the production and absorption of ammonia from the gut, and surgical or interventional therapies. A multidisciplinary approach for testing the severity of neurologic impairment and response to therapy is needed to help determine if and when liver transplantation is required.

Prevent potential precipitating factors

An important concept in managing hepatic encephalopathy is to recognize that every cirrhotic patient is at risk and to make an effort to address potential precipitating factors during regular clinic visits. This includes reviewing medication dosing and adverse effects, emphasizing abstinence from alcohol and other toxic substances, and preventing bleeding from esophageal varices with endoscopic band ligation.

 

 

Diet therapy

The prevalence of malnutrition in cirrhosis may be as high as 100%. Vitamin and nutritional deficiencies should be evaluated by a nutrition specialist, and nutritional needs should be reassessed on a regular basis. Protein restriction is no longer recommended and may even be harmful.

Guidelines of the European Society of Parenteral and Enteric Nutrition in 2006 recommended that patients with liver disease should have an energy intake of 35 to 40 kcal/kg of body weight daily, with a total daily protein intake of 1.2 to 1.5 mg/kg of body weight.⁴¹ Frequent meals and bedtime snacks are encouraged to avoid periods of prolonged fasting and catabolism of muscle protein and to improve nitrogen balance. Branched-chain amino acids and vegetable protein supplements are suggested to help meet the daily requirements.⁴²

Drug therapy to reduce neurotoxins

Drug treatment is directed at reducing the neurotoxins that accumulate in cirrhosis. A variety of agents have been used.

Lactulose (Kristalose) is approved by the US Food and Drug Administration (FDA) as a first-line treatment. It has been shown to improve quality of life and cognitive function in patients with cirrhosis and minimal hepatic encephalopathy, although it has failed to improve mortality rates.³⁷

Lactulose, a cathartic disaccharide, is metabolized by colonic bacteria into short-chain fatty acids. The acidic microenvironment has three major effects:

• It aids the transformation of ammonia to ammonium (NH4⁺), which is then trapped in the stool, leaving less ammonia to be absorbed
• It has a cathartic effect
• It reduces the breakdown of nitrogenous compounds into ammonia.⁴³

Lactulose has an excessively sweet taste. Its side effects include flatulence, abdominal discomfort, and diarrhea. The usual oral dose is 15 to 45 mL/day given in multiple doses to induce two to three soft bowel movements daily. At this dosage, the monthly cost varies between $60 and $120.

Lactilol, a nonabsorbable disaccharide, is as effective as lactulose but with fewer side effects. It is not available in the United States.

Rifaximin (Xifaxan), a derivative of rifamycin, is FDA-approved for the maintenance of remission of hepatic encephalopathy but is not recommended as a first-line agent. It inhibits bacterial RNA synthesis in the gut. Less than 0.4% of an oral dose is absorbed.⁴⁴

In a randomized, double-blind, placebo-controlled trial in patients who had had at least two episodes of hepatic encephalopathy while on lactulose therapy, taking rifaximin 550 mg twice a day for 6 months provided a prolonged remission from recurrences of encephalopathy compared with placebo.⁴⁵ Side effects included nausea, vomiting, abdominal pain, weight loss, and Clostridium difficile colitis, which was reported in two cases in the study.⁴⁵

Unfortunately, the effects of this drug beyond 6 months of therapy have not been studied. In addition, the drug is expensive: 1 month of treatment with rifaximin can cost between $700 and $1,500. Combining lactulose and rifaximin adds to the costs and the side effects, and contributes to poor adherence to therapy.

Other antibiotics such as metronidazole (Flagyl), vancomycin, and neomycin have been used as alternatives to lactulose, based on the principle that they reduce ammonia-producing bacteria in the gut. However, their efficacy in hepatic encephalopathy remains to be determined.

In controlled trials, neomycin combined with sorbitol, magnesium sulfate, or lactulose was as effective as lactulose, but when used alone, neomycin was no better than placebo.^46,47 Neomycin was approved many years ago as an adjunct in the management of hepatic coma, but it has since fallen out of favor in the management of hepatic encephalopathy because of poor trial results and because of neurotoxicity and ototoxicity.

Branched-chain amino acids (leucine, isoleucine, and valine)⁴⁸ are reported to increase ammonia intake in muscle and to improve cognitive functions on the PSE scale in minimal hepatic encephalopathy,^49,50 but they did not decrease the rate of recurrence of hepatic encephalopathy.⁵¹ While debate continues over their efficacy in the management of hepatic encephalopathy, branched-chain amino acids may be used to improve nutritional status and muscle mass of patients with cirrhosis. However, the dosing is not standardized, and long-term compliance may be problematic.

Other medical therapies include zinc,¹⁶ sodium benzoate,⁵⁰ and l-ornithine-l-aspartate^52,53 to stimulate residual urea cycle activities; probiotics (which pose a risk of sepsis from fungi and lactobacilli); and laxatives.

Liver dialysis

Adsorbing toxins from the blood via liver dialysis or using a non-cell-based liver support system such as MARS (Molecular Adsorbent Recirculating System, Gambro, Inc.) appears to improve the amino acid profile in hepatic encephalopathy, but its role has not been clarified, and its use is limited to clinical trials.^54,55

Transjugular intrahepatic shunts and large portosystemic shunts may need to be closed in order to reverse encephalopathy refractory to drug therapy.^26,27,56

Liver transplantation

The current scoring system for end-stage liver disease does not include hepatic encephalopathy as a criterion for prioritizing patients on the transplantation list because it was originally developed to assess short-term prognosis in patients undergoing transjugular intrahepatic shunting. As a consequence, patients with end-stage liver disease are at increased risk of repeated episodes of encephalopathy, hospital readmission, and death. Therefore, the American Association for the Study of Liver Diseases recommends referral to a transplantation center when the patient experiences a first episode of overt hepatic encephalopathy to initiate a workup for liver transplantation.³⁴

Liver transplantation improves survival in patients with severe hepatic dysfunction, but the presence of neurologic deficits may result in significant morbidity and in death.^57,58 After transplantation, resolution of cognitive dysfunction, brain edema, and white-matter changes have been reported,⁵⁹ but neuronal cell death and persistent cognitive impairment after resolution of overt hepatic encephalopathy are also described.^60–63

Whether neurologic impairment will resolve after liver transplantation depends on a number of factors: the severity of encephalopathy before transplantation; the nature of the neurologic deficits; advanced age; history of alcohol abuse and the presence of alcoholic brain damage; persistence of portosystemic shunts after transplant; emergency transplantation; complications during surgery; and side effects of immunosuppressive drugs.^57,58,64

The optimal timing of liver transplantation is not clearly defined for patients who have had bouts of hepatic encephalopathy, and more study is needed to determine the reversibility of clinical symptoms and brain damage. It is in these situations that neuropsychiatric testing and advanced neuroimaging can help determine the efficacy of therapeutic interventions, and it should be considered part of the pretransplantation evaluation.

Managing sleep disturbances

Insomnia and other changes in sleep-wake patterns are common in patients with cirrhosis, especially advanced cirrhosis.⁶⁵ It is not known whether these changes represent early stages of hepatic encephalopathy.⁶⁶ Patients often complain of fatigue, the need for frequent naps, and lethargy during the day and restlessness and inability to sleep at night. This affects the patient’s behavior and daytime functioning, and it also burdens household members and caregivers.

Long-acting benzodiazepines should be avoided when treating sleep disorders in cirrhosis because they may precipitate the encephalopathy. In a randomized controlled trial, hydroxyzine (Vistaril) at a dose of 25 mg at bedtime improved sleep behavior in 40% of patients with cirrhosis and subclinical hepatic encephalopathy, but 1 of 17 patients developed acute encephalopathy, which reversed with cessation of the hydroxyzine.⁶⁶ Clearly, caution and close monitoring are required when giving hydroxyzine for sleep disorders in cirrhotic patients.

Hepatic encephalopathy is a serious but often reversible complication that arises when the liver cannot detoxify the portal venous blood (Table 1).¹

Prompt identification and treatment are essential, because once overt encephalopathy develops the prognosis worsens rapidly. Thus, internists and other primary care physicians who care for patients with severe liver disease play a key role in identifying the condition. They will often see the patients when hepatic encephalopathy is in its early stages and its neuropsychiatric manifestations—reduced attention, diminishing fine motor skills, or impaired communication—are subtle. Since primary care physicians see patients over a longer span of time, they are more likely to recognize these subtle changes.

PROPOSED PATHOGENETIC FACTORS

About 5.5 million cases of chronic liver disease and cirrhosis were reported in the United States in 2001. Hepatic encephalopathy is becoming more common as the prevalence of cirrhosis increases,² and this will have important economic repercussions; in 2001, charges from hospitalizations because of hepatic encephalopathy were estimated at $932 million.³

Hepatic encephalopathy develops as cirrhosis progresses or as a result of portosystemic shunting, so that the liver cannot detoxify the portal venous blood. Several neurotoxins (notably ammonia) and inflammatory mediators play key roles in its pathogenesis, inducing low-grade brain edema and producing a wide spectrum of neuropsychiatric manifestations.⁴ Yet its pathogenesis is not entirely understood, impeding advances in its diagnosis and therapy.

Several hypotheses about the pathogenesis of hepatic encephalopathy have emerged in the last few years, and a number of factors are reported to directly or indirectly affect brain function in this condition. Ammonia and glutamine are the neurotoxins most often implicated in this syndrome⁵; others include inflammatory mediators, certain amino acids, and manganese.^5,6

Ammonia causes brain swelling

Ammonia is primarily the byproduct of bacterial metabolism of protein and nitrogenous compounds in the colon and of glutamine metabolism in enterocytes.⁷

Normally, gut-absorbed ammonia is delivered via the portal vein to the liver, where most of it is metabolized into urea, leaving a small amount to be metabolized in the muscles, heart, brain, and kidneys. In cirrhosis and other conditions associated with hepatic encephalopathy, less ammonia is metabolized into urea and more of it reaches the astrocytes in the brain. The brain lacks a urea cycle but metabolizes ammonia to glutamine via glutamine synthase, an enzyme unique to astrocytes.

Ammonia causes swelling of astrocytes and brain edema via generation of glutamine, an osmotically active substance.

Glutamine causes swelling, oxidative stress

Glutamine draws water into astrocytes and induces changes of type II astrocytosis (also called Alzheimer type II astrocytosis)⁵ characterized by swelling, enlarged and pale nuclei, and displacement of chromatin to the periphery of the cell. Inhibition of glutamine synthase prevents astrocyte swelling in animals.⁸

Glutamine also enhances the activation of several receptors, including N-methyl-d-aspartate (NMDA) receptors,^9,10 gammaaminobutyric acid (GABA) receptors, and peripheral-type benzodiazepine receptors on the mitochondrial membrane.^10–12 A state of oxidative stress ensues, and this affects oxidation of protein and RNA, neurotransmitter synthesis, and neurotransmission at the neuronal junction.¹³ Reactive nitrogen and oxide radicals induce the release of inflammatory mediators such as interleukins 1 and 6, tumor necrosis factor, interferons, and neurosteroids, and contribute to edema and neurotoxicity.^6,10 Neurosteroids are byproducts of mitochondrial metabolism of steroid hormones in the astrocyte.

Manganese enhances neurosteroid synthesis

Manganese enhances neurosteroid synthesis via activation of translocator proteins on the astrocyte membrane. It was first recognized as a factor in hepatic encephalopathy when cirrhotic patients experiencing extrapyramidal symptoms were found to have deposits of manganese in the caudate nucleus and in the globus pallidus on magnetic resonance imaging (MRI). Such deposits were also seen in specimens of brain tissue on autopsy of these patients. When the encephalopathy resolved, so did the abnormalities on MRI.^14,15

Changes in the blood-brain barrier

Astrocytes contribute to the selective permeability of the blood-brain barrier. Disruptions in the permeability of the blood-brain barrier underlie hepatic encephalopathy, with poor diffusion of molecules out of astrocytes.

For instance, zinc, which plays a regulatory role in gene transcription and synaptic plasticity, accumulates in the astrocytes, causing relative zinc deficiency and further affecting neurotransmitter synthesis and neurotransmission at the neuronal synapse.^6,16

 

 

Hyponatremia

Hyponatremia (a serum sodium concentration < 130 mmol/L) is increasingly being recognized as an independent predictor of overt hepatic encephalopathy and is reported to increase the risk by a factor of eight.¹⁷

Neuronal dysfunction

Astrocytes are integral to the physiologic functioning of the neurons, and it is becoming clear that both neurons and astrocytes are affected in hepatic encephalopathy.

Additionally, neuroinflammation and a decrease in energy metabolism by the brain are described during episodes of hepatic encephalopathy.¹⁸

Amino acid imbalance

An imbalance between aromatic amino acids (ie, high levels of tyrosine and phenylalanine) and branched-chain amino acids (leucine, isoleucine, and valine) has been linked with encephalopathy in patients with liver disease, ^19–21 but it is not totally clear whether this imbalance contributes to hepatic encephalopathy or is a consequence of it.

Low-grade brain edema

Edema of the brain occurs in all forms of hepatic encephalopathy, but in cirrhosis it is characteristically of low grade. The mechanism behind this low-grade edema is not clear. Studies have shown that swelling of astrocytes is not global but involves certain areas of the brain and is associated with compensatory extrusion of intracellular myoinositol.²² This, in combination with a mild degree of brain atrophy²³ observed in patients with chronic liver disease, is thought to keep the brain from extreme swelling and herniation, a phenomenon usually seen in acute hepatic failure.^24,25

Transjugular intrahepatic portosystemic shunting and encephalopathy

The incidence rate of hepatic encephalopathy after placement of a portosystemic shunt to treat portal hypertension ranges from 30% to 55% and is similar to the rate in cirrhotic patients without a shunt.²⁶ In 5% to 8% of patients, the hepatic encephalopathy is refractory and requires intentional occlusion of the shunt.^26,27 An elevated serum creatinine level appears to be a risk factor for refractory hepatic encephalopathy in patients with a portosystemic shunt.²⁶

In one study,²⁸ when transjugular intrahepatic portosystemic shunting was done early in the treatment of cirrhotic patients with acute variceal bleeding, the rates of treatment failure and death were significantly less than in a control group that received endoscopic therapy, and no significant difference was noted in the rate of encephalopathy or of serious adverse effects between the groups.

Whether to place a portosystemic shunt in a patient with cirrhosis and a history of hepatic encephalopathy depends on the possible underlying causes of the encephalopathy. For example, if encephalopathy was precipitated by variceal bleeding, shunt placement will prevent further bleeding and will make a recurrence of encephalopathy less likely. However, if the encephalopathy is persistent and uncontrollable, then shunt placement is contraindicated.²⁷

A SPECTRUM OF SYMPTOMS

The spectrum of symptoms extends from a subclinical syndrome that may not be clinically apparent (early-stage or “minimal” hepatic encephalopathy) to full-blown neuropsychiatric manifestations such as cognitive impairment, confusion, slow speech, loss of fine motor skills, asterixis, peripheral neuropathy, clonus, the Babinski sign, decerebrate and decorticate posturing, seizures, extrapyramidal symptoms, and coma.⁴ The clinical manifestations are usually reversible with prompt treatment, but recurrence is common, typically induced by an event such as gastrointestinal bleeding or an infection.

Minimal hepatic encephalopathy is important to recognize

Although this subclinical syndrome is a very early stage, it is nevertheless associated with higher rates of morbidity and can affect quality of life, including the patient’s ability to drive a car.^29,30

Abnormal changes in the brain begin at this stage and eventually progress to more damage and to the development of overt clinical symptoms.

The exact prevalence of minimal hepatic encephalopathy is not known because it is difficult to diagnose, but reported rates range between 30% and 84% of patients with cirrhosis.³¹ Progression from minimal to overt hepatic encephalopathy is 3.7 times more likely than in patients without the diagnosis of minimal hepatic encephalopathy.³²

Thus, minimal hepatic encephalopathy is important to identify,²⁹ so that treatment can be started.

Overt encephalopathy and survival

The prevalence of overt encephalopathy in cirrhosis ranges from 30% to 40% and is even higher in the advanced stages. Once encephalopathy develops, the prognosis worsens rapidly. In patients who do not undergo liver transplantation, the survival rate at 1 year is 42%, and the survival rate at 3 years is 23%.³³

These rates are worse than those after liver transplantation, and the American Association for the Study of Liver Diseases recommends that patients with cirrhosis who develop a first episode of encephalopathy be considered for liver transplantation and be referred to a transplantation center.³⁴

CHALLENGES IN DIAGNOSIS

Since the symptoms of hepatic encephalopathy are not specific and can be subtle in the early stage, its diagnosis may be a challenge. It is important to recognize that this neuropsychiatric complication occurs in people with severe comorbidities and requires dedicated time for evaluation and management.

 

 

Special tests may be needed to detect subclinical hepatic encephalopathy

In subclinical hepatic encephalopathy, the apparent lack of manifestations poses a great diagnostic challenge, but a thorough history may uncover poor social interaction, personality changes, poor performance at work, and recent traffic violations or motor vehicle accidents. Primary care physicians are usually the first to suspect the condition because they are familiar with the patient’s baseline mental and physical conditions.

For example, the primary care physician may notice decreased attention and worsening memory during a follow-up visit, or the physician may ask whether the patient has difficulty with work performance and handwork (psychomotor and fine motor skills), and whether there have been traffic violations or car accidents (visuospatial skills). Such clues, although not restrictive, may help identify patients with minimal hepatic encephalopathy and prompt referral for neuropsychiatric testing.

Neurologic deficits described in the subclinical form are in the domains of attention and concentration, working memory, visuospatial ability, and fine motor skills; communication skills remain intact.³⁵ These deficits are not reliably detected on standard clinical evaluation but can be detected by neuropsychiatric and neurophysiologic testing.

While several tests for minimal hepatic encephalopathy have been developed, they need to be validated in large trials in the United States.

Neurophysiologic tests include electroencephalography and auditory or visual event-related P300 (evoked potential) testing.

Neuropsychiatric tests traditionally involved several batteries administered and interpreted by specialized personnel. They were time-consuming and were not practical in a typical office setting. They were later refined into the Psychometric Hepatic Encephalopathy Score test (ie, the PSE syndrome test).³⁶ This combines a digit symbol test, a serial dotting test, a line-tracing test, and a number-connection or figure-connection test. An abnormal result in at least three of the four subtests constitutes an overall abnormal PSE syndrome test.

The PSE syndrome test has been validated for standard use in Germany, Spain, Italy, the United Kingdom, and India.³⁵ In 1999, the Working Group on Hepatic Encephalopathy designated it as the official test for minimal hepatic encephalopathy.¹ But the test has not been validated for use in the United States. Other tests have been developed, but their use is also limited by a lack of validation and by copyright laws. These factors constitute major obstacles to the diagnosis of subclinical hepatic encephalopathy in the United States. Nonetheless, physicians who suspect minimal hepatic encephalopathy may start lactulose therapy³⁷ and schedule frequent follow-up visits to address and manage potential precipitating factors for overt hepatic encephalopathy.

Staging the severity of the encephalopathy

When symptoms are overt, staging should be done to define the severity of the disease. The most commonly used staging scales are the West Haven Grading System (Table 2)³⁸ and the Glasgow Coma Scale (Table 3).³⁹

It is essential to exclude stroke, cerebral bleeding, and brain tumor before making a diagnosis of a first episode of hepatic encephalopathy. Thereafter, such exclusion must be guided by whether the patient has risk factors for these conditions or persistent symptoms of encephalopathy that do not respond to medical therapy.

Symptoms often resolve if precipitating factors are treated (Table 4). The most common precipitating factors include infections, dehydration, drug toxicity, and variceal bleeding.

Laboratory tests can identify metabolic derangements

Although laboratory tests are not diagnostic for hepatic encephalopathy, they can identify metabolic derangements that could contribute to it.

Blood ammonia levels are often measured in cirrhotic patients suspected of having hepatic encephalopathy, but this is not a reliable indicator, since many conditions and even prolonged tourniquet application during blood-drawing can raise blood ammonia levels (Table 5).

Imaging can help exclude other diagnoses

Conventional imaging studies of the brain, ie, computed tomography and MRI, are useful only to exclude a stroke, a brain tumor, or an intracranial or subdural hematoma. They may identify changes in the white matter and deposits of manganese in the basal ganglia in patients with cirrhosis with or without subclinical hepatic encephalopathy, but they are not likely to show low-grade brain edema.⁴⁰

Neurophysiologic imaging studies such as magnetic resonance spectroscopy, magnetic transfer imaging, and water-mapping techniques have helped elucidate pathologic mechanisms of hepatic encephalopathy and are available in research centers, but they are not currently considered for diagnosis.

SEVERAL LINES OF TREATMENT

Treatment of hepatic encephalopathy involves a preemptive approach to address potential precipitating factors, medical therapy to reduce the production and absorption of ammonia from the gut, and surgical or interventional therapies. A multidisciplinary approach for testing the severity of neurologic impairment and response to therapy is needed to help determine if and when liver transplantation is required.

Prevent potential precipitating factors

An important concept in managing hepatic encephalopathy is to recognize that every cirrhotic patient is at risk and to make an effort to address potential precipitating factors during regular clinic visits. This includes reviewing medication dosing and adverse effects, emphasizing abstinence from alcohol and other toxic substances, and preventing bleeding from esophageal varices with endoscopic band ligation.

 

 

Diet therapy

The prevalence of malnutrition in cirrhosis may be as high as 100%. Vitamin and nutritional deficiencies should be evaluated by a nutrition specialist, and nutritional needs should be reassessed on a regular basis. Protein restriction is no longer recommended and may even be harmful.

Guidelines of the European Society of Parenteral and Enteric Nutrition in 2006 recommended that patients with liver disease should have an energy intake of 35 to 40 kcal/kg of body weight daily, with a total daily protein intake of 1.2 to 1.5 mg/kg of body weight.⁴¹ Frequent meals and bedtime snacks are encouraged to avoid periods of prolonged fasting and catabolism of muscle protein and to improve nitrogen balance. Branched-chain amino acids and vegetable protein supplements are suggested to help meet the daily requirements.⁴²

Drug therapy to reduce neurotoxins

Drug treatment is directed at reducing the neurotoxins that accumulate in cirrhosis. A variety of agents have been used.

Lactulose (Kristalose) is approved by the US Food and Drug Administration (FDA) as a first-line treatment. It has been shown to improve quality of life and cognitive function in patients with cirrhosis and minimal hepatic encephalopathy, although it has failed to improve mortality rates.³⁷

Lactulose, a cathartic disaccharide, is metabolized by colonic bacteria into short-chain fatty acids. The acidic microenvironment has three major effects:

• It aids the transformation of ammonia to ammonium (NH4⁺), which is then trapped in the stool, leaving less ammonia to be absorbed
• It has a cathartic effect
• It reduces the breakdown of nitrogenous compounds into ammonia.⁴³

Lactulose has an excessively sweet taste. Its side effects include flatulence, abdominal discomfort, and diarrhea. The usual oral dose is 15 to 45 mL/day given in multiple doses to induce two to three soft bowel movements daily. At this dosage, the monthly cost varies between $60 and $120.

Lactilol, a nonabsorbable disaccharide, is as effective as lactulose but with fewer side effects. It is not available in the United States.

Rifaximin (Xifaxan), a derivative of rifamycin, is FDA-approved for the maintenance of remission of hepatic encephalopathy but is not recommended as a first-line agent. It inhibits bacterial RNA synthesis in the gut. Less than 0.4% of an oral dose is absorbed.⁴⁴

In a randomized, double-blind, placebo-controlled trial in patients who had had at least two episodes of hepatic encephalopathy while on lactulose therapy, taking rifaximin 550 mg twice a day for 6 months provided a prolonged remission from recurrences of encephalopathy compared with placebo.⁴⁵ Side effects included nausea, vomiting, abdominal pain, weight loss, and Clostridium difficile colitis, which was reported in two cases in the study.⁴⁵

Unfortunately, the effects of this drug beyond 6 months of therapy have not been studied. In addition, the drug is expensive: 1 month of treatment with rifaximin can cost between $700 and $1,500. Combining lactulose and rifaximin adds to the costs and the side effects, and contributes to poor adherence to therapy.

Other antibiotics such as metronidazole (Flagyl), vancomycin, and neomycin have been used as alternatives to lactulose, based on the principle that they reduce ammonia-producing bacteria in the gut. However, their efficacy in hepatic encephalopathy remains to be determined.

In controlled trials, neomycin combined with sorbitol, magnesium sulfate, or lactulose was as effective as lactulose, but when used alone, neomycin was no better than placebo.^46,47 Neomycin was approved many years ago as an adjunct in the management of hepatic coma, but it has since fallen out of favor in the management of hepatic encephalopathy because of poor trial results and because of neurotoxicity and ototoxicity.

Branched-chain amino acids (leucine, isoleucine, and valine)⁴⁸ are reported to increase ammonia intake in muscle and to improve cognitive functions on the PSE scale in minimal hepatic encephalopathy,^49,50 but they did not decrease the rate of recurrence of hepatic encephalopathy.⁵¹ While debate continues over their efficacy in the management of hepatic encephalopathy, branched-chain amino acids may be used to improve nutritional status and muscle mass of patients with cirrhosis. However, the dosing is not standardized, and long-term compliance may be problematic.

Other medical therapies include zinc,¹⁶ sodium benzoate,⁵⁰ and l-ornithine-l-aspartate^52,53 to stimulate residual urea cycle activities; probiotics (which pose a risk of sepsis from fungi and lactobacilli); and laxatives.

Liver dialysis

Adsorbing toxins from the blood via liver dialysis or using a non-cell-based liver support system such as MARS (Molecular Adsorbent Recirculating System, Gambro, Inc.) appears to improve the amino acid profile in hepatic encephalopathy, but its role has not been clarified, and its use is limited to clinical trials.^54,55

Transjugular intrahepatic shunts and large portosystemic shunts may need to be closed in order to reverse encephalopathy refractory to drug therapy.^26,27,56

Liver transplantation

The current scoring system for end-stage liver disease does not include hepatic encephalopathy as a criterion for prioritizing patients on the transplantation list because it was originally developed to assess short-term prognosis in patients undergoing transjugular intrahepatic shunting. As a consequence, patients with end-stage liver disease are at increased risk of repeated episodes of encephalopathy, hospital readmission, and death. Therefore, the American Association for the Study of Liver Diseases recommends referral to a transplantation center when the patient experiences a first episode of overt hepatic encephalopathy to initiate a workup for liver transplantation.³⁴

Liver transplantation improves survival in patients with severe hepatic dysfunction, but the presence of neurologic deficits may result in significant morbidity and in death.^57,58 After transplantation, resolution of cognitive dysfunction, brain edema, and white-matter changes have been reported,⁵⁹ but neuronal cell death and persistent cognitive impairment after resolution of overt hepatic encephalopathy are also described.^60–63

Whether neurologic impairment will resolve after liver transplantation depends on a number of factors: the severity of encephalopathy before transplantation; the nature of the neurologic deficits; advanced age; history of alcohol abuse and the presence of alcoholic brain damage; persistence of portosystemic shunts after transplant; emergency transplantation; complications during surgery; and side effects of immunosuppressive drugs.^57,58,64

The optimal timing of liver transplantation is not clearly defined for patients who have had bouts of hepatic encephalopathy, and more study is needed to determine the reversibility of clinical symptoms and brain damage. It is in these situations that neuropsychiatric testing and advanced neuroimaging can help determine the efficacy of therapeutic interventions, and it should be considered part of the pretransplantation evaluation.

Managing sleep disturbances

Insomnia and other changes in sleep-wake patterns are common in patients with cirrhosis, especially advanced cirrhosis.⁶⁵ It is not known whether these changes represent early stages of hepatic encephalopathy.⁶⁶ Patients often complain of fatigue, the need for frequent naps, and lethargy during the day and restlessness and inability to sleep at night. This affects the patient’s behavior and daytime functioning, and it also burdens household members and caregivers.

Long-acting benzodiazepines should be avoided when treating sleep disorders in cirrhosis because they may precipitate the encephalopathy. In a randomized controlled trial, hydroxyzine (Vistaril) at a dose of 25 mg at bedtime improved sleep behavior in 40% of patients with cirrhosis and subclinical hepatic encephalopathy, but 1 of 17 patients developed acute encephalopathy, which reversed with cessation of the hydroxyzine.⁶⁶ Clearly, caution and close monitoring are required when giving hydroxyzine for sleep disorders in cirrhotic patients.

A 23-year-old man presents with a sore throat, dysphagia, and general malaise that began 1 week ago. He also reports a 5-pound weight loss. He has not recently taken antibiotics or inhaled glucocorticoids, and he has no history of tobacco use or trauma to his mouth. He has no personal or family history of oral cancer. He uses cocaine on occasion. He reports feeling feverish and having a decreased appetite.

An examination of his mouth reveals white plaques of varying sizes (Figure 1). The plaques are easily removed using a tongue blade, with no bleeding. No regional lymphadenopathy is noted.

Q: Based on the history, the symptoms, and the physical examination, which of the following is the most likely diagnosis in this patient?

• Oral hairy leukoplakia
• Squamous cell carcinoma
• Oral candidiasis
• Herpetic gingivostomatitis
• Streptococcal pharyngitis

A: Oral candidiasis is correct.

Otherwise known as thrush, it is common in infants and in denture wearers, and it also can occur in diabetes mellitus, antibiotic therapy, chemotherapy, radiation therapy, and cellular immune deficiency states such as cancer or human immunodeficiency virus (HIV) infection.¹ Patients using inhaled glucocorticoids are also at risk and should always be advised to rinse their mouth out with water after inhaled steroid use.

Although Candida albicans is the species most often responsible for candidal infections, other candidal species are increasingly responsible for infections in immunocompromised patients. Candida is part of the normal flora in many adults.

Oral hairy leukoplakia is caused by the Epstein-Barr virus and is often seen in HIV infection. It is a white, painless, corrugated lesion, typically found on the lateral aspect of the tongue, and it cannot be scraped from the adherent surfaces. It can also be found on the dorsum of the tongue, the buccal surfaces, and the floor of the mouth. In an asymptomatic patient with oral hairy leukoplakia, HIV infection with moderate immunosuppression is most likely present.² Oral hairy leukoplakia is diagnosed by biopsy of suspected lesions. It is not a premalignant lesion, and how to best treat it is still being investigated.³

Squamous cell carcinoma of the oral cavity can present as nonhealing ulcers or masses, dental changes, or exophytic lesions with or without pain.¹ They may be accompanied by cervical nodal disease. Malignancies of the oral cavity account for 14% of all head and neck cancers, with squamous cell carcinoma the predominant type.⁴ Alcohol and tobacco use increase the risk. Alcohol and tobacco together have a synergistic effect on the incidence of oral carcinoma.^1,4 Predisposing lesions are leukoplakia, lichen planus of the erosive subtype, submucosal fibrosis, and erythroplakia. Oral infection with human papillomavirus has been shown to increase the risk of oral cancer by a factor of 14, and papillomavirus type 16 is detected in 72% of patients with oropharyngeal cancer.⁵

Herpetic gingivostomatitis is a manifestation of herpes simplex virus infection. The initial infection may be asymptomatic or may produce groups of vesicles that develop into shallow, painful, and superficial ulcerations on an erythematous base.^1,3 If the gingiva is involved, it is erythematous, boggy, and tender.³ Infections are self-limited, lasting up to 2 weeks, but there is potential for recurrence because of the ability of herpes simplex virus to undergo latency. Recurrence is usually heralded by prodromal symptoms 24 hours before onset, with tingling, pain, or burning at the infected site. The diagnosis can be made clinically, but the Tzanck smear test, viral culture, direct fluorescent antibody test, or polymerase chain reaction test can be used to confirm the diagnosis. In patients who are immunocompromised, infections tend to be more severe and to last longer.

Streptococcal pharyngitis, most often caused by group A beta-hemolytic streptococci, is the most common type of bacterial pharyngitis in the clinical setting. The bacteria incubate for 2 to 5 days. The condition mainly affects younger children.⁶ Patients with “strep throat” often present with a sore throat and high-grade fever. Other symptoms include chills, myalgia, headache, and nausea. Findings on examination may include petechiae of the palate, pharyngeal and tonsillar erythema and exudates, and anterior cervical adenopathy.⁶ Children often present with coinciding abdominal complaints. A rapid antigen detection test for streptococcal infection can be performed in the office for quick diagnosis, but if clinical suspicion is high, a throat culture is necessary to confirm the diagnosis. Treatment is to prevent complications such as rheumatic fever.⁶

 

FEATURES AND DIAGNOSIS OF ORAL CANDIDIASIS

Lesions of oral candidiasis can vary in their appearance. The pseudomembranous form is the most characteristic, with white adherent “cottage-cheese-like” plaques that wipe away, causing minimal bleeding.^1,7 The erythematous or atrophic form is associated with denture use and causes a “beefy” appearance on the dorsum of the tongue or on the mucosa that supports a denture.^1,7 A third form affects the angles of the mouth, causing angular cheilitis (perlèche).^7,8 Chronic infection appears as localized, firmly adherent plaques with an irregular surface similar to hyperkeratosis caused by chronic frictional irritation.⁷

Oral candidiasis can occur in different forms at the same time. Patients often describe minimal symptoms such as dysgeusia or dry mouth.^1,7 Infections causing dysphagia or odynophagia warrant suspicion for involvement of the esophagus.

The diagnosis is made empirically if the lesions resolve with anticandidal therapy. A more definitive diagnosis can be made by microscopy with a potassium hydroxide preparation showing pseudohyphae. Formal culture can also determine the yeast’s susceptibility to medication in recurrent or resistant cases.²

Oral candidiasis may be the manifesting symptom of HIV infection, and more than 90% of patients with adult immunodeficiency syndrome have an episode of thrush.⁸ When candidiasis is diagnosed without obvious cause, HIV testing should be offered, regardless of a patient’s lack of obvious risk factors. Other oral lesions in HIV patients are oral hairy leukoplakia, Kaposi sarcoma, periodontal and gingival infections, aphthous ulcers, herpes simplex stomatitis, and xerostomia.² With highly active antiretroviral therapy, the incidence of oral candidiasis has decreased by about 50%.²

Our patient was diagnosed with HIV when screened after this initial presentation. Lower CD4 counts and higher viral loads increase the patient’s risk for oral candidiasis and other lesions. This patient’s initial CD4 count was 524 cells/μL, and his viral load was 11,232 copies/mL.

TREATMENT

In HIV-negative patients or in HIV-positive patients with a CD4 count greater than 200 cells/μL, the treatment of oral candidiasis involves topical antifungal agents, including a nystatin suspension (Nystat-Rx) or clotrimazole (Mycelex) troches.^3,7,9 Treatment should be continued for at least 7 days after resolution of the infection. If resolution does not occur, oral fluconazole (Diflucan) 200 mg daily should be given.

For HIV patients with CD4 counts below 200 cells/μL, oral fluconazole or itraconazole (Sporanox) is recommended, with posaconazole (Noxafil) as an alternative for refractory disease.^3,9 Giving fluconazole prophylactically to prevent oral candidiasis is not recommended because of the risk of adverse effects, lack of survival benefit, associated cost, and potential to develop antifungal resistance.^3,9

A 23-year-old man presents with a sore throat, dysphagia, and general malaise that began 1 week ago. He also reports a 5-pound weight loss. He has not recently taken antibiotics or inhaled glucocorticoids, and he has no history of tobacco use or trauma to his mouth. He has no personal or family history of oral cancer. He uses cocaine on occasion. He reports feeling feverish and having a decreased appetite.

An examination of his mouth reveals white plaques of varying sizes (Figure 1). The plaques are easily removed using a tongue blade, with no bleeding. No regional lymphadenopathy is noted.

Q: Based on the history, the symptoms, and the physical examination, which of the following is the most likely diagnosis in this patient?

• Oral hairy leukoplakia
• Squamous cell carcinoma
• Oral candidiasis
• Herpetic gingivostomatitis
• Streptococcal pharyngitis

A: Oral candidiasis is correct.

Otherwise known as thrush, it is common in infants and in denture wearers, and it also can occur in diabetes mellitus, antibiotic therapy, chemotherapy, radiation therapy, and cellular immune deficiency states such as cancer or human immunodeficiency virus (HIV) infection.¹ Patients using inhaled glucocorticoids are also at risk and should always be advised to rinse their mouth out with water after inhaled steroid use.

Although Candida albicans is the species most often responsible for candidal infections, other candidal species are increasingly responsible for infections in immunocompromised patients. Candida is part of the normal flora in many adults.

Oral hairy leukoplakia is caused by the Epstein-Barr virus and is often seen in HIV infection. It is a white, painless, corrugated lesion, typically found on the lateral aspect of the tongue, and it cannot be scraped from the adherent surfaces. It can also be found on the dorsum of the tongue, the buccal surfaces, and the floor of the mouth. In an asymptomatic patient with oral hairy leukoplakia, HIV infection with moderate immunosuppression is most likely present.² Oral hairy leukoplakia is diagnosed by biopsy of suspected lesions. It is not a premalignant lesion, and how to best treat it is still being investigated.³

Squamous cell carcinoma of the oral cavity can present as nonhealing ulcers or masses, dental changes, or exophytic lesions with or without pain.¹ They may be accompanied by cervical nodal disease. Malignancies of the oral cavity account for 14% of all head and neck cancers, with squamous cell carcinoma the predominant type.⁴ Alcohol and tobacco use increase the risk. Alcohol and tobacco together have a synergistic effect on the incidence of oral carcinoma.^1,4 Predisposing lesions are leukoplakia, lichen planus of the erosive subtype, submucosal fibrosis, and erythroplakia. Oral infection with human papillomavirus has been shown to increase the risk of oral cancer by a factor of 14, and papillomavirus type 16 is detected in 72% of patients with oropharyngeal cancer.⁵

Herpetic gingivostomatitis is a manifestation of herpes simplex virus infection. The initial infection may be asymptomatic or may produce groups of vesicles that develop into shallow, painful, and superficial ulcerations on an erythematous base.^1,3 If the gingiva is involved, it is erythematous, boggy, and tender.³ Infections are self-limited, lasting up to 2 weeks, but there is potential for recurrence because of the ability of herpes simplex virus to undergo latency. Recurrence is usually heralded by prodromal symptoms 24 hours before onset, with tingling, pain, or burning at the infected site. The diagnosis can be made clinically, but the Tzanck smear test, viral culture, direct fluorescent antibody test, or polymerase chain reaction test can be used to confirm the diagnosis. In patients who are immunocompromised, infections tend to be more severe and to last longer.

Streptococcal pharyngitis, most often caused by group A beta-hemolytic streptococci, is the most common type of bacterial pharyngitis in the clinical setting. The bacteria incubate for 2 to 5 days. The condition mainly affects younger children.⁶ Patients with “strep throat” often present with a sore throat and high-grade fever. Other symptoms include chills, myalgia, headache, and nausea. Findings on examination may include petechiae of the palate, pharyngeal and tonsillar erythema and exudates, and anterior cervical adenopathy.⁶ Children often present with coinciding abdominal complaints. A rapid antigen detection test for streptococcal infection can be performed in the office for quick diagnosis, but if clinical suspicion is high, a throat culture is necessary to confirm the diagnosis. Treatment is to prevent complications such as rheumatic fever.⁶

 

FEATURES AND DIAGNOSIS OF ORAL CANDIDIASIS

Lesions of oral candidiasis can vary in their appearance. The pseudomembranous form is the most characteristic, with white adherent “cottage-cheese-like” plaques that wipe away, causing minimal bleeding.^1,7 The erythematous or atrophic form is associated with denture use and causes a “beefy” appearance on the dorsum of the tongue or on the mucosa that supports a denture.^1,7 A third form affects the angles of the mouth, causing angular cheilitis (perlèche).^7,8 Chronic infection appears as localized, firmly adherent plaques with an irregular surface similar to hyperkeratosis caused by chronic frictional irritation.⁷

Oral candidiasis can occur in different forms at the same time. Patients often describe minimal symptoms such as dysgeusia or dry mouth.^1,7 Infections causing dysphagia or odynophagia warrant suspicion for involvement of the esophagus.

The diagnosis is made empirically if the lesions resolve with anticandidal therapy. A more definitive diagnosis can be made by microscopy with a potassium hydroxide preparation showing pseudohyphae. Formal culture can also determine the yeast’s susceptibility to medication in recurrent or resistant cases.²

Oral candidiasis may be the manifesting symptom of HIV infection, and more than 90% of patients with adult immunodeficiency syndrome have an episode of thrush.⁸ When candidiasis is diagnosed without obvious cause, HIV testing should be offered, regardless of a patient’s lack of obvious risk factors. Other oral lesions in HIV patients are oral hairy leukoplakia, Kaposi sarcoma, periodontal and gingival infections, aphthous ulcers, herpes simplex stomatitis, and xerostomia.² With highly active antiretroviral therapy, the incidence of oral candidiasis has decreased by about 50%.²

Our patient was diagnosed with HIV when screened after this initial presentation. Lower CD4 counts and higher viral loads increase the patient’s risk for oral candidiasis and other lesions. This patient’s initial CD4 count was 524 cells/μL, and his viral load was 11,232 copies/mL.

TREATMENT

In HIV-negative patients or in HIV-positive patients with a CD4 count greater than 200 cells/μL, the treatment of oral candidiasis involves topical antifungal agents, including a nystatin suspension (Nystat-Rx) or clotrimazole (Mycelex) troches.^3,7,9 Treatment should be continued for at least 7 days after resolution of the infection. If resolution does not occur, oral fluconazole (Diflucan) 200 mg daily should be given.

For HIV patients with CD4 counts below 200 cells/μL, oral fluconazole or itraconazole (Sporanox) is recommended, with posaconazole (Noxafil) as an alternative for refractory disease.^3,9 Giving fluconazole prophylactically to prevent oral candidiasis is not recommended because of the risk of adverse effects, lack of survival benefit, associated cost, and potential to develop antifungal resistance.^3,9

A 23-year-old man presents with a sore throat, dysphagia, and general malaise that began 1 week ago. He also reports a 5-pound weight loss. He has not recently taken antibiotics or inhaled glucocorticoids, and he has no history of tobacco use or trauma to his mouth. He has no personal or family history of oral cancer. He uses cocaine on occasion. He reports feeling feverish and having a decreased appetite.

An examination of his mouth reveals white plaques of varying sizes (Figure 1). The plaques are easily removed using a tongue blade, with no bleeding. No regional lymphadenopathy is noted.

Q: Based on the history, the symptoms, and the physical examination, which of the following is the most likely diagnosis in this patient?

• Oral hairy leukoplakia
• Squamous cell carcinoma
• Oral candidiasis
• Herpetic gingivostomatitis
• Streptococcal pharyngitis

A: Oral candidiasis is correct.

Otherwise known as thrush, it is common in infants and in denture wearers, and it also can occur in diabetes mellitus, antibiotic therapy, chemotherapy, radiation therapy, and cellular immune deficiency states such as cancer or human immunodeficiency virus (HIV) infection.¹ Patients using inhaled glucocorticoids are also at risk and should always be advised to rinse their mouth out with water after inhaled steroid use.

Although Candida albicans is the species most often responsible for candidal infections, other candidal species are increasingly responsible for infections in immunocompromised patients. Candida is part of the normal flora in many adults.

Oral hairy leukoplakia is caused by the Epstein-Barr virus and is often seen in HIV infection. It is a white, painless, corrugated lesion, typically found on the lateral aspect of the tongue, and it cannot be scraped from the adherent surfaces. It can also be found on the dorsum of the tongue, the buccal surfaces, and the floor of the mouth. In an asymptomatic patient with oral hairy leukoplakia, HIV infection with moderate immunosuppression is most likely present.² Oral hairy leukoplakia is diagnosed by biopsy of suspected lesions. It is not a premalignant lesion, and how to best treat it is still being investigated.³

Squamous cell carcinoma of the oral cavity can present as nonhealing ulcers or masses, dental changes, or exophytic lesions with or without pain.¹ They may be accompanied by cervical nodal disease. Malignancies of the oral cavity account for 14% of all head and neck cancers, with squamous cell carcinoma the predominant type.⁴ Alcohol and tobacco use increase the risk. Alcohol and tobacco together have a synergistic effect on the incidence of oral carcinoma.^1,4 Predisposing lesions are leukoplakia, lichen planus of the erosive subtype, submucosal fibrosis, and erythroplakia. Oral infection with human papillomavirus has been shown to increase the risk of oral cancer by a factor of 14, and papillomavirus type 16 is detected in 72% of patients with oropharyngeal cancer.⁵

Herpetic gingivostomatitis is a manifestation of herpes simplex virus infection. The initial infection may be asymptomatic or may produce groups of vesicles that develop into shallow, painful, and superficial ulcerations on an erythematous base.^1,3 If the gingiva is involved, it is erythematous, boggy, and tender.³ Infections are self-limited, lasting up to 2 weeks, but there is potential for recurrence because of the ability of herpes simplex virus to undergo latency. Recurrence is usually heralded by prodromal symptoms 24 hours before onset, with tingling, pain, or burning at the infected site. The diagnosis can be made clinically, but the Tzanck smear test, viral culture, direct fluorescent antibody test, or polymerase chain reaction test can be used to confirm the diagnosis. In patients who are immunocompromised, infections tend to be more severe and to last longer.

Streptococcal pharyngitis, most often caused by group A beta-hemolytic streptococci, is the most common type of bacterial pharyngitis in the clinical setting. The bacteria incubate for 2 to 5 days. The condition mainly affects younger children.⁶ Patients with “strep throat” often present with a sore throat and high-grade fever. Other symptoms include chills, myalgia, headache, and nausea. Findings on examination may include petechiae of the palate, pharyngeal and tonsillar erythema and exudates, and anterior cervical adenopathy.⁶ Children often present with coinciding abdominal complaints. A rapid antigen detection test for streptococcal infection can be performed in the office for quick diagnosis, but if clinical suspicion is high, a throat culture is necessary to confirm the diagnosis. Treatment is to prevent complications such as rheumatic fever.⁶

 

FEATURES AND DIAGNOSIS OF ORAL CANDIDIASIS

Lesions of oral candidiasis can vary in their appearance. The pseudomembranous form is the most characteristic, with white adherent “cottage-cheese-like” plaques that wipe away, causing minimal bleeding.^1,7 The erythematous or atrophic form is associated with denture use and causes a “beefy” appearance on the dorsum of the tongue or on the mucosa that supports a denture.^1,7 A third form affects the angles of the mouth, causing angular cheilitis (perlèche).^7,8 Chronic infection appears as localized, firmly adherent plaques with an irregular surface similar to hyperkeratosis caused by chronic frictional irritation.⁷

Oral candidiasis can occur in different forms at the same time. Patients often describe minimal symptoms such as dysgeusia or dry mouth.^1,7 Infections causing dysphagia or odynophagia warrant suspicion for involvement of the esophagus.

The diagnosis is made empirically if the lesions resolve with anticandidal therapy. A more definitive diagnosis can be made by microscopy with a potassium hydroxide preparation showing pseudohyphae. Formal culture can also determine the yeast’s susceptibility to medication in recurrent or resistant cases.²

Oral candidiasis may be the manifesting symptom of HIV infection, and more than 90% of patients with adult immunodeficiency syndrome have an episode of thrush.⁸ When candidiasis is diagnosed without obvious cause, HIV testing should be offered, regardless of a patient’s lack of obvious risk factors. Other oral lesions in HIV patients are oral hairy leukoplakia, Kaposi sarcoma, periodontal and gingival infections, aphthous ulcers, herpes simplex stomatitis, and xerostomia.² With highly active antiretroviral therapy, the incidence of oral candidiasis has decreased by about 50%.²

Our patient was diagnosed with HIV when screened after this initial presentation. Lower CD4 counts and higher viral loads increase the patient’s risk for oral candidiasis and other lesions. This patient’s initial CD4 count was 524 cells/μL, and his viral load was 11,232 copies/mL.

TREATMENT

In HIV-negative patients or in HIV-positive patients with a CD4 count greater than 200 cells/μL, the treatment of oral candidiasis involves topical antifungal agents, including a nystatin suspension (Nystat-Rx) or clotrimazole (Mycelex) troches.^3,7,9 Treatment should be continued for at least 7 days after resolution of the infection. If resolution does not occur, oral fluconazole (Diflucan) 200 mg daily should be given.

For HIV patients with CD4 counts below 200 cells/μL, oral fluconazole or itraconazole (Sporanox) is recommended, with posaconazole (Noxafil) as an alternative for refractory disease.^3,9 Giving fluconazole prophylactically to prevent oral candidiasis is not recommended because of the risk of adverse effects, lack of survival benefit, associated cost, and potential to develop antifungal resistance.^3,9

Health care providers often need to evaluate allergic disorders such as allergic rhinoconjunctivitis, asthma, and allergies to foods, drugs, latex, and venom, both in the hospital and in the clinic.

Unfortunately, some symptoms, such as chronic nasal symptoms, can occur in both allergic and nonallergic disorders, and this overlap can confound the diagnosis and therapy. Studies suggest that when clinicians use the history and physical examination alone in evaluating possible allergic disease, the accuracy of their diagnoses rarely exceeds 50%.¹

Blood tests are now available that measure immunoglobulin E (IgE) directed against specific antigens. These in vitro tests can be important tools in assessing a patient whose history suggests an allergic disease.² However, neither allergy skin testing nor these blood tests are intended to be used for screening: they may be most useful as confirmatory diagnostic tests in cases in which the pretest clinical impression of allergic disease is high.

ALLERGY IS MEDIATED BY IgE

In susceptible people, IgE is produced by B cells in response to specific antigens such as foods, pollens, latex, and drugs. This antigen-specific (or allergen-specific) IgE circulates in the serum and binds to high-affinity IgE receptors on immune effector cells such as mast cells located throughout the body.

Upon subsequent exposure to the same allergen, IgE receptors cross-link and initiate downstream signaling events that trigger mast cell degranulation and an immediate allergic response—hence the term immediate (or Gell-Coombs type I) hypersensitivity.³

Common manifestations of type I hypersensitivity reactions include signs and symptoms that can be:

• Cutaneous (eg, acute urticaria, angioedema)
• Respiratory (eg, acute bronchospasm, rhinoconjunctivitis)
• Cardiovascular (eg, tachycardia, hypotension)
• Gastrointestinal (eg, vomiting, diarrhea)
• Generalized (eg, anaphylactic shock). By definition, anaphylaxis is a life-threatening reaction that occurs on exposure to an allergen and involves acute respiratory distress, cardiovascular failure, or involvement of two or more organ systems.⁴

MOST IgE BLOOD TESTS ARE IMMUNOASSAYS

The blood tests for allergic disease are immunoassays that measure the level of IgE specific to a particular allergen. The tests can be used to evaluate sensitivity to various allergens, for example, to common inhalants such as dust mites and pollens and to foods, drugs, venom, and latex.

Types of immunoassays include enzyme-linked immunosorbent assays (ELISAs), fluorescent enzyme immunoassays (FEIAs), and radioallergosorbent assays (RASTs). At present, most commercial laboratories use one of three autoanalyzer systems to measure specific IgE:

• ImmunoCAP (Phadia AB, Uppsala, Sweden)
• Immulite (Siemens AG, Berlin, Germany)
• HYTEC-288 (Hycor/Agilent, Garden Grove, CA).

These systems use a solid-phase polymer (cellulose or avidin) in which the antigen is embedded. The polymer also facilitates binding of IgE and, therefore, increases the sensitivity of the test.⁵ Specific IgE from the patient’s serum binds to the allergen embedded in the polymer, and then unbound antibodies are washed off.

Despite the term “RAST,” these systems do not use radiation. A fluorescent antibody is added that binds to the patient’s IgE, and the amount of IgE present is calculated from the amount of fluorescence.⁶ Results are reported in kilounits of antibody per liter (kU/L) or nanograms per milliliter (ng/mL).^5–7

INTERPRETATION IS INDIVIDUALIZED

In general, the sensitivity of these tests ranges from 60% to 95% and their specificity from 30% to 95%, with a concordance among different immunoassays of 75% to 90%.⁸

Levels of IgE for a particular allergen are also divided into semiquantitative classes, from class I to class V or VI. In general, class I and class II correlate with a low level of allergen sensitization and, often, with a low likelihood of a clinical reaction. On the other hand, classes V and VI reflect higher degrees of sensitization and generally correlate with IgE-mediated clinical reactions upon allergen exposure.

The interpretation of a positive (ie, “nonzero”) test result must be individualized on the basis of clinical presentation and risk factors. A specialist can make an important contribution by helping to interpret any positive test result or a negative test result that does not correlate with the patient’s history.

ADVANTAGES OF ALLERGY BLOOD TESTING

Allergy blood testing is convenient, since it involves only a standard blood draw.

In theory, allergy blood testing may be safer, since it does not expose the patient to any allergens. On the other hand, many patients experience bruising from venipuncture performed for any reason: 16% in one survey.⁹ In another survey,¹⁰ adverse reactions of any type occurred in 0.49% of patients undergoing venipuncture but only in 0.04% of those undergoing allergy skin testing. Therefore, allergy blood testing may be most appropriate in situations in which a patient’s history suggests that he or she may be at risk of a systemic reaction from a traditional skin test or in cases in which skin testing is not possible (eg, extensive eczema).

Another advantage of allergy blood testing is that it is not affected by drugs such as antihistamines or tricyclic antidepressants that suppress the histamine response, which is a problem with skin testing.

Allergy blood testing may also be useful in patients on long-term glucocorticoid therapy, although the data conflict. Prolonged oral glucocorticoid use is associated with a decrease in mast cell density and histamine content in the skin,^11,12 although in one study a corticosteroid was found not to affect the results of skin-prick testing for allergy.¹³ Thus, allergy blood testing can be performed in patients who have severe eczema or dermatographism or who cannot safely suspend taking antihistamines or tricyclic antidepressants.

 

LIMITATIONS OF THESE TESTS

A limitation of allergy blood tests is that there is no gold-standard test for many allergic conditions. (Double-blind, placebo-controlled oral food challenge testing has been proposed as the gold-standard test for food allergy, and nasal allergen provocation challenge has been proposed for allergic rhinitis.)

Also, allergy blood tests can give false-positive results because of nonspecific binding of antibody in the assay.

Of note: evidence of sensitization to a particular allergen (ie, a positive blood test result) is not synonymous with clinically relevant disease (ie, clinical sensitivity).

Conversely, these tests can give false-negative results in patients who have true IgE-mediated disease as confirmed by skin testing or allergen challenge. The sensitivity of blood allergy testing is approximately 25% to 30% lower than that of skin testing, based on comparative studies.² The blood tests are usually considered positive if the allergen-specific IgE level is greater than 0.35 kU/L; however, sensitization to certain inhalant allergens can occur at levels as low as 0.12 kU/L.¹⁴

Specific IgE levels measured by different commercial assays are not always interchangeable or equivalent, so a clinician should consistently select the same immunoassay if possible when assessing any given patient over time.¹⁵

Levels of specific IgE have been shown to depend on age, allergen specificity, total serum IgE, and, with inhalant allergens, the season of the year.^15,16

Other limitations of blood testing are its cost and a delay of several days to a week in obtaining the results.¹⁷

WHEN TO ORDER ALLERGY BLOOD TESTING

The allergy evaluation should begin with a thorough history to look for possible triggers for the patient’s symptoms.

For example, respiratory conditions such as asthma and rhinitis may be exacerbated during particular times of the year when certain pollens are commonly present. For patients with this pattern, blood testing for allergy to common inhalants, including pollens, may be appropriate. Similarly, peanut allergy evaluation is indicated for a child who has suffered an anaphylactic reaction after consuming peanut butter. Blood testing is also indicated in patients with a history of venom anaphylaxis, especially if venom skin testing was negative.

In cases in which the patient does not have a clear history of sensitization, blood testing for allergy to multiple foods may find evidence of sensitization that does not necessarily correlate with clinical disease.¹⁸

Likewise, blood tests are not likely to be clinically relevant in conditions not mediated by IgE, such as food intolerances (eg, lactose intolerance), celiac disease, the DRESS syndrome (drug rash, eosinophilia, and systemic symptoms), Stevens-Johnson syndrome, toxic epidermal necrolysis, or other types of drug hypersensitivity reactions, such as serum sickness.³

INTERPRETING COMMONLY ORDERED BLOOD TESTS FOR ALLERGY

Tests for allergy to hundreds of substances are available.

Foods

Milk, eggs, soy, wheat, peanuts, tree nuts, fish, and shellfish account for most cases of food allergy in the United States.¹⁸

IgE-mediated hypersensitivity to milk, eggs, and peanuts tends to be more common in children, whereas peanuts, tree nuts, fish, and shellfish are more commonly associated with reactions in adults.¹⁸ Children are more likely to outgrow allergy to milk, soy, wheat, and eggs than allergy to peanuts, tree nuts, fish, and shellfish—only about 20% of children outgrow peanut allergy.¹⁸

Patients with an IgE-mediated reaction to foods should be closely followed by a specialist, who can best help determine the appropriateness of additional testing (such as an oral challenge under observation), avoidance recommendations, and the introduction of foods back into the diet.¹⁹

Specific IgE tests for allergy to a variety of foods are available and can be very useful for diagnosis when used in the appropriate setting.

Double-blind, placebo-controlled studies have established a relationship between quantitative levels of specific IgE and the 95% likelihood of experiencing a subsequent clinical reaction upon exposure to that allergen. One of the most frequently cited studies is summarized in Table 1.^7,8,18 In many of these studies the gold standard for food allergy was a positive double-blind, placebo-controlled oral food challenge. Of note, these values predict the likelihood of a clinical reaction but not necessarily its severity.

One caveat about these studies is that many were initially performed in children with a history of food allergy, many of whom had atopic dermatitis, and the findings have not been systematically reexamined in larger studies in more heterogeneous populations.

For example, at least eight studies tried to identify a diagnostic IgE level for cow’s milk allergy. The 95% confidence intervals varied widely, depending on the study design, the age of the study population, the prevalence of food allergy in the population, and the statistical method used for analysis.⁵ For most other foods for which blood tests are available, few studies have been performed to establish predictive values similar to those in Table 1.

Thus, slight elevations in antigen-specific IgE (> 0.35 kU/L) may correlate only with in vitro sensitization in a patient who has no clinical reactivity upon oral exposure to a particular antigen.

Broad food panels have been shown to have false-positive rates higher than 50%—ie, in more than half of cases, positive results have no clinical relevance. Therefore, these large food panels should not be used for screening.¹⁹ Instead, it is recommended that tests be limited to relevant foods based on the patient’s history when evaluating symptoms consistent with an IgE-mediated reaction to a particular food.

Food-specific IgE evaluation is also not helpful in evaluating non-IgE adverse reactions to foods (eg, intolerances).

Therefore, the patient’s history remains the most important tool for evaluation of food allergy. In cases in which the patient’s history suggests a food-associated IgE-mediated reaction and the blood test is negative, the patient should be referred to a specialist for skin testing with commercial extracts or even fresh food extracts, given the higher sensitivity of in vivo testing.²⁰

 

 

Inhalants

Common aeroallergens associated with allergic rhinitis, allergic conjunctivitis, and allergic asthma include dust mites, animal dander, cockroach debris, molds, trees, grasses, weeds, and ragweed. Dust mites, animal dander, and mold spores are perennial allergens and may trigger symptoms year-round. Pollen, including pollen from trees, grasses, and weeds, is generally present in a seasonal pattern in many parts of the United States.

A positive blood test for an inhalant allergen can reinforce the physician’s clinical impression in making a diagnosis of allergic rhinoconjunctivitis. Interestingly, studies have suggested a high rate of false-positives based on history alone when in vivo and in vitro allergy testing were negative for IgE-mediated respiratory disease.²¹

Various studies have aimed to establish threshold values of aeroallergen-specific IgE that predict the likelihood of clinically relevant disease. Unfortunately, other factors also contribute to clinical symptoms of rhinoconjunctivitis; these include concurrent inflammation, infection, physical stress, psychological stress, exposure to irritants, and hormonal changes. These factors introduce variability and make specific IgE cutoffs for inhalant allergens unreliable.²²

Prospective studies have suggested that skin testing correlates better with nasal allergen challenge (the gold standard) than blood testing for the diagnosis of inhalant allergy, though more recent studies using modern technologies demonstrate reasonable concordance (67%) between skin testing and blood testing (specifically, ImmunoCAP).^23,24 According to current guidelines, skin tests are the preferred method for diagnosing IgE-mediated sensitivity to inhalants.²⁵

Compared with skin prick tests as the gold standard, the sensitivity of specific IgE immunoassays is approximately 70% to 75%.²⁵ Nevertheless, specific IgE values greater than 0.35 kU/L are generally considered positive for aeroallergen sensitization, although lower levels of dog-specific IgE have recently been shown to correlate with clinical disease.¹⁴

Drugs, including penicillins

A variety of clinical reactions can occur in response to oral, intravenous, or topical medications.

At present, blood tests are available for the evaluation of IgE-mediated adverse reactions to only a limited number of drugs. Reactions involving other mechanisms, such as those related to the drug’s metabolism, intolerances (eg, nausea), idiosyncratic reactions (eg, Stevens-Johnson syndrome, the DRESS syndrome), or other types of reactions can be diagnosed only by history and physical examination.

The development of specific IgE tests for sensitivity to medications has been limited by incomplete characterization of metabolic products and the possibility that a single medication can have different epitopes or IgE binding sites in different individuals.²⁶

With a few exceptions, blood tests for allergy to most drugs are considered positive at IgE values greater than 0.35 kU/L. The sensitivity and specificity vary widely, based on a limited number of studies (Table 2).^26–33

In vitro allergy testing has been most studied for beta-lactam antibiotics (eg, penicillin) and not so much for other drugs.

Table 2 summarizes the sensitivity and specificity of blood allergy tests that are commercially available for drugs.

Penicillin, a beta-lactam antibiotic, is degraded into various metabolites known as the major determinant (penicilloyl) and the minor determinants (eg, benzylpenicilloate and benzylpenilloate), which act as haptens. Specific IgE testing is not available for all these determinants.

The sensitivity of blood tests for allergy to penicilloyl (penicillin) and amino-penicillins such as amoxicilloyl (amoxicillin) is reported as between 32% and 50%, and the specificity as 96% to 98%.²⁹

By definition, any nonzero level of IgE specific for penicillin or its derivatives is considered a positive result and may be associated with a higher risk of IgE-mediated reaction to penicillins. However, in a situation analogous to that in people with food allergy who have a food-specific IgE titer lower than the empirically established threshold value (Table 1), low-titer values to penicillin may not predict anaphylactic sensitivity in a penicillin oral challenge.²⁸ Further studies are needed to determine if there is a threshold level of penicillin-specific IgE above which a patient has a higher likelihood of an IgE-mediated systemic reaction.

Other drugs. Specific IgE blood tests are also available for certain neuromuscular agents, insulin, cefaclor (Ceclor), chlorhexidine (contained in various antiseptic products), and gelatin (Table 2). These substances have not been as well studied as penicillins, and the sensitivity and specificity data reported in Table 2 are limited by few studies and small study sizes.

Neuromuscular blocking agents. Tests for IgE against neuromuscular blocking agents are reported to have low sensitivity (30%–60%) using a cutoff value of 0.35 kU/L.³⁰ In small studies, the sensitivity was higher (68% to 92%) when threshold values for rocuronium-specific IgE were lowered from 0.35 to 0.13 kU/L.²⁹

Chlorhexidine, an antiseptic commonly used in surgery, has been linked to IgE-mediated reactions.³¹ Chlorhexidine-specific IgE levels greater than 0.35 kU/L are considered positive, based on very limited data.

Insulin. Blood tests for allergy to insulin are also commercially available. However, studies have shown a significant overlap in the range of insulin-specific IgE in patients with a clinical history consistent with insulin allergy and in controls. Therefore, this test has a very limited ability to distinguish people who do not have a history of a reaction to insulin.³² More research is needed to determine the clinical utility of insulin-specific IgE testing.

Gelatin. IgE-mediated reactions have occurred after exposure to gelatin (from either cows or pigs) contained in foods and vaccines, including measles-mumps-rubella and yellow fever. One study identified gelatin-specific IgE in 10 of 11 children with a history of systemic reaction to measles or mumps vaccine.³³ In the same study, gelatin-specific IgE levels were negative in 24 children who had developed non-IgE-mediated reactions to the vaccine.³³

Tests for IgE against bovine gelatin are commercially available; results are considered positive for values higher than 0.35 kU/L. A negative test result does not exclude the possibility of an allergic reaction to porcine gelatin, which can also be found in foods and vaccines, but tests for anti-porcine gelatin IgE are not commercially available.

 

 

Latex

Latex, obtained from the rubber tree Hevea brasiliensis, has 13 known polypeptides (allergens Hev b 1–13) that cause IgE-mediated reactions, particularly in health care workers and patients with spina bifida.³⁴ Overall, the incidence of latex allergy has decreased in the United States as most medical institutions have implemented a latex-free environment.

In vitro testing is the only mode of evaluation for allergy to latex approved by the US Food and Drug Administration (FDA).³⁵ Its sensitivity is 80% and its specificity is 95%.³⁶

In a 2007 study, 145 people at risk for latex allergy, including 104 health care workers, 31 patients with spina bifida, and 10 patients requiring multiple surgeries, underwent latex-specific IgE analysis for sensitivity to various recombinant and native latex allergens.³⁴ The three groups differed in their latex allergy profiles, highlighting the diversity of clinical response to latex in high-risk groups and our current inability to establish specific cutoff points for quantitative latex-specific IgE. Thus, at present, any nonzero latex-specific IgE value is considered positive.

A formal evaluation for allergy is recommended for patients who have a strong history of an IgE-mediated reaction to latex and a latex-specific IgE value of zero. Blood tests for allergy to some native or recombinant latex allergens are available; these allergens may be underrepresented in the native total latex extract.³³ Skin testing for allergy to latex, although not FDA-approved or standardized, can also be useful in this setting.³⁷

Insect venom

Type I hypersensitivity reactions can occur from the stings of Vespidae (vespids), Apidae (bees), and Formicidae (fire ants). Large localized reactions after an insect sting are not infrequent and typically do not predict anaphylactic sensitivity with future stings, even though they are considered mild IgE-mediated reactions. However, systemic reactions are considered life-threatening and warrant allergy testing.³⁸

The level of venom-specific IgE usually increases weeks to months after a sting.³⁹ Therefore, blood tests can be falsely negative if performed within a short time of the sting.

Patients who have suffered a systemic reaction to venom and have evidence of sensitization by either in vitro or in vivo allergy testing are candidates for venom immunotherapy.⁴⁰

At present, any nonzero venom-specific IgE test is considered positive, as there is no specific value for venom-specific IgE that predicts clinical risk.

A negative blood test does not exclude the possibility of an IgE-mediated reaction.⁴¹ In cases in which a patient has a clinical history compatible with venom allergy but the blood test is negative, the patient should be referred to an allergist for further evaluation, including venom skin testing and possibly repeat blood testing at a later time.

Conversely, specific IgE testing to venom is recommended when a patient has a history consistent with venom allergy and negative skin test results.³⁸

As mentioned previously, in vitro test performance can vary with the laboratory and testing method used, and sending samples directly to a reference laboratory could be considered.⁴¹

TESTING FOR IgG AGAINST FOODS IS UNVALIDATED AND INAPPROPRIATE

In recent years, some practitioners of alternative medicine have started testing for allergen-specific IgG or IgG4 as part of evaluations for hypersensitivity, especially in cases in which patients describe atypical gastrointestinal, neurologic, or other symptoms after eating specific foods.¹⁹

However, this testing often finds IgG or IgG4 against foods that are well tolerated. At present, allergen-specific IgG testing lacks scientific evidence to support its clinical use in the evaluation of allergic disease.^5,19

Health care providers often need to evaluate allergic disorders such as allergic rhinoconjunctivitis, asthma, and allergies to foods, drugs, latex, and venom, both in the hospital and in the clinic.

Unfortunately, some symptoms, such as chronic nasal symptoms, can occur in both allergic and nonallergic disorders, and this overlap can confound the diagnosis and therapy. Studies suggest that when clinicians use the history and physical examination alone in evaluating possible allergic disease, the accuracy of their diagnoses rarely exceeds 50%.¹

Blood tests are now available that measure immunoglobulin E (IgE) directed against specific antigens. These in vitro tests can be important tools in assessing a patient whose history suggests an allergic disease.² However, neither allergy skin testing nor these blood tests are intended to be used for screening: they may be most useful as confirmatory diagnostic tests in cases in which the pretest clinical impression of allergic disease is high.

ALLERGY IS MEDIATED BY IgE

In susceptible people, IgE is produced by B cells in response to specific antigens such as foods, pollens, latex, and drugs. This antigen-specific (or allergen-specific) IgE circulates in the serum and binds to high-affinity IgE receptors on immune effector cells such as mast cells located throughout the body.

Upon subsequent exposure to the same allergen, IgE receptors cross-link and initiate downstream signaling events that trigger mast cell degranulation and an immediate allergic response—hence the term immediate (or Gell-Coombs type I) hypersensitivity.³

Common manifestations of type I hypersensitivity reactions include signs and symptoms that can be:

• Cutaneous (eg, acute urticaria, angioedema)
• Respiratory (eg, acute bronchospasm, rhinoconjunctivitis)
• Cardiovascular (eg, tachycardia, hypotension)
• Gastrointestinal (eg, vomiting, diarrhea)
• Generalized (eg, anaphylactic shock). By definition, anaphylaxis is a life-threatening reaction that occurs on exposure to an allergen and involves acute respiratory distress, cardiovascular failure, or involvement of two or more organ systems.⁴

MOST IgE BLOOD TESTS ARE IMMUNOASSAYS

The blood tests for allergic disease are immunoassays that measure the level of IgE specific to a particular allergen. The tests can be used to evaluate sensitivity to various allergens, for example, to common inhalants such as dust mites and pollens and to foods, drugs, venom, and latex.

Types of immunoassays include enzyme-linked immunosorbent assays (ELISAs), fluorescent enzyme immunoassays (FEIAs), and radioallergosorbent assays (RASTs). At present, most commercial laboratories use one of three autoanalyzer systems to measure specific IgE:

• ImmunoCAP (Phadia AB, Uppsala, Sweden)
• Immulite (Siemens AG, Berlin, Germany)
• HYTEC-288 (Hycor/Agilent, Garden Grove, CA).

These systems use a solid-phase polymer (cellulose or avidin) in which the antigen is embedded. The polymer also facilitates binding of IgE and, therefore, increases the sensitivity of the test.⁵ Specific IgE from the patient’s serum binds to the allergen embedded in the polymer, and then unbound antibodies are washed off.

Despite the term “RAST,” these systems do not use radiation. A fluorescent antibody is added that binds to the patient’s IgE, and the amount of IgE present is calculated from the amount of fluorescence.⁶ Results are reported in kilounits of antibody per liter (kU/L) or nanograms per milliliter (ng/mL).^5–7

INTERPRETATION IS INDIVIDUALIZED

In general, the sensitivity of these tests ranges from 60% to 95% and their specificity from 30% to 95%, with a concordance among different immunoassays of 75% to 90%.⁸

Levels of IgE for a particular allergen are also divided into semiquantitative classes, from class I to class V or VI. In general, class I and class II correlate with a low level of allergen sensitization and, often, with a low likelihood of a clinical reaction. On the other hand, classes V and VI reflect higher degrees of sensitization and generally correlate with IgE-mediated clinical reactions upon allergen exposure.

The interpretation of a positive (ie, “nonzero”) test result must be individualized on the basis of clinical presentation and risk factors. A specialist can make an important contribution by helping to interpret any positive test result or a negative test result that does not correlate with the patient’s history.

ADVANTAGES OF ALLERGY BLOOD TESTING

Allergy blood testing is convenient, since it involves only a standard blood draw.

In theory, allergy blood testing may be safer, since it does not expose the patient to any allergens. On the other hand, many patients experience bruising from venipuncture performed for any reason: 16% in one survey.⁹ In another survey,¹⁰ adverse reactions of any type occurred in 0.49% of patients undergoing venipuncture but only in 0.04% of those undergoing allergy skin testing. Therefore, allergy blood testing may be most appropriate in situations in which a patient’s history suggests that he or she may be at risk of a systemic reaction from a traditional skin test or in cases in which skin testing is not possible (eg, extensive eczema).

Another advantage of allergy blood testing is that it is not affected by drugs such as antihistamines or tricyclic antidepressants that suppress the histamine response, which is a problem with skin testing.

Allergy blood testing may also be useful in patients on long-term glucocorticoid therapy, although the data conflict. Prolonged oral glucocorticoid use is associated with a decrease in mast cell density and histamine content in the skin,^11,12 although in one study a corticosteroid was found not to affect the results of skin-prick testing for allergy.¹³ Thus, allergy blood testing can be performed in patients who have severe eczema or dermatographism or who cannot safely suspend taking antihistamines or tricyclic antidepressants.

 

LIMITATIONS OF THESE TESTS

A limitation of allergy blood tests is that there is no gold-standard test for many allergic conditions. (Double-blind, placebo-controlled oral food challenge testing has been proposed as the gold-standard test for food allergy, and nasal allergen provocation challenge has been proposed for allergic rhinitis.)

Also, allergy blood tests can give false-positive results because of nonspecific binding of antibody in the assay.

Of note: evidence of sensitization to a particular allergen (ie, a positive blood test result) is not synonymous with clinically relevant disease (ie, clinical sensitivity).

Conversely, these tests can give false-negative results in patients who have true IgE-mediated disease as confirmed by skin testing or allergen challenge. The sensitivity of blood allergy testing is approximately 25% to 30% lower than that of skin testing, based on comparative studies.² The blood tests are usually considered positive if the allergen-specific IgE level is greater than 0.35 kU/L; however, sensitization to certain inhalant allergens can occur at levels as low as 0.12 kU/L.¹⁴

Specific IgE levels measured by different commercial assays are not always interchangeable or equivalent, so a clinician should consistently select the same immunoassay if possible when assessing any given patient over time.¹⁵

Levels of specific IgE have been shown to depend on age, allergen specificity, total serum IgE, and, with inhalant allergens, the season of the year.^15,16

Other limitations of blood testing are its cost and a delay of several days to a week in obtaining the results.¹⁷

WHEN TO ORDER ALLERGY BLOOD TESTING

The allergy evaluation should begin with a thorough history to look for possible triggers for the patient’s symptoms.

For example, respiratory conditions such as asthma and rhinitis may be exacerbated during particular times of the year when certain pollens are commonly present. For patients with this pattern, blood testing for allergy to common inhalants, including pollens, may be appropriate. Similarly, peanut allergy evaluation is indicated for a child who has suffered an anaphylactic reaction after consuming peanut butter. Blood testing is also indicated in patients with a history of venom anaphylaxis, especially if venom skin testing was negative.

In cases in which the patient does not have a clear history of sensitization, blood testing for allergy to multiple foods may find evidence of sensitization that does not necessarily correlate with clinical disease.¹⁸

Likewise, blood tests are not likely to be clinically relevant in conditions not mediated by IgE, such as food intolerances (eg, lactose intolerance), celiac disease, the DRESS syndrome (drug rash, eosinophilia, and systemic symptoms), Stevens-Johnson syndrome, toxic epidermal necrolysis, or other types of drug hypersensitivity reactions, such as serum sickness.³

INTERPRETING COMMONLY ORDERED BLOOD TESTS FOR ALLERGY

Tests for allergy to hundreds of substances are available.

Foods

Milk, eggs, soy, wheat, peanuts, tree nuts, fish, and shellfish account for most cases of food allergy in the United States.¹⁸

IgE-mediated hypersensitivity to milk, eggs, and peanuts tends to be more common in children, whereas peanuts, tree nuts, fish, and shellfish are more commonly associated with reactions in adults.¹⁸ Children are more likely to outgrow allergy to milk, soy, wheat, and eggs than allergy to peanuts, tree nuts, fish, and shellfish—only about 20% of children outgrow peanut allergy.¹⁸

Patients with an IgE-mediated reaction to foods should be closely followed by a specialist, who can best help determine the appropriateness of additional testing (such as an oral challenge under observation), avoidance recommendations, and the introduction of foods back into the diet.¹⁹

Specific IgE tests for allergy to a variety of foods are available and can be very useful for diagnosis when used in the appropriate setting.

Double-blind, placebo-controlled studies have established a relationship between quantitative levels of specific IgE and the 95% likelihood of experiencing a subsequent clinical reaction upon exposure to that allergen. One of the most frequently cited studies is summarized in Table 1.^7,8,18 In many of these studies the gold standard for food allergy was a positive double-blind, placebo-controlled oral food challenge. Of note, these values predict the likelihood of a clinical reaction but not necessarily its severity.

One caveat about these studies is that many were initially performed in children with a history of food allergy, many of whom had atopic dermatitis, and the findings have not been systematically reexamined in larger studies in more heterogeneous populations.

For example, at least eight studies tried to identify a diagnostic IgE level for cow’s milk allergy. The 95% confidence intervals varied widely, depending on the study design, the age of the study population, the prevalence of food allergy in the population, and the statistical method used for analysis.⁵ For most other foods for which blood tests are available, few studies have been performed to establish predictive values similar to those in Table 1.

Thus, slight elevations in antigen-specific IgE (> 0.35 kU/L) may correlate only with in vitro sensitization in a patient who has no clinical reactivity upon oral exposure to a particular antigen.

Broad food panels have been shown to have false-positive rates higher than 50%—ie, in more than half of cases, positive results have no clinical relevance. Therefore, these large food panels should not be used for screening.¹⁹ Instead, it is recommended that tests be limited to relevant foods based on the patient’s history when evaluating symptoms consistent with an IgE-mediated reaction to a particular food.

Food-specific IgE evaluation is also not helpful in evaluating non-IgE adverse reactions to foods (eg, intolerances).

Therefore, the patient’s history remains the most important tool for evaluation of food allergy. In cases in which the patient’s history suggests a food-associated IgE-mediated reaction and the blood test is negative, the patient should be referred to a specialist for skin testing with commercial extracts or even fresh food extracts, given the higher sensitivity of in vivo testing.²⁰

 

 

Inhalants

Common aeroallergens associated with allergic rhinitis, allergic conjunctivitis, and allergic asthma include dust mites, animal dander, cockroach debris, molds, trees, grasses, weeds, and ragweed. Dust mites, animal dander, and mold spores are perennial allergens and may trigger symptoms year-round. Pollen, including pollen from trees, grasses, and weeds, is generally present in a seasonal pattern in many parts of the United States.

A positive blood test for an inhalant allergen can reinforce the physician’s clinical impression in making a diagnosis of allergic rhinoconjunctivitis. Interestingly, studies have suggested a high rate of false-positives based on history alone when in vivo and in vitro allergy testing were negative for IgE-mediated respiratory disease.²¹

Various studies have aimed to establish threshold values of aeroallergen-specific IgE that predict the likelihood of clinically relevant disease. Unfortunately, other factors also contribute to clinical symptoms of rhinoconjunctivitis; these include concurrent inflammation, infection, physical stress, psychological stress, exposure to irritants, and hormonal changes. These factors introduce variability and make specific IgE cutoffs for inhalant allergens unreliable.²²

Prospective studies have suggested that skin testing correlates better with nasal allergen challenge (the gold standard) than blood testing for the diagnosis of inhalant allergy, though more recent studies using modern technologies demonstrate reasonable concordance (67%) between skin testing and blood testing (specifically, ImmunoCAP).^23,24 According to current guidelines, skin tests are the preferred method for diagnosing IgE-mediated sensitivity to inhalants.²⁵

Compared with skin prick tests as the gold standard, the sensitivity of specific IgE immunoassays is approximately 70% to 75%.²⁵ Nevertheless, specific IgE values greater than 0.35 kU/L are generally considered positive for aeroallergen sensitization, although lower levels of dog-specific IgE have recently been shown to correlate with clinical disease.¹⁴

Drugs, including penicillins

A variety of clinical reactions can occur in response to oral, intravenous, or topical medications.

At present, blood tests are available for the evaluation of IgE-mediated adverse reactions to only a limited number of drugs. Reactions involving other mechanisms, such as those related to the drug’s metabolism, intolerances (eg, nausea), idiosyncratic reactions (eg, Stevens-Johnson syndrome, the DRESS syndrome), or other types of reactions can be diagnosed only by history and physical examination.

The development of specific IgE tests for sensitivity to medications has been limited by incomplete characterization of metabolic products and the possibility that a single medication can have different epitopes or IgE binding sites in different individuals.²⁶

With a few exceptions, blood tests for allergy to most drugs are considered positive at IgE values greater than 0.35 kU/L. The sensitivity and specificity vary widely, based on a limited number of studies (Table 2).^26–33

In vitro allergy testing has been most studied for beta-lactam antibiotics (eg, penicillin) and not so much for other drugs.

Table 2 summarizes the sensitivity and specificity of blood allergy tests that are commercially available for drugs.

Penicillin, a beta-lactam antibiotic, is degraded into various metabolites known as the major determinant (penicilloyl) and the minor determinants (eg, benzylpenicilloate and benzylpenilloate), which act as haptens. Specific IgE testing is not available for all these determinants.

The sensitivity of blood tests for allergy to penicilloyl (penicillin) and amino-penicillins such as amoxicilloyl (amoxicillin) is reported as between 32% and 50%, and the specificity as 96% to 98%.²⁹

By definition, any nonzero level of IgE specific for penicillin or its derivatives is considered a positive result and may be associated with a higher risk of IgE-mediated reaction to penicillins. However, in a situation analogous to that in people with food allergy who have a food-specific IgE titer lower than the empirically established threshold value (Table 1), low-titer values to penicillin may not predict anaphylactic sensitivity in a penicillin oral challenge.²⁸ Further studies are needed to determine if there is a threshold level of penicillin-specific IgE above which a patient has a higher likelihood of an IgE-mediated systemic reaction.

Other drugs. Specific IgE blood tests are also available for certain neuromuscular agents, insulin, cefaclor (Ceclor), chlorhexidine (contained in various antiseptic products), and gelatin (Table 2). These substances have not been as well studied as penicillins, and the sensitivity and specificity data reported in Table 2 are limited by few studies and small study sizes.

Neuromuscular blocking agents. Tests for IgE against neuromuscular blocking agents are reported to have low sensitivity (30%–60%) using a cutoff value of 0.35 kU/L.³⁰ In small studies, the sensitivity was higher (68% to 92%) when threshold values for rocuronium-specific IgE were lowered from 0.35 to 0.13 kU/L.²⁹

Chlorhexidine, an antiseptic commonly used in surgery, has been linked to IgE-mediated reactions.³¹ Chlorhexidine-specific IgE levels greater than 0.35 kU/L are considered positive, based on very limited data.

Insulin. Blood tests for allergy to insulin are also commercially available. However, studies have shown a significant overlap in the range of insulin-specific IgE in patients with a clinical history consistent with insulin allergy and in controls. Therefore, this test has a very limited ability to distinguish people who do not have a history of a reaction to insulin.³² More research is needed to determine the clinical utility of insulin-specific IgE testing.

Gelatin. IgE-mediated reactions have occurred after exposure to gelatin (from either cows or pigs) contained in foods and vaccines, including measles-mumps-rubella and yellow fever. One study identified gelatin-specific IgE in 10 of 11 children with a history of systemic reaction to measles or mumps vaccine.³³ In the same study, gelatin-specific IgE levels were negative in 24 children who had developed non-IgE-mediated reactions to the vaccine.³³

Tests for IgE against bovine gelatin are commercially available; results are considered positive for values higher than 0.35 kU/L. A negative test result does not exclude the possibility of an allergic reaction to porcine gelatin, which can also be found in foods and vaccines, but tests for anti-porcine gelatin IgE are not commercially available.

 

 

Latex

Latex, obtained from the rubber tree Hevea brasiliensis, has 13 known polypeptides (allergens Hev b 1–13) that cause IgE-mediated reactions, particularly in health care workers and patients with spina bifida.³⁴ Overall, the incidence of latex allergy has decreased in the United States as most medical institutions have implemented a latex-free environment.

In vitro testing is the only mode of evaluation for allergy to latex approved by the US Food and Drug Administration (FDA).³⁵ Its sensitivity is 80% and its specificity is 95%.³⁶

In a 2007 study, 145 people at risk for latex allergy, including 104 health care workers, 31 patients with spina bifida, and 10 patients requiring multiple surgeries, underwent latex-specific IgE analysis for sensitivity to various recombinant and native latex allergens.³⁴ The three groups differed in their latex allergy profiles, highlighting the diversity of clinical response to latex in high-risk groups and our current inability to establish specific cutoff points for quantitative latex-specific IgE. Thus, at present, any nonzero latex-specific IgE value is considered positive.

A formal evaluation for allergy is recommended for patients who have a strong history of an IgE-mediated reaction to latex and a latex-specific IgE value of zero. Blood tests for allergy to some native or recombinant latex allergens are available; these allergens may be underrepresented in the native total latex extract.³³ Skin testing for allergy to latex, although not FDA-approved or standardized, can also be useful in this setting.³⁷

Insect venom

Type I hypersensitivity reactions can occur from the stings of Vespidae (vespids), Apidae (bees), and Formicidae (fire ants). Large localized reactions after an insect sting are not infrequent and typically do not predict anaphylactic sensitivity with future stings, even though they are considered mild IgE-mediated reactions. However, systemic reactions are considered life-threatening and warrant allergy testing.³⁸

The level of venom-specific IgE usually increases weeks to months after a sting.³⁹ Therefore, blood tests can be falsely negative if performed within a short time of the sting.

Patients who have suffered a systemic reaction to venom and have evidence of sensitization by either in vitro or in vivo allergy testing are candidates for venom immunotherapy.⁴⁰

At present, any nonzero venom-specific IgE test is considered positive, as there is no specific value for venom-specific IgE that predicts clinical risk.

A negative blood test does not exclude the possibility of an IgE-mediated reaction.⁴¹ In cases in which a patient has a clinical history compatible with venom allergy but the blood test is negative, the patient should be referred to an allergist for further evaluation, including venom skin testing and possibly repeat blood testing at a later time.

Conversely, specific IgE testing to venom is recommended when a patient has a history consistent with venom allergy and negative skin test results.³⁸

As mentioned previously, in vitro test performance can vary with the laboratory and testing method used, and sending samples directly to a reference laboratory could be considered.⁴¹

TESTING FOR IgG AGAINST FOODS IS UNVALIDATED AND INAPPROPRIATE

In recent years, some practitioners of alternative medicine have started testing for allergen-specific IgG or IgG4 as part of evaluations for hypersensitivity, especially in cases in which patients describe atypical gastrointestinal, neurologic, or other symptoms after eating specific foods.¹⁹

However, this testing often finds IgG or IgG4 against foods that are well tolerated. At present, allergen-specific IgG testing lacks scientific evidence to support its clinical use in the evaluation of allergic disease.^5,19