The Journal of Family Practice

EVIDENCE SUMMARY

Three meta-analyses that included only randomized controlled trials (RCTs) compared various CBT delivery methods with controls (wait-listed for treatment or general sleep hygiene education) to assess sleep outcomes for adults with insomnia.^1-3 TABLE 1^1-3 summarizes the results.

CBT is comparable to pharmacotherapy

A 2002 comparative meta-analysis of 21 RCTs with a total of 470 patients examined the effectiveness of CBT (stimulus control and/or sleep restriction) compared with pharmacotherapy (benzodiazepines or benzodiazepine agonists) for treating primary insomnia of longer than one month’s duration in adults with no comorbid medical or psychiatric diagnoses.⁴ The CBT group received intervention over an average of 5 weeks, and the pharmacotherapy group received intervention over an average of 2 weeks.

CBT produced greater reductions in sleep onset latency than pharmacotherapy based on mean weighted effect size (1.05 vs 0.45 weighted effect size; 95% confidence interval, 0.17-1.04; P=.01). Although both CBT and pharmacotherapy improved sleep outcomes, no statistical differences were found in wake after sleep onset time, total sleep time, number of awakenings, or sleep quality ratings (TABLE 2⁴).

Continue to: CBT has significant benefit for comorbid insomnia

A 2015 meta-analysis of 23 studies enrolling a total of 1379 adults with a number of illnesses (chronic pain, alcohol dependence, breast cancer, psychiatric disorders, chronic obstructive pulmonary disease, fibromyalgia) and comorbid insomnia investigated the qualitative effectiveness of individual or group CBT therapy.⁵ Subjects received at least 4 face-to-face sessions and at least 2 components of CBT.

The primary outcome showed that sleep quality improved, as measured by a 6.36-point reduction in the Insomnia Severity Index (ISI; a 7-question scale on which 0=no insomnia and 28=severe insomnia) and a 3.3-point reduction in the Pittsburgh Sleep Quality Index (PSQI; a 7-category assessment tool on which 0=perfect quality and 21=poor quality). The effect size was large for both ISI and PSQI, as indicated by standard mean differences greater than 0.8 (1.22 and 0.88, respectively) and was sustained for as long as 18 months.

RECOMMENDATIONS

The American College of Physicians strongly recommends that all adult patients receive CBT as initial treatment for chronic insomnia disorder. It can be performed in multiple settings, including the primary care setting. Compared with hypnotics, CBT is unlikely to have any adverse effects.⁶

EVIDENCE SUMMARY

Three meta-analyses that included only randomized controlled trials (RCTs) compared various CBT delivery methods with controls (wait-listed for treatment or general sleep hygiene education) to assess sleep outcomes for adults with insomnia.^1-3 TABLE 1^1-3 summarizes the results.

CBT is comparable to pharmacotherapy

A 2002 comparative meta-analysis of 21 RCTs with a total of 470 patients examined the effectiveness of CBT (stimulus control and/or sleep restriction) compared with pharmacotherapy (benzodiazepines or benzodiazepine agonists) for treating primary insomnia of longer than one month’s duration in adults with no comorbid medical or psychiatric diagnoses.⁴ The CBT group received intervention over an average of 5 weeks, and the pharmacotherapy group received intervention over an average of 2 weeks.

CBT produced greater reductions in sleep onset latency than pharmacotherapy based on mean weighted effect size (1.05 vs 0.45 weighted effect size; 95% confidence interval, 0.17-1.04; P=.01). Although both CBT and pharmacotherapy improved sleep outcomes, no statistical differences were found in wake after sleep onset time, total sleep time, number of awakenings, or sleep quality ratings (TABLE 2⁴).

Continue to: CBT has significant benefit for comorbid insomnia

A 2015 meta-analysis of 23 studies enrolling a total of 1379 adults with a number of illnesses (chronic pain, alcohol dependence, breast cancer, psychiatric disorders, chronic obstructive pulmonary disease, fibromyalgia) and comorbid insomnia investigated the qualitative effectiveness of individual or group CBT therapy.⁵ Subjects received at least 4 face-to-face sessions and at least 2 components of CBT.

The primary outcome showed that sleep quality improved, as measured by a 6.36-point reduction in the Insomnia Severity Index (ISI; a 7-question scale on which 0=no insomnia and 28=severe insomnia) and a 3.3-point reduction in the Pittsburgh Sleep Quality Index (PSQI; a 7-category assessment tool on which 0=perfect quality and 21=poor quality). The effect size was large for both ISI and PSQI, as indicated by standard mean differences greater than 0.8 (1.22 and 0.88, respectively) and was sustained for as long as 18 months.

RECOMMENDATIONS

The American College of Physicians strongly recommends that all adult patients receive CBT as initial treatment for chronic insomnia disorder. It can be performed in multiple settings, including the primary care setting. Compared with hypnotics, CBT is unlikely to have any adverse effects.⁶

EVIDENCE SUMMARY

Three meta-analyses that included only randomized controlled trials (RCTs) compared various CBT delivery methods with controls (wait-listed for treatment or general sleep hygiene education) to assess sleep outcomes for adults with insomnia.^1-3 TABLE 1^1-3 summarizes the results.

CBT is comparable to pharmacotherapy

A 2002 comparative meta-analysis of 21 RCTs with a total of 470 patients examined the effectiveness of CBT (stimulus control and/or sleep restriction) compared with pharmacotherapy (benzodiazepines or benzodiazepine agonists) for treating primary insomnia of longer than one month’s duration in adults with no comorbid medical or psychiatric diagnoses.⁴ The CBT group received intervention over an average of 5 weeks, and the pharmacotherapy group received intervention over an average of 2 weeks.

CBT produced greater reductions in sleep onset latency than pharmacotherapy based on mean weighted effect size (1.05 vs 0.45 weighted effect size; 95% confidence interval, 0.17-1.04; P=.01). Although both CBT and pharmacotherapy improved sleep outcomes, no statistical differences were found in wake after sleep onset time, total sleep time, number of awakenings, or sleep quality ratings (TABLE 2⁴).

Continue to: CBT has significant benefit for comorbid insomnia

A 2015 meta-analysis of 23 studies enrolling a total of 1379 adults with a number of illnesses (chronic pain, alcohol dependence, breast cancer, psychiatric disorders, chronic obstructive pulmonary disease, fibromyalgia) and comorbid insomnia investigated the qualitative effectiveness of individual or group CBT therapy.⁵ Subjects received at least 4 face-to-face sessions and at least 2 components of CBT.

The primary outcome showed that sleep quality improved, as measured by a 6.36-point reduction in the Insomnia Severity Index (ISI; a 7-question scale on which 0=no insomnia and 28=severe insomnia) and a 3.3-point reduction in the Pittsburgh Sleep Quality Index (PSQI; a 7-category assessment tool on which 0=perfect quality and 21=poor quality). The effect size was large for both ISI and PSQI, as indicated by standard mean differences greater than 0.8 (1.22 and 0.88, respectively) and was sustained for as long as 18 months.

RECOMMENDATIONS

The American College of Physicians strongly recommends that all adult patients receive CBT as initial treatment for chronic insomnia disorder. It can be performed in multiple settings, including the primary care setting. Compared with hypnotics, CBT is unlikely to have any adverse effects.⁶

A 44-year-old African-American woman with sickle cell trait presented to the clinic to establish care. She complained of polyarthralgias that she’d had since adolescence; the pain was worst in her right shoulder. She reported morning stiffness that lasted up to 8 hours, an intermittent facial rash, oral ulcers, joint edema (of which she had pictures on her phone), and photosensitivity. She took ibuprofen and acetaminophen as needed for pain. She once worked as a medical assistant but hadn’t been able to work since 2014 due to pain. She reported having been told as a teenager that she might have juvenile arthritis, but she didn’t recall ever having diagnostic tests performed or receiving treatment other than anti-inflammatories.

A couple of weeks after an initial visit with a rheumatologist, the patient returned to the family medicine clinic. She said she was upset that the specialist had x-rayed her hands, but had not checked her shoulder, which was the primary source of her pain. She also had pain in her hands, hips, feet, and knees.

On physical exam, the patient looked fatigued. A musculoskeletal exam revealed no joint effusions or edema, but was significant for right shoulder pain with reduced abduction to 90°. Gross motor strength was 5/5 in all 4 extremities. Laboratory testing revealed an antinuclear antibody titer of 1:160 and was negative for double-stranded DNA. Bilateral hand and foot x-rays showed no joint erosions. An x-ray of the right shoulder was obtained, which showed evidence of osteopenia and an erosion in the humeral head (FIGURES 1A and 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history of morning stiffness and the joint erosion observed on x-ray were highly suggestive of rheumatoid arthritis (RA).

Joint stiffness due to osteoarthritis is worse with activity and generally lasts only a few minutes, while joint stiffness due to rheumatoid arthritis is worse at rest and lasts 30 minutes or more.

RA is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It is the most common form of inflammatory arthritis, affecting 1% of the population worldwide.¹ It causes cartilage and bone to erode, leading to the deformation and destruction of joints. If RA is left untreated or is unresponsive to therapy, it can eventually lead to loss of physical function.

Making the diagnosis

The distinctive signs of RA are joint erosions and rheumatoid nodules, which are often absent on initial presentation.

Classification criteria. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA² are based on the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the synovitis, and a cumulative score of at least 6/10 from the following 4 domains:

1. Number and site of involved joints
   • 2 to 10 large joints (shoulders, elbows, hips, knees, ankles)=1 point
   • 1 to 3 small joints (metacarpophalangeal [MCP] joints, proximal interphalangeal [PIP] joints, 2nd-5th metatarsophalangeal joints, thumb interphalangeal joints, wrists)=2 points
   • 4 to 10 small joints=3 points
   • More than 10 joints (including at least 1 small joint)=5 points
2. Serologic abnormality (rheumatoid factor [RF] and anti-cyclic citrullinated peptide)
   • Low positive=2 points
   • High positive=3 points
3. Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP])=1 point
4. Symptom duration of at least 6 weeks=1 point.

These criteria are best suited for early disease. For patients with longstanding symptoms, diagnosis is based on an erosive disease with a history of criteria fulfillment, or a currently inactive longstanding disease, with or without treatment, that has previously fulfilled the criteria.³

Continue to: The differential Dx is extensive

The differential includes polyarthralgias such as viral polyarthritis, systemic rheumatic diseases, and osteoarthritis.

Viral polyarthritis is caused by rubella, parvovirus B19⁴, alphaviruses, and hepatitis B. Symptoms can last from 3 days to several weeks, but rarely persist beyond 6 weeks; alphaviruses, however, can last 3 to 6 months.⁵ The common symptom triad includes fever, arthritis, and rash. Chikungunya is an example of an alphavirus that has become a global disease. Alphavirus arthritis can mimic seronegative RA and even satisfy the classification criteria for RA if the initial symptoms of fever and rash and history of travel to endemic regions are not appreciated.⁵

Systemic rheumatic diseases. Early RA may mimic the arthritis of systemic lupus erythematosus (SLE), Sjögren’s syndrome, dermatomyositis, or mixed connective tissue disease.⁶ In contrast to RA, these disorders generally have systemic features, such as rashes, dry mouth and eyes, myositis, or nephritis, and generate autobodies, which are not seen with RA. The CRP is often normal in patients with active SLE, even when the ESR is elevated.

Immediate treatment with disease-modifying antirheumatic drugs is important to achieve disease control and prevent disability.

Osteoarthritis (OA) can be confused with RA, particularly when small joints are involved. A thorough history helps elucidate the diagnosis. For example, OA of the fingers affects distal interphalangeal joints and is associated with Heberden’s nodes, while RA more commonly affects MCP and PIP joints. Swelling from OA is typically firm, while swelling due to RA is warm, boggy, and tender. Joint stiffness due to OA is worse with activity and generally lasts only a few minutes, while joint stiffness due to RA is worse at rest and lasts 30 minutes or more. X-rays show joint-space narrowing with OA, but no erosions or cysts. RF may be present at low levels in older patients with OA, while it is usually associated with high levels in patients with seropositive RA.

Continue to: Treat with disease-modifying antirheumatic drugs

Immediate treatment of RA with disease-modifying antirheumatic drugs (DMARDs) is important to achieve control of the disease and prevent disability.

Our patient. We ordered a purified protein derivative skin test in preparation for the patient to start therapy with a DMARD. Our patient followed up with Rheumatology and was started on indomethacin, with an initial dose of 25 mg bid. (DMARDs are first-line therapy; indomethacin is a second-line choice. In this case, the patient declined DMARDs after hearing they lowered the body’s ability to fight infection.) An RF level measured 6.74 IU/ml, which is within normal limits. The patient was subsequently lost to follow-up.

CORRESPONDENCE
Barbara Kiersz, DO, 6835 Austin Center Blvd., Austin, TX 78731; [email protected].

A 44-year-old African-American woman with sickle cell trait presented to the clinic to establish care. She complained of polyarthralgias that she’d had since adolescence; the pain was worst in her right shoulder. She reported morning stiffness that lasted up to 8 hours, an intermittent facial rash, oral ulcers, joint edema (of which she had pictures on her phone), and photosensitivity. She took ibuprofen and acetaminophen as needed for pain. She once worked as a medical assistant but hadn’t been able to work since 2014 due to pain. She reported having been told as a teenager that she might have juvenile arthritis, but she didn’t recall ever having diagnostic tests performed or receiving treatment other than anti-inflammatories.

A couple of weeks after an initial visit with a rheumatologist, the patient returned to the family medicine clinic. She said she was upset that the specialist had x-rayed her hands, but had not checked her shoulder, which was the primary source of her pain. She also had pain in her hands, hips, feet, and knees.

On physical exam, the patient looked fatigued. A musculoskeletal exam revealed no joint effusions or edema, but was significant for right shoulder pain with reduced abduction to 90°. Gross motor strength was 5/5 in all 4 extremities. Laboratory testing revealed an antinuclear antibody titer of 1:160 and was negative for double-stranded DNA. Bilateral hand and foot x-rays showed no joint erosions. An x-ray of the right shoulder was obtained, which showed evidence of osteopenia and an erosion in the humeral head (FIGURES 1A and 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history of morning stiffness and the joint erosion observed on x-ray were highly suggestive of rheumatoid arthritis (RA).

Joint stiffness due to osteoarthritis is worse with activity and generally lasts only a few minutes, while joint stiffness due to rheumatoid arthritis is worse at rest and lasts 30 minutes or more.

RA is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It is the most common form of inflammatory arthritis, affecting 1% of the population worldwide.¹ It causes cartilage and bone to erode, leading to the deformation and destruction of joints. If RA is left untreated or is unresponsive to therapy, it can eventually lead to loss of physical function.

Making the diagnosis

The distinctive signs of RA are joint erosions and rheumatoid nodules, which are often absent on initial presentation.

Classification criteria. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA² are based on the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the synovitis, and a cumulative score of at least 6/10 from the following 4 domains:

1. Number and site of involved joints
   • 2 to 10 large joints (shoulders, elbows, hips, knees, ankles)=1 point
   • 1 to 3 small joints (metacarpophalangeal [MCP] joints, proximal interphalangeal [PIP] joints, 2nd-5th metatarsophalangeal joints, thumb interphalangeal joints, wrists)=2 points
   • 4 to 10 small joints=3 points
   • More than 10 joints (including at least 1 small joint)=5 points
2. Serologic abnormality (rheumatoid factor [RF] and anti-cyclic citrullinated peptide)
   • Low positive=2 points
   • High positive=3 points
3. Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP])=1 point
4. Symptom duration of at least 6 weeks=1 point.

These criteria are best suited for early disease. For patients with longstanding symptoms, diagnosis is based on an erosive disease with a history of criteria fulfillment, or a currently inactive longstanding disease, with or without treatment, that has previously fulfilled the criteria.³

Continue to: The differential Dx is extensive

The differential includes polyarthralgias such as viral polyarthritis, systemic rheumatic diseases, and osteoarthritis.

Viral polyarthritis is caused by rubella, parvovirus B19⁴, alphaviruses, and hepatitis B. Symptoms can last from 3 days to several weeks, but rarely persist beyond 6 weeks; alphaviruses, however, can last 3 to 6 months.⁵ The common symptom triad includes fever, arthritis, and rash. Chikungunya is an example of an alphavirus that has become a global disease. Alphavirus arthritis can mimic seronegative RA and even satisfy the classification criteria for RA if the initial symptoms of fever and rash and history of travel to endemic regions are not appreciated.⁵

Systemic rheumatic diseases. Early RA may mimic the arthritis of systemic lupus erythematosus (SLE), Sjögren’s syndrome, dermatomyositis, or mixed connective tissue disease.⁶ In contrast to RA, these disorders generally have systemic features, such as rashes, dry mouth and eyes, myositis, or nephritis, and generate autobodies, which are not seen with RA. The CRP is often normal in patients with active SLE, even when the ESR is elevated.

Immediate treatment with disease-modifying antirheumatic drugs is important to achieve disease control and prevent disability.

Osteoarthritis (OA) can be confused with RA, particularly when small joints are involved. A thorough history helps elucidate the diagnosis. For example, OA of the fingers affects distal interphalangeal joints and is associated with Heberden’s nodes, while RA more commonly affects MCP and PIP joints. Swelling from OA is typically firm, while swelling due to RA is warm, boggy, and tender. Joint stiffness due to OA is worse with activity and generally lasts only a few minutes, while joint stiffness due to RA is worse at rest and lasts 30 minutes or more. X-rays show joint-space narrowing with OA, but no erosions or cysts. RF may be present at low levels in older patients with OA, while it is usually associated with high levels in patients with seropositive RA.

Continue to: Treat with disease-modifying antirheumatic drugs

Immediate treatment of RA with disease-modifying antirheumatic drugs (DMARDs) is important to achieve control of the disease and prevent disability.

Our patient. We ordered a purified protein derivative skin test in preparation for the patient to start therapy with a DMARD. Our patient followed up with Rheumatology and was started on indomethacin, with an initial dose of 25 mg bid. (DMARDs are first-line therapy; indomethacin is a second-line choice. In this case, the patient declined DMARDs after hearing they lowered the body’s ability to fight infection.) An RF level measured 6.74 IU/ml, which is within normal limits. The patient was subsequently lost to follow-up.

CORRESPONDENCE
Barbara Kiersz, DO, 6835 Austin Center Blvd., Austin, TX 78731; [email protected].

A 44-year-old African-American woman with sickle cell trait presented to the clinic to establish care. She complained of polyarthralgias that she’d had since adolescence; the pain was worst in her right shoulder. She reported morning stiffness that lasted up to 8 hours, an intermittent facial rash, oral ulcers, joint edema (of which she had pictures on her phone), and photosensitivity. She took ibuprofen and acetaminophen as needed for pain. She once worked as a medical assistant but hadn’t been able to work since 2014 due to pain. She reported having been told as a teenager that she might have juvenile arthritis, but she didn’t recall ever having diagnostic tests performed or receiving treatment other than anti-inflammatories.

A couple of weeks after an initial visit with a rheumatologist, the patient returned to the family medicine clinic. She said she was upset that the specialist had x-rayed her hands, but had not checked her shoulder, which was the primary source of her pain. She also had pain in her hands, hips, feet, and knees.

On physical exam, the patient looked fatigued. A musculoskeletal exam revealed no joint effusions or edema, but was significant for right shoulder pain with reduced abduction to 90°. Gross motor strength was 5/5 in all 4 extremities. Laboratory testing revealed an antinuclear antibody titer of 1:160 and was negative for double-stranded DNA. Bilateral hand and foot x-rays showed no joint erosions. An x-ray of the right shoulder was obtained, which showed evidence of osteopenia and an erosion in the humeral head (FIGURES 1A and 1B).

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

The patient’s history of morning stiffness and the joint erosion observed on x-ray were highly suggestive of rheumatoid arthritis (RA).

Joint stiffness due to osteoarthritis is worse with activity and generally lasts only a few minutes, while joint stiffness due to rheumatoid arthritis is worse at rest and lasts 30 minutes or more.

RA is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It is the most common form of inflammatory arthritis, affecting 1% of the population worldwide.¹ It causes cartilage and bone to erode, leading to the deformation and destruction of joints. If RA is left untreated or is unresponsive to therapy, it can eventually lead to loss of physical function.

Making the diagnosis

The distinctive signs of RA are joint erosions and rheumatoid nodules, which are often absent on initial presentation.

Classification criteria. The 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA² are based on the presence of synovitis in at least one joint, the absence of an alternative diagnosis that better explains the synovitis, and a cumulative score of at least 6/10 from the following 4 domains:

1. Number and site of involved joints
   • 2 to 10 large joints (shoulders, elbows, hips, knees, ankles)=1 point
   • 1 to 3 small joints (metacarpophalangeal [MCP] joints, proximal interphalangeal [PIP] joints, 2nd-5th metatarsophalangeal joints, thumb interphalangeal joints, wrists)=2 points
   • 4 to 10 small joints=3 points
   • More than 10 joints (including at least 1 small joint)=5 points
2. Serologic abnormality (rheumatoid factor [RF] and anti-cyclic citrullinated peptide)
   • Low positive=2 points
   • High positive=3 points
3. Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP])=1 point
4. Symptom duration of at least 6 weeks=1 point.

These criteria are best suited for early disease. For patients with longstanding symptoms, diagnosis is based on an erosive disease with a history of criteria fulfillment, or a currently inactive longstanding disease, with or without treatment, that has previously fulfilled the criteria.³

Continue to: The differential Dx is extensive

The differential includes polyarthralgias such as viral polyarthritis, systemic rheumatic diseases, and osteoarthritis.

Viral polyarthritis is caused by rubella, parvovirus B19⁴, alphaviruses, and hepatitis B. Symptoms can last from 3 days to several weeks, but rarely persist beyond 6 weeks; alphaviruses, however, can last 3 to 6 months.⁵ The common symptom triad includes fever, arthritis, and rash. Chikungunya is an example of an alphavirus that has become a global disease. Alphavirus arthritis can mimic seronegative RA and even satisfy the classification criteria for RA if the initial symptoms of fever and rash and history of travel to endemic regions are not appreciated.⁵

Systemic rheumatic diseases. Early RA may mimic the arthritis of systemic lupus erythematosus (SLE), Sjögren’s syndrome, dermatomyositis, or mixed connective tissue disease.⁶ In contrast to RA, these disorders generally have systemic features, such as rashes, dry mouth and eyes, myositis, or nephritis, and generate autobodies, which are not seen with RA. The CRP is often normal in patients with active SLE, even when the ESR is elevated.

Immediate treatment with disease-modifying antirheumatic drugs is important to achieve disease control and prevent disability.

Osteoarthritis (OA) can be confused with RA, particularly when small joints are involved. A thorough history helps elucidate the diagnosis. For example, OA of the fingers affects distal interphalangeal joints and is associated with Heberden’s nodes, while RA more commonly affects MCP and PIP joints. Swelling from OA is typically firm, while swelling due to RA is warm, boggy, and tender. Joint stiffness due to OA is worse with activity and generally lasts only a few minutes, while joint stiffness due to RA is worse at rest and lasts 30 minutes or more. X-rays show joint-space narrowing with OA, but no erosions or cysts. RF may be present at low levels in older patients with OA, while it is usually associated with high levels in patients with seropositive RA.

Continue to: Treat with disease-modifying antirheumatic drugs

Immediate treatment of RA with disease-modifying antirheumatic drugs (DMARDs) is important to achieve control of the disease and prevent disability.

Our patient. We ordered a purified protein derivative skin test in preparation for the patient to start therapy with a DMARD. Our patient followed up with Rheumatology and was started on indomethacin, with an initial dose of 25 mg bid. (DMARDs are first-line therapy; indomethacin is a second-line choice. In this case, the patient declined DMARDs after hearing they lowered the body’s ability to fight infection.) An RF level measured 6.74 IU/ml, which is within normal limits. The patient was subsequently lost to follow-up.

CORRESPONDENCE
Barbara Kiersz, DO, 6835 Austin Center Blvd., Austin, TX 78731; [email protected].

Thrombocytopenia and neutropenia are commonly encountered laboratory abnormalities. The presence of either requires that you promptly evaluate for life-threatening causes and identify the appropriate etiology. This article identifies key questions to ask. It also includes algorithms and tables that will facilitate your evaluation of patients with isolated thrombocytopenia or isolated neutropenia and speed the way toward appropriate treatment.

Thrombocytopenia: A look at the numbers

Thrombocytopenia is defined as a platelet count <150,000/mcL.¹ The blood abnormality is either suspected based on the patient’s signs or symptoms, such as ecchymoses, petechiae, purpura, epistaxis, gingival bleeding, or melena, or it is incidentally discovered during review of a complete blood count (CBC).

The development of clinical symptoms is closely related to the severity of the thrombocytopenia, with platelet counts <30,000/mcL more likely to result in clinical symptoms with minor trauma and counts <5,000/mcL potentially resulting in spontaneous bleeding. While most patients will have asymptomatic, incidentally-found thrombocytopenia, and likely a benign etiology, those with the signs/symptoms just described, evidence of infection, or thrombosis are more likely to have a serious etiology and require an expedited work-up. Although pregnancy may be associated with thrombocytopenia, this review confines itself to the causes of thrombocytopenia in non-pregnant adults.

Rule out pseudothrombocytopenia

When isolated thrombocytopenia is discovered incidentally in an asymptomatic person, the first step is to perform a repeat CBC with a peripheral smear to confirm the presence of thrombocytopenia, rule out laboratory error, and assess for platelet clumping. If thrombocytopenia is confirmed and platelet clumping is present, it may be due to the calcium chelator in the ethylenediaminetetraacetic anticoagulant contained within the laboratory transport tube; this cause of pseudothrombocytopenia occurs in up to 0.29% of the population.¹ Obtaining a platelet count from a citrated or heparinized tube avoids this phenomenon.

Is the patient’s thrombocytopenia drug induced?

Once true thrombocytopenia is confirmed, the next step is to review the patient’s prescribed medications, as well as any illicit drugs used, for potential causes of drug-induced thrombocytopenia. DITP can be either immune-mediated or nonimmune-mediated.

Immune-mediated drug-induced thrombocytopenia typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.

Immune-mediated DITP typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.² (See TABLE 1³ for a list of medications that can induce thrombocytopenia.) It should be noted that most patients who take the medications listed in TABLE 1 do not experience thrombocytopenia; nonetheless, it is a potential risk associated with their use.

Heparin-induced thrombocytopenia (HIT) is a unique form of immune-mediated DITP in that it is caused by antibody complexes, resulting in platelet activation, clumping, and thrombotic events.⁴ HIT occurs <1% of patients in intensive care units, but can occur in any patient on long-term heparin therapy. It manifests as a >50% drop in platelet count within 5 to 14 days of the introduction of heparin; however, in those previously exposed to heparin, it can occur within 24 hours.^4,5

Continue to: Non-immune-mediated DITP

Non-immune-mediated DITP, resulting from myelosuppression, chemotherapeutic agents, or valproic acid, is less common.^1,2

Acute and chronic alcohol use. Although alcohol is not a drug per se, it can also result in thrombocytopenia. The mechanism is the direct suppression of bone marrow, although alcohol also causes B12 and folate deficiency, further contributing to the development of the blood abnormality.¹

Is there thrombosis?

In addition to exploring a connection between thrombocytopenia and the drugs a patient is taking, it’s also important to look for evidence of thrombosis. The causes of thrombocytopenia that paradoxically result in thrombosis are: disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, catastrophic antiphospholipid antibody syndrome, and the previously mentioned HIT. TABLE 2^4,6-9 outlines the clinical settings, laboratory findings, and treatments of thrombocytopenia associated with thrombosis.

Is an infectious cause to blame?

If the patient is ill, consider infectious causes of thrombocytopenia. Thrombocytopenia associated with infection may result from an immune-mediated response to an illness itself, to treatment of an illness, to splenic sequestration, or to bone marrow suppression. TABLE 3^1,9-11 lists common infections that may cause thrombocytopenia.

Of note, infection with Helicobacter pylori can cause asymptomatic thrombocytopenia via an immune-mediated mechanism.¹² Eradication of H pylori results in a variable elevation in platelets, on average 30,000/mcL in 50% of patients with the infection.¹³

Is there pancytopenia?

A review of the peripheral smear, with attention to abnormalities in other cell lines, may assist in arriving at a diagnosis. If the peripheral smear reveals pancytopenia, then, in addition to many of the etiologies described earlier, one should also consider vitamin B12 or folate deficiency, copper deficiency, drug- and viral-induced aplastic anemia, paroxysmal nocturnal hemoglobinuria, leukemias, myelodysplastic disorders, and systemic lupus erythematosis.¹⁴ Pancytopenia is also seen with hypersplenism, which is often associated with cirrhosis.¹⁵ If the etiology isn’t readily apparent, a bone marrow biopsy may be required.

Continue to: Is immune thrombocytopenia to blame?

Immune thrombocytopenia (ITP) is an autoimmune disorder resulting in the destruction of normal platelets and may be primary or secondary to processes described previously (HIT, H pylori infection, etc). Consider ITP if, after a thorough work-up, a cause of isolated thrombocytopenia is not identified.¹⁶ Treatment for ITP is outlined in TABLE 4.¹⁶ FIGURE 1 is an algorithm for the complete evaluation of thrombocytopenia in adults.

Treatment: Platelet transfusions

In general, patients who are not actively bleeding are considered stable and do not require platelet transfusions to minimize their risk of bleeding or prevent bleeding during a planned procedure unless their platelet count falls below the levels specified in TABLE 5.¹⁷ For patients who are actively bleeding, a more aggressive approach may be required. Locally-derived transfusion protocols typically guide transfusions for the actively hemorrhaging patient. The American Association of Blood Banks has put forth evidence-based guidelines for platelet transfusions when a patient is given a diagnosis of thrombocytopenia (see TABLE 5).¹⁷ Single-donor platelets have a shelf life of 3 to 5 days, and one unit will raise platelets 30,000 to 50,000/mcL.

Neutropenia: Prevalence varies by ethnicity

An absolute neutrophil count (ANC) of <1500 cells/mcL traditionally defines neutropenia, with an ANC of 1000 to 1500 cells/mcL constituting mild neutropenia; 500 to 999 cells/mcL, moderate; and <500 cells/mcL, severe.¹⁸ Similar to the evaluation of thrombocytopenia, it is important to repeat the CBC prior to initiating a work-up in order to confirm that the neutropenia is not a laboratory error. Additionally, patients with signs or symptoms of infection should be worked up expeditiously.

Heparin-induced thrombocytopenia occurs in <1% of patients in intensive care units and typically is manifested by a ≥50% drop in platelet count within 5 to 14 days of introducing heparin.

The prevalence of neutropenia varies by ethnicity. According to the National Health and Nutrition Examination Survey 1999 to 2004, the prevalence was 4.5%, 0.79%, and 0.38% in black, white, and Mexican-American participants, respectively.¹⁹ FIGURE 2 outlines the outpatient work-up of adult patients with neutropenia not related to chemotherapy.

Continue to: Is the patient severely ill?

The prognosis of the patient is related both to the etiology of the neutropenia, as well as to the nadir of the neutrophil count. Patients who have an ANC <500 cells/mcL or who have inadequate bone marrow reserves are at highest risk for an overwhelming infection.^20,21 The absence of oral ulcers and gingivitis and/or the presence of purulent material at the site of an infection are signs of adequate bone marrow reserves.

Additionally, neutropenia may be the source—or the result—of a serious life-threatening illness. This distinction may not be readily apparent at the time of the patient’s presentation. If signs or symptoms of a severe illness are apparent (fever, hypotension, tachycardia, ANC <500 cells/mcL), admit the patient to the hospital for evaluation and initiation of antibiotics. 

Is the neutropenia chronic?

A review of previous CBCs will identify whether this condition is new or chronic. A persistent, mild neutropenia (ANC 1000-1500 cells/mcL) in a healthy individual is consistent with benign familial or ethnic neutropenia (see TABLE 6).²⁰ If prior CBCs are unavailable, then a diagnosis of chronic neutropenia may be established by verifying the persistence of mild neutropenia over time.

Cyclic neutropenia is a periodic neutropenia (occurring every 2-5 weeks) associated with mild illnesses that are related to the nadir of the neutrophil count. The diagnosis is established by obtaining serial CBCs twice weekly for 4 to 6 weeks, which reflect cycling of the neutrophil count.^20,22

Are any medications contributing to the neutropenia?

Medications that suppress bone marrow or that interfere with other immune-mediated processes are the most common cause of acquired neutropenia.²³ Drug-induced agranulocytosis is defined as an ANC <500 cells/mcL due to exposure to a drug that results in immunologic or cytotoxic destruction of neutrophils.²⁴

A persistent, mild neutropenia in a healthy individual is consistent with benign familial or ethnic neutropenia.

A systematic review of case reports of drug-induced agranulocytosis (a decrease in peripheral neutrophil count to <500 cells/mcL) revealed that although at least 125 drugs were probably related to agranulocytosis, only 11 drugs were responsible for 50% of cases (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine), and fatality rates were higher (10% vs 3%) among those patients with a nadir <100 cells/mcL.²⁵ TABLE 7²⁵ lists medications that can be associated with agranulocytosis. Depending on prior exposure to a drug, neutropenia/agranulocytosis can occur within hours to months of exposure to the causal drug and can take a few days to 3 weeks to resolve after cessation.^25,26

Continue to: Has the patient had any recent illnesses?

The usual response to an infection is an increase in neutrophil count. However, certain bacterial, rickettsial, parasitic, and viral infections can result in neutropenia (see TABLE 8^23,27-29). Viral infections may cause transient neutropenia because of either bone marrow suppression or increased peripheral destruction, while neutropenia related to an overwhelming bacterial infection results from the depletion of bone marrow reserves.^23,27

Do you suspect a nutritional deficiency?

Patients with a nutritional deficiency of B12, folate, or copper are likely to exhibit a deficiency in more than just neutrophils.^23,27 In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.²⁰

Does your patient have symptoms of a connective tissue disease?

In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.

Neutropenia, in association with arthralgias, joint swelling, splenomegaly, or rash may be a manifestation of an underlying collagen vascular disorder, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).²⁰ If the clinical scenario supports one of these diagnoses, undertake or refer the patient for a rheumatologic evaluation. This may include studies of anti-cyclic citrullinated peptide antibodies, rheumatoid factor to evaluate for RA, and/or antinuclear antibodies to evaluate for SLE.^30,31 While most neutropenias associated with autoimmune disease are mild, neutropenia associated with Felty syndrome (RA, splenomegaly, and neutropenia) may be severe (ANC <100 cells/mcL).^20,23

Is the etiology unclear?

Patients with moderate to severe neutropenia without an apparent etiology, in the setting of aplastic anemia, or in the presence of splenomegaly and/or lymphadenopathy, should undergo a hematologic evaluation and/or bone marrow biopsy, given that hematologic malignancy is a potential cause.^20,27

The treatment of neutropenia hinges on correctly identifying the etiology of the diminished neutrophil count. If the cause is a medication, infection, underlying rheumatologic condition, or nutritional deficiency, then either treating the entity or withdrawing the offending medication should result in resolution of the neutropenia. If the cause is determined to be familial or ethnic, then patient reassurance is all that is required.

CORRESPONDENCE
Richard W. Temple, MD, FAAFP, CDR MC USN, Camp Lejeune Family Medicine Residency, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547-2538; [email protected].

Thrombocytopenia and neutropenia are commonly encountered laboratory abnormalities. The presence of either requires that you promptly evaluate for life-threatening causes and identify the appropriate etiology. This article identifies key questions to ask. It also includes algorithms and tables that will facilitate your evaluation of patients with isolated thrombocytopenia or isolated neutropenia and speed the way toward appropriate treatment.

Thrombocytopenia: A look at the numbers

Thrombocytopenia is defined as a platelet count <150,000/mcL.¹ The blood abnormality is either suspected based on the patient’s signs or symptoms, such as ecchymoses, petechiae, purpura, epistaxis, gingival bleeding, or melena, or it is incidentally discovered during review of a complete blood count (CBC).

The development of clinical symptoms is closely related to the severity of the thrombocytopenia, with platelet counts <30,000/mcL more likely to result in clinical symptoms with minor trauma and counts <5,000/mcL potentially resulting in spontaneous bleeding. While most patients will have asymptomatic, incidentally-found thrombocytopenia, and likely a benign etiology, those with the signs/symptoms just described, evidence of infection, or thrombosis are more likely to have a serious etiology and require an expedited work-up. Although pregnancy may be associated with thrombocytopenia, this review confines itself to the causes of thrombocytopenia in non-pregnant adults.

Rule out pseudothrombocytopenia

When isolated thrombocytopenia is discovered incidentally in an asymptomatic person, the first step is to perform a repeat CBC with a peripheral smear to confirm the presence of thrombocytopenia, rule out laboratory error, and assess for platelet clumping. If thrombocytopenia is confirmed and platelet clumping is present, it may be due to the calcium chelator in the ethylenediaminetetraacetic anticoagulant contained within the laboratory transport tube; this cause of pseudothrombocytopenia occurs in up to 0.29% of the population.¹ Obtaining a platelet count from a citrated or heparinized tube avoids this phenomenon.

Is the patient’s thrombocytopenia drug induced?

Once true thrombocytopenia is confirmed, the next step is to review the patient’s prescribed medications, as well as any illicit drugs used, for potential causes of drug-induced thrombocytopenia. DITP can be either immune-mediated or nonimmune-mediated.

Immune-mediated drug-induced thrombocytopenia typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.

Immune-mediated DITP typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.² (See TABLE 1³ for a list of medications that can induce thrombocytopenia.) It should be noted that most patients who take the medications listed in TABLE 1 do not experience thrombocytopenia; nonetheless, it is a potential risk associated with their use.

Heparin-induced thrombocytopenia (HIT) is a unique form of immune-mediated DITP in that it is caused by antibody complexes, resulting in platelet activation, clumping, and thrombotic events.⁴ HIT occurs <1% of patients in intensive care units, but can occur in any patient on long-term heparin therapy. It manifests as a >50% drop in platelet count within 5 to 14 days of the introduction of heparin; however, in those previously exposed to heparin, it can occur within 24 hours.^4,5

Continue to: Non-immune-mediated DITP

Non-immune-mediated DITP, resulting from myelosuppression, chemotherapeutic agents, or valproic acid, is less common.^1,2

Acute and chronic alcohol use. Although alcohol is not a drug per se, it can also result in thrombocytopenia. The mechanism is the direct suppression of bone marrow, although alcohol also causes B12 and folate deficiency, further contributing to the development of the blood abnormality.¹

Is there thrombosis?

In addition to exploring a connection between thrombocytopenia and the drugs a patient is taking, it’s also important to look for evidence of thrombosis. The causes of thrombocytopenia that paradoxically result in thrombosis are: disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, catastrophic antiphospholipid antibody syndrome, and the previously mentioned HIT. TABLE 2^4,6-9 outlines the clinical settings, laboratory findings, and treatments of thrombocytopenia associated with thrombosis.

Is an infectious cause to blame?

If the patient is ill, consider infectious causes of thrombocytopenia. Thrombocytopenia associated with infection may result from an immune-mediated response to an illness itself, to treatment of an illness, to splenic sequestration, or to bone marrow suppression. TABLE 3^1,9-11 lists common infections that may cause thrombocytopenia.

Of note, infection with Helicobacter pylori can cause asymptomatic thrombocytopenia via an immune-mediated mechanism.¹² Eradication of H pylori results in a variable elevation in platelets, on average 30,000/mcL in 50% of patients with the infection.¹³

Is there pancytopenia?

A review of the peripheral smear, with attention to abnormalities in other cell lines, may assist in arriving at a diagnosis. If the peripheral smear reveals pancytopenia, then, in addition to many of the etiologies described earlier, one should also consider vitamin B12 or folate deficiency, copper deficiency, drug- and viral-induced aplastic anemia, paroxysmal nocturnal hemoglobinuria, leukemias, myelodysplastic disorders, and systemic lupus erythematosis.¹⁴ Pancytopenia is also seen with hypersplenism, which is often associated with cirrhosis.¹⁵ If the etiology isn’t readily apparent, a bone marrow biopsy may be required.

Continue to: Is immune thrombocytopenia to blame?

Immune thrombocytopenia (ITP) is an autoimmune disorder resulting in the destruction of normal platelets and may be primary or secondary to processes described previously (HIT, H pylori infection, etc). Consider ITP if, after a thorough work-up, a cause of isolated thrombocytopenia is not identified.¹⁶ Treatment for ITP is outlined in TABLE 4.¹⁶ FIGURE 1 is an algorithm for the complete evaluation of thrombocytopenia in adults.

Treatment: Platelet transfusions

In general, patients who are not actively bleeding are considered stable and do not require platelet transfusions to minimize their risk of bleeding or prevent bleeding during a planned procedure unless their platelet count falls below the levels specified in TABLE 5.¹⁷ For patients who are actively bleeding, a more aggressive approach may be required. Locally-derived transfusion protocols typically guide transfusions for the actively hemorrhaging patient. The American Association of Blood Banks has put forth evidence-based guidelines for platelet transfusions when a patient is given a diagnosis of thrombocytopenia (see TABLE 5).¹⁷ Single-donor platelets have a shelf life of 3 to 5 days, and one unit will raise platelets 30,000 to 50,000/mcL.

Neutropenia: Prevalence varies by ethnicity

An absolute neutrophil count (ANC) of <1500 cells/mcL traditionally defines neutropenia, with an ANC of 1000 to 1500 cells/mcL constituting mild neutropenia; 500 to 999 cells/mcL, moderate; and <500 cells/mcL, severe.¹⁸ Similar to the evaluation of thrombocytopenia, it is important to repeat the CBC prior to initiating a work-up in order to confirm that the neutropenia is not a laboratory error. Additionally, patients with signs or symptoms of infection should be worked up expeditiously.

Heparin-induced thrombocytopenia occurs in <1% of patients in intensive care units and typically is manifested by a ≥50% drop in platelet count within 5 to 14 days of introducing heparin.

The prevalence of neutropenia varies by ethnicity. According to the National Health and Nutrition Examination Survey 1999 to 2004, the prevalence was 4.5%, 0.79%, and 0.38% in black, white, and Mexican-American participants, respectively.¹⁹ FIGURE 2 outlines the outpatient work-up of adult patients with neutropenia not related to chemotherapy.

Continue to: Is the patient severely ill?

The prognosis of the patient is related both to the etiology of the neutropenia, as well as to the nadir of the neutrophil count. Patients who have an ANC <500 cells/mcL or who have inadequate bone marrow reserves are at highest risk for an overwhelming infection.^20,21 The absence of oral ulcers and gingivitis and/or the presence of purulent material at the site of an infection are signs of adequate bone marrow reserves.

Additionally, neutropenia may be the source—or the result—of a serious life-threatening illness. This distinction may not be readily apparent at the time of the patient’s presentation. If signs or symptoms of a severe illness are apparent (fever, hypotension, tachycardia, ANC <500 cells/mcL), admit the patient to the hospital for evaluation and initiation of antibiotics. 

Is the neutropenia chronic?

A review of previous CBCs will identify whether this condition is new or chronic. A persistent, mild neutropenia (ANC 1000-1500 cells/mcL) in a healthy individual is consistent with benign familial or ethnic neutropenia (see TABLE 6).²⁰ If prior CBCs are unavailable, then a diagnosis of chronic neutropenia may be established by verifying the persistence of mild neutropenia over time.

Cyclic neutropenia is a periodic neutropenia (occurring every 2-5 weeks) associated with mild illnesses that are related to the nadir of the neutrophil count. The diagnosis is established by obtaining serial CBCs twice weekly for 4 to 6 weeks, which reflect cycling of the neutrophil count.^20,22

Are any medications contributing to the neutropenia?

Medications that suppress bone marrow or that interfere with other immune-mediated processes are the most common cause of acquired neutropenia.²³ Drug-induced agranulocytosis is defined as an ANC <500 cells/mcL due to exposure to a drug that results in immunologic or cytotoxic destruction of neutrophils.²⁴

A persistent, mild neutropenia in a healthy individual is consistent with benign familial or ethnic neutropenia.

A systematic review of case reports of drug-induced agranulocytosis (a decrease in peripheral neutrophil count to <500 cells/mcL) revealed that although at least 125 drugs were probably related to agranulocytosis, only 11 drugs were responsible for 50% of cases (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine), and fatality rates were higher (10% vs 3%) among those patients with a nadir <100 cells/mcL.²⁵ TABLE 7²⁵ lists medications that can be associated with agranulocytosis. Depending on prior exposure to a drug, neutropenia/agranulocytosis can occur within hours to months of exposure to the causal drug and can take a few days to 3 weeks to resolve after cessation.^25,26

Continue to: Has the patient had any recent illnesses?

The usual response to an infection is an increase in neutrophil count. However, certain bacterial, rickettsial, parasitic, and viral infections can result in neutropenia (see TABLE 8^23,27-29). Viral infections may cause transient neutropenia because of either bone marrow suppression or increased peripheral destruction, while neutropenia related to an overwhelming bacterial infection results from the depletion of bone marrow reserves.^23,27

Do you suspect a nutritional deficiency?

Patients with a nutritional deficiency of B12, folate, or copper are likely to exhibit a deficiency in more than just neutrophils.^23,27 In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.²⁰

Does your patient have symptoms of a connective tissue disease?

In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.

Neutropenia, in association with arthralgias, joint swelling, splenomegaly, or rash may be a manifestation of an underlying collagen vascular disorder, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).²⁰ If the clinical scenario supports one of these diagnoses, undertake or refer the patient for a rheumatologic evaluation. This may include studies of anti-cyclic citrullinated peptide antibodies, rheumatoid factor to evaluate for RA, and/or antinuclear antibodies to evaluate for SLE.^30,31 While most neutropenias associated with autoimmune disease are mild, neutropenia associated with Felty syndrome (RA, splenomegaly, and neutropenia) may be severe (ANC <100 cells/mcL).^20,23

Is the etiology unclear?

Patients with moderate to severe neutropenia without an apparent etiology, in the setting of aplastic anemia, or in the presence of splenomegaly and/or lymphadenopathy, should undergo a hematologic evaluation and/or bone marrow biopsy, given that hematologic malignancy is a potential cause.^20,27

The treatment of neutropenia hinges on correctly identifying the etiology of the diminished neutrophil count. If the cause is a medication, infection, underlying rheumatologic condition, or nutritional deficiency, then either treating the entity or withdrawing the offending medication should result in resolution of the neutropenia. If the cause is determined to be familial or ethnic, then patient reassurance is all that is required.

CORRESPONDENCE
Richard W. Temple, MD, FAAFP, CDR MC USN, Camp Lejeune Family Medicine Residency, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547-2538; [email protected].

Thrombocytopenia and neutropenia are commonly encountered laboratory abnormalities. The presence of either requires that you promptly evaluate for life-threatening causes and identify the appropriate etiology. This article identifies key questions to ask. It also includes algorithms and tables that will facilitate your evaluation of patients with isolated thrombocytopenia or isolated neutropenia and speed the way toward appropriate treatment.

Thrombocytopenia: A look at the numbers

Thrombocytopenia is defined as a platelet count <150,000/mcL.¹ The blood abnormality is either suspected based on the patient’s signs or symptoms, such as ecchymoses, petechiae, purpura, epistaxis, gingival bleeding, or melena, or it is incidentally discovered during review of a complete blood count (CBC).

The development of clinical symptoms is closely related to the severity of the thrombocytopenia, with platelet counts <30,000/mcL more likely to result in clinical symptoms with minor trauma and counts <5,000/mcL potentially resulting in spontaneous bleeding. While most patients will have asymptomatic, incidentally-found thrombocytopenia, and likely a benign etiology, those with the signs/symptoms just described, evidence of infection, or thrombosis are more likely to have a serious etiology and require an expedited work-up. Although pregnancy may be associated with thrombocytopenia, this review confines itself to the causes of thrombocytopenia in non-pregnant adults.

Rule out pseudothrombocytopenia

When isolated thrombocytopenia is discovered incidentally in an asymptomatic person, the first step is to perform a repeat CBC with a peripheral smear to confirm the presence of thrombocytopenia, rule out laboratory error, and assess for platelet clumping. If thrombocytopenia is confirmed and platelet clumping is present, it may be due to the calcium chelator in the ethylenediaminetetraacetic anticoagulant contained within the laboratory transport tube; this cause of pseudothrombocytopenia occurs in up to 0.29% of the population.¹ Obtaining a platelet count from a citrated or heparinized tube avoids this phenomenon.

Is the patient’s thrombocytopenia drug induced?

Once true thrombocytopenia is confirmed, the next step is to review the patient’s prescribed medications, as well as any illicit drugs used, for potential causes of drug-induced thrombocytopenia. DITP can be either immune-mediated or nonimmune-mediated.

Immune-mediated drug-induced thrombocytopenia typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.

Immune-mediated DITP typically occurs within 1 to 2 weeks of medication exposure and begins to improve within 1 to 2 days of stopping the offending drug.² (See TABLE 1³ for a list of medications that can induce thrombocytopenia.) It should be noted that most patients who take the medications listed in TABLE 1 do not experience thrombocytopenia; nonetheless, it is a potential risk associated with their use.

Heparin-induced thrombocytopenia (HIT) is a unique form of immune-mediated DITP in that it is caused by antibody complexes, resulting in platelet activation, clumping, and thrombotic events.⁴ HIT occurs <1% of patients in intensive care units, but can occur in any patient on long-term heparin therapy. It manifests as a >50% drop in platelet count within 5 to 14 days of the introduction of heparin; however, in those previously exposed to heparin, it can occur within 24 hours.^4,5

Continue to: Non-immune-mediated DITP

Non-immune-mediated DITP, resulting from myelosuppression, chemotherapeutic agents, or valproic acid, is less common.^1,2

Acute and chronic alcohol use. Although alcohol is not a drug per se, it can also result in thrombocytopenia. The mechanism is the direct suppression of bone marrow, although alcohol also causes B12 and folate deficiency, further contributing to the development of the blood abnormality.¹

Is there thrombosis?

In addition to exploring a connection between thrombocytopenia and the drugs a patient is taking, it’s also important to look for evidence of thrombosis. The causes of thrombocytopenia that paradoxically result in thrombosis are: disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, catastrophic antiphospholipid antibody syndrome, and the previously mentioned HIT. TABLE 2^4,6-9 outlines the clinical settings, laboratory findings, and treatments of thrombocytopenia associated with thrombosis.

Is an infectious cause to blame?

If the patient is ill, consider infectious causes of thrombocytopenia. Thrombocytopenia associated with infection may result from an immune-mediated response to an illness itself, to treatment of an illness, to splenic sequestration, or to bone marrow suppression. TABLE 3^1,9-11 lists common infections that may cause thrombocytopenia.

Of note, infection with Helicobacter pylori can cause asymptomatic thrombocytopenia via an immune-mediated mechanism.¹² Eradication of H pylori results in a variable elevation in platelets, on average 30,000/mcL in 50% of patients with the infection.¹³

Is there pancytopenia?

A review of the peripheral smear, with attention to abnormalities in other cell lines, may assist in arriving at a diagnosis. If the peripheral smear reveals pancytopenia, then, in addition to many of the etiologies described earlier, one should also consider vitamin B12 or folate deficiency, copper deficiency, drug- and viral-induced aplastic anemia, paroxysmal nocturnal hemoglobinuria, leukemias, myelodysplastic disorders, and systemic lupus erythematosis.¹⁴ Pancytopenia is also seen with hypersplenism, which is often associated with cirrhosis.¹⁵ If the etiology isn’t readily apparent, a bone marrow biopsy may be required.

Continue to: Is immune thrombocytopenia to blame?

Immune thrombocytopenia (ITP) is an autoimmune disorder resulting in the destruction of normal platelets and may be primary or secondary to processes described previously (HIT, H pylori infection, etc). Consider ITP if, after a thorough work-up, a cause of isolated thrombocytopenia is not identified.¹⁶ Treatment for ITP is outlined in TABLE 4.¹⁶ FIGURE 1 is an algorithm for the complete evaluation of thrombocytopenia in adults.

Treatment: Platelet transfusions

In general, patients who are not actively bleeding are considered stable and do not require platelet transfusions to minimize their risk of bleeding or prevent bleeding during a planned procedure unless their platelet count falls below the levels specified in TABLE 5.¹⁷ For patients who are actively bleeding, a more aggressive approach may be required. Locally-derived transfusion protocols typically guide transfusions for the actively hemorrhaging patient. The American Association of Blood Banks has put forth evidence-based guidelines for platelet transfusions when a patient is given a diagnosis of thrombocytopenia (see TABLE 5).¹⁷ Single-donor platelets have a shelf life of 3 to 5 days, and one unit will raise platelets 30,000 to 50,000/mcL.

Neutropenia: Prevalence varies by ethnicity

An absolute neutrophil count (ANC) of <1500 cells/mcL traditionally defines neutropenia, with an ANC of 1000 to 1500 cells/mcL constituting mild neutropenia; 500 to 999 cells/mcL, moderate; and <500 cells/mcL, severe.¹⁸ Similar to the evaluation of thrombocytopenia, it is important to repeat the CBC prior to initiating a work-up in order to confirm that the neutropenia is not a laboratory error. Additionally, patients with signs or symptoms of infection should be worked up expeditiously.

Heparin-induced thrombocytopenia occurs in <1% of patients in intensive care units and typically is manifested by a ≥50% drop in platelet count within 5 to 14 days of introducing heparin.

The prevalence of neutropenia varies by ethnicity. According to the National Health and Nutrition Examination Survey 1999 to 2004, the prevalence was 4.5%, 0.79%, and 0.38% in black, white, and Mexican-American participants, respectively.¹⁹ FIGURE 2 outlines the outpatient work-up of adult patients with neutropenia not related to chemotherapy.

Continue to: Is the patient severely ill?

The prognosis of the patient is related both to the etiology of the neutropenia, as well as to the nadir of the neutrophil count. Patients who have an ANC <500 cells/mcL or who have inadequate bone marrow reserves are at highest risk for an overwhelming infection.^20,21 The absence of oral ulcers and gingivitis and/or the presence of purulent material at the site of an infection are signs of adequate bone marrow reserves.

Additionally, neutropenia may be the source—or the result—of a serious life-threatening illness. This distinction may not be readily apparent at the time of the patient’s presentation. If signs or symptoms of a severe illness are apparent (fever, hypotension, tachycardia, ANC <500 cells/mcL), admit the patient to the hospital for evaluation and initiation of antibiotics. 

Is the neutropenia chronic?

A review of previous CBCs will identify whether this condition is new or chronic. A persistent, mild neutropenia (ANC 1000-1500 cells/mcL) in a healthy individual is consistent with benign familial or ethnic neutropenia (see TABLE 6).²⁰ If prior CBCs are unavailable, then a diagnosis of chronic neutropenia may be established by verifying the persistence of mild neutropenia over time.

Cyclic neutropenia is a periodic neutropenia (occurring every 2-5 weeks) associated with mild illnesses that are related to the nadir of the neutrophil count. The diagnosis is established by obtaining serial CBCs twice weekly for 4 to 6 weeks, which reflect cycling of the neutrophil count.^20,22

Are any medications contributing to the neutropenia?

Medications that suppress bone marrow or that interfere with other immune-mediated processes are the most common cause of acquired neutropenia.²³ Drug-induced agranulocytosis is defined as an ANC <500 cells/mcL due to exposure to a drug that results in immunologic or cytotoxic destruction of neutrophils.²⁴

A persistent, mild neutropenia in a healthy individual is consistent with benign familial or ethnic neutropenia.

A systematic review of case reports of drug-induced agranulocytosis (a decrease in peripheral neutrophil count to <500 cells/mcL) revealed that although at least 125 drugs were probably related to agranulocytosis, only 11 drugs were responsible for 50% of cases (carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, and ticlopidine), and fatality rates were higher (10% vs 3%) among those patients with a nadir <100 cells/mcL.²⁵ TABLE 7²⁵ lists medications that can be associated with agranulocytosis. Depending on prior exposure to a drug, neutropenia/agranulocytosis can occur within hours to months of exposure to the causal drug and can take a few days to 3 weeks to resolve after cessation.^25,26

Continue to: Has the patient had any recent illnesses?

The usual response to an infection is an increase in neutrophil count. However, certain bacterial, rickettsial, parasitic, and viral infections can result in neutropenia (see TABLE 8^23,27-29). Viral infections may cause transient neutropenia because of either bone marrow suppression or increased peripheral destruction, while neutropenia related to an overwhelming bacterial infection results from the depletion of bone marrow reserves.^23,27

Do you suspect a nutritional deficiency?

Patients with a nutritional deficiency of B12, folate, or copper are likely to exhibit a deficiency in more than just neutrophils.^23,27 In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.²⁰

Does your patient have symptoms of a connective tissue disease?

In developed countries, people with neutropenia may have a history of malnutrition due to a disease (eg, anorexia nervosa) or surgery (eg, gastric bypass) that causes severe calorie restriction.

Neutropenia, in association with arthralgias, joint swelling, splenomegaly, or rash may be a manifestation of an underlying collagen vascular disorder, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).²⁰ If the clinical scenario supports one of these diagnoses, undertake or refer the patient for a rheumatologic evaluation. This may include studies of anti-cyclic citrullinated peptide antibodies, rheumatoid factor to evaluate for RA, and/or antinuclear antibodies to evaluate for SLE.^30,31 While most neutropenias associated with autoimmune disease are mild, neutropenia associated with Felty syndrome (RA, splenomegaly, and neutropenia) may be severe (ANC <100 cells/mcL).^20,23

Is the etiology unclear?

Patients with moderate to severe neutropenia without an apparent etiology, in the setting of aplastic anemia, or in the presence of splenomegaly and/or lymphadenopathy, should undergo a hematologic evaluation and/or bone marrow biopsy, given that hematologic malignancy is a potential cause.^20,27

The treatment of neutropenia hinges on correctly identifying the etiology of the diminished neutrophil count. If the cause is a medication, infection, underlying rheumatologic condition, or nutritional deficiency, then either treating the entity or withdrawing the offending medication should result in resolution of the neutropenia. If the cause is determined to be familial or ethnic, then patient reassurance is all that is required.

CORRESPONDENCE
Richard W. Temple, MD, FAAFP, CDR MC USN, Camp Lejeune Family Medicine Residency, Naval Medical Center Camp Lejeune, 100 Brewster Blvd, Camp Lejeune, NC 28547-2538; [email protected].

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].

CASE

A 44-year-old nurse describes persistent fatigue and itching over the last 2 months. She is taking ramipril 5 mg/d for hypertension and has a family history of rheumatic disease. Lab tests reveal a recurrent moderate elevation of gamma glutamyl-transpeptidase (gGT; 75 U/L) associated with, on some occasions, mild elevation of alanine aminotransferase (ALT) levels (100 U/L) of unknown origin. She has no history of hepatitis virus infection, hepatotoxic medications, or alcohol intake. She is overweight with a body mass index of 28.5 kg/m² and a waist circumference of 99 cm (39 inches). Liver ultrasonography detects an enlarged liver with diffuse echostructure dishomogeneity, but no signs of cirrhosis or portal hypertension. The patient’s biliary tree is not dilated.

How would you proceed with the care of this patient?

Cholestasis is characterized by the alteration of bile flow through any part of the biliary system, from the hepatocyte basocellular membrane to the duodenum. The condition is classified as intrahepatic when the cause is a defect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common bile duct).

Suspect intrahepatic cholestasis in a patient with chronic itching, normal transaminases, and mildly elevated gamma glutamyl-transpeptidase.

The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise—of cholestasis

Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of the enzyme autotaxin, which produces the neuronal activator lysophosphatidic acid. Retention of pruritogenic substances that normally are excreted into bile might contribute to pruritus as well.¹ Jaundice, dark urine, and pale and fatty stools occur with advanced disease. However, a cholestatic condition can be detected in asymptomatic patients with elevated biochemical markers.

Continue to: Mildly elevated gGT and/or alkaline phosphatase (ALP)

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography

Abdominal ultrasonography is a first-line diagnostic tool for cholestasis.

While biopsy is considered the gold standard for diagnosing and staging chronic cholestatic liver disease and can exclude an extrahepatic obstruction, it should be employed only if blood tests have been confirmed, second-level tests have been performed, and ultrasound is inconclusive.¹² (More on biopsy in a bit.)

Ultrasonography is a low-cost, widely available, noninvasive test that allows easy identification of extrahepatic dilatation of the biliary tree and sometimes the underlying cause, as well. Ultrasonography identifies extrahepatic cholestasis by allowing visualization of an enlarged choledochus (>7 mm) or common hepatic duct (>5 mm) and an intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of the portal vein.¹³ However, ultrasonography has a low diagnostic sensitivity for many conditions (eg, 15% to 89% for detecting common bile duct stones),¹⁴ requiring other diagnostic procedures, such as endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP), before reaching a diagnosis.

For asymptomatic patients with cirrhosis or those at an early stage of liver disease, ultrasound at 6-month intervals combined with serum liver function tests can be useful to track disease progression and screen for hepatocellular carcinoma or cholangiocarcinoma.^15,16

New noninvasive methods. Noninvasive tools for evaluating the presence and severity of liver fibrosis and for differentiating cirrhosis from noncirrhotic conditions have positive predictive values >85% to 90% for some chronic liver diseases.¹⁷ Transient elastography, which assesses liver stiffness, is one such method. Although it is often used successfully, morbid obesity, small intercostal spaces, and ascites limit its diagnostic capability.¹⁸ Recently, some questions about the validity of elastography to assess the extent of fibrosis in patients with chronic cholestatic conditions have been reported.^19,20

Suspect intrahepatic cholestasis? Your next steps

If imaging techniques do not show bile duct obstruction and you suspect the intrahepatic form, second-level tests could have strategic importance. This is where antimitochondrial antibodies (AMAs) come in. AMAs are immunoglobulins (IgG and IgM) directed against mitochondrial antigens. They are important markers for PBC, which is a T-lymphocyte-mediated attack on small intralobular bile ducts resulting in their gradual destruction and eventual disappearance. The sustained loss of intralobular bile ducts leads to signs and symptoms of cholestasis and eventually results in cirrhosis and liver failure.

AMA serum levels show high sensitivity and specificity (90% and 95%, respectively) for PBC.²¹ Some PBC patients (<5%) show histologic confirmation of the disease, but have negative AMA tests (AMA negative PBC or autoimmune cholangitis).²² Therefore, according to the American Association for the Study of Liver Diseases, diagnosis of PBC is guided by the combination of serologic, biochemical, and histologic criteria.²³ Many PBC patients with or without a positive AMA (≥1:40) also have positive circulating antinuclear antibodies (ANA; ≥1:80). The recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has allowed identification of subgroups of patients who have a more aggressive form of PBC. Patients with PBC often have elevated levels of circulating IgM (>280 mg/dL).

Continue to: Other circulating antibodies

Other circulating antibodies can help discriminate among cholestatic disorders. In particular, positive tests for perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are found in 25% to 95% of patients with primary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium and large ducts of the intrahepatic and extrahepatic biliary tree.²⁴ Anti-smooth muscle antibodies (SMA) can be observed in both PSC and autoimmune hepatitis.

Alkaline phosphatase levels are useful for monitoring evolution of primary biliary cholangitis disease.

Finally, there are syndromes with serologic and histologic overlap that are characterized by the simultaneous presence of PBC with autoimmune hepatitis or PSC or overlap of PSC with autoimmune hepatitis.

Liver biopsy fills in the rest of the diagnostic picture

Unfortunately, blood tests reveal little about organ integrity and are not useful for disease staging. The decision to perform a liver biopsy should be based on several factors, including the patient’s age, serum parameters, the need to stage the disease, therapy choices, and prognosis.¹² One should also consider that biopsy is a costly procedure with potentially serious adverse effects; it should not be repeated frequently. However, when a biopsy is done, it provides critical information, including damage to medium-sized intrahepatic bile ducts with neoductular formation or bile duct scars and strictures.

Treating intrahepatic cholestasis

Although FPs often can provide most—or even all—of the care for patients with stable conditions, a specialist consultation might recommend further testing to identify the underlying disease, which is essential to establish the most appropriate treatment.

Treatment of patients with PBC is based on administering hydrophilic secondary bile salt ursodeoxycholic acid (UDCA) 15 mg/kg/d, which is used to equilibrate the ratio between hydrophilic and hydrophobic bile salts in the liver and bile,²⁵ and is the only treatment approved by the US Food and Drug Administration (FDA) for PBC.⁴ Tauroursodeoxycholate is better absorbed than UDCA, and, although partially deconjugated and reconjugated with glycine, it undergoes reduced biotransformation to more hydrophobic metabolites and has benefits, including antioxidant, immunomodulation, and neuroprotective effects over UDCA—especially for long-term therapy in PBC.²⁶ However, it is not used often in clinical practice.

Continue to: Bile acid administration counters the cytotoxic effect...

Bile acid administration counters the cytotoxic effect of hydrophobic bile salts. Although it seems that UDCA might improve biochemical and histologic features of the disease at earlier stages (I-II), it fails in patients with more advanced disease.²⁷ In addition, monitoring and defining response to UDCA is inconsistent, partly because of variations in guideline criteria.^28,29

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor.

Recently a new molecule, obeticholic acid (OCA), has been approved by the FDA. A farnesoid X receptor agonist, OCA is indicated for treating patients who do not tolerate UDCA or as an adjunct to UDCA in those with a partial response to UDCA, defined as lowering ALP levels by <1.5 times the baseline value after 12 months of treatment.

Treating PSC is more complex. Combination therapy with prednisone and azathioprine is recommended only when there is an overlap syndrome between PSC and autoimmune hepatitis.⁴ UDCA at a high dosage (15-20 mg/kg/d) is used to facilitate long-lasting biochemical remission. These patients also need to be monitored for inflammatory bowel diseases, which affect up to 75% of patients,³⁰ and for cholangiocarcinoma, which is a life-limiting complication because of a lack of therapy options. Finally, these patients might need endoscopic-guided dilatation of the biliary tree when they have evidence of dominant fibrotic strictures of the greater bile ducts.^14,31

Addressing the systemic effects of intrahepatic cholestasis

Pruritus. A number of potential pruritogens, including bile salts, endogenous opioids, histamine, serotonin, and lisophosphatidic acid (LPA), can be targeted to relieve pruritus.

• Bile acid resin binders such as cholestyramine are the first step for treating pruritus. UDCA also can be useful, mainly for intrahepatic cholestasis during pregnancy. Rifampicin, 300 mg/d, improves cholestatic pruritus, but is associated with hepatotoxicity and a number of severe reactions, such as nausea, loss of appetite, hemolytic anemia, and thrombocytopenia.³¹
• Most evidence favors a role for opioids in relieving itch, and micro-opioid receptor antagonists (naltrexone, naloxone, nalmefene) that exert an antipruritic effect can be effective.
• Sertraline (a selective serotonin reuptake inhibitor), 50 to 75 mg/d, usually is well tolerated in patients with chronic cholestasis and exerts a beneficial effect on pruritus in approximately 40% of patients.³²
• Extracorporeal albumin dialysis removes albumin-bound pruritogens and has been found to be effective in patients with liver failure. Steroids and UV light also can be used in select patients.
• The potent neuronal activator LPA and its converting enzyme autotaxin have been identified in the serum of patients with cholestatic pruritus; experimental modalities using LPA antagonists are ongoing for treating pruritus in patients who do not respond to other medications.³³

Continue to: Malnutrition

Malnutrition. Many patients with cholestasis are at risk for malnutrition, which can be exacerbated in those with cirrhosis. Causes of malnutrition include poor oral intake, malabsorption, or dental problems that prevent the patient from chewing. Assess the nutritional status of every patient with chronic cholestasis, and stress the importance of multivitamin supplementation to reverse systemic alterations caused by malnutrition.³⁴

When the patient has advanced disease

Despite progress in diagnostic techniques, life expectancy and quality of life for patients with advanced cholestatic conditions remain poor. Patients routinely experience fatigue, pruritus, and complications of cirrhosis including ascites, encephalopathy, and bleeding. Cholestasis also carries the risk of life-threatening complications, partly because of comorbidities such as osteoporosis and malabsorption.

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications.

Liver transplantation can improve the life expectancy of patients with advanced disease, but because of long waiting lists, candidates for transplant often die before an organ becomes available. For many patients who are not in end-stage condition, targeted therapy is crucial to slow disease progression and is recommended along with hepatitis A and B vaccinations and nutritional counseling.³⁵

Extrahepatic cholestasis is suspected? How to proceed

Computer tomography (CT) is recommended for better identification of neoplastic causes of biliary obstruction and for staging purposes. MRCP is an excellent noninvasive imaging technique for evaluating biliary ducts.³⁶

MRCP has 92% to 93% sensitivity and 97% to 98% specificity for diagnosing biliary duct stones.³⁷ MRCP also is the first-choice modality for evaluating bile ducts in patients with suspected PSC. If performed in expert centers, the diagnostic accuracy reaches that of ERCP. A meta-analysis of studies from 2000 to 2006 has shown a sensitivity of 86% and specificity of 94% for diagnosing PSC.³⁸

Endoscopic ultrasonography, which uses an ultrasonographic probe, allows clinicians to evaluate the integrity of the biliary and pancreatic ducts and is effective for diagnosing and staging cancer of the ampulla of Vater (sensitivity 93% vs 7% for abdominal ultrasonography and 29% for CT), and identifying biliary stones and biliary tree strictures.

Continue to: ERCP

ERCP is widely employed for diagnosing and treating pancreatobiliary diseases; however, its use has dropped over the last 10 years because of the risk of complications. ERCP is nearly exclusively used as a therapeutic procedure for pancreatic sphincterotomy, biliary dilatations, and removing biliary stones. It also has a diagnostic role in dominant stenosis or suspected biliary malignancy using brushing cytology and sampling biopsies of the bile ducts.

Treating extrahepatic cholestasis

Treatment of the different underlying conditions that cause extrahepatic cholestasis is surgical. Thus, the potential surgical techniques that can resolve or improve an extrahepatic cholestatic condition are guided by the surgeon and beyond the scope of this article.

Treating osteopenia: A concern for intra- and extrahepatic cholestasis

Vitamin D deficiency as a consequence of reduced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic and extrahepatic cholestasis can lead to reduced bone formation.³⁹ However, osteopenia can occur even in early stages of the disease. Prescribing bisphosphonates, in combination with calcium and vitamin D3_, to improve bone mineral density is a good practice.⁴⁰

CASE

Blood tests and ultrasound imaging suggest the presence of a chronic liver disease. Other lab tests indicate that the patient has an ALP level 3 times normal. This finding, together with the other tests, points to a likely diagnosis of intrahepatic cholestatic liver disease. Serology confirms positivity for ANA (1:160) and AMA (1:640). The clinician suspects PBC, so the patient is referred to a liver specialist for further evaluation and to determine whether a liver biopsy is needed.

The liver specialist confirms the diagnosis of PBC, performs a transient elastographym, which indicates a low-grade liver fibrosis (F1 out of 4), and starts therapy with UDCA.

CORRESPONDENCE
Ignazio Grattagliano, MD, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142, Florence, Italy; [email protected].