What is the diagnosis? Is a cardiology consult warranted?

AN ABERRANT CONDUCTION PATTERN

The finding seen in this electrocardiogram is known as the Ashman phenomenon, an aberrant conduction pattern seen in atrial dysrhythmias, mainly atrial fibrillation, atrial tachycardia, and atrial ectopy, when a relatively long cycle is followed by a relatively short cycle. The beat terminating the short cycle often has the morphology of right bundle branch block.

This pattern was first described by Gouaux and Ashman in 1947; however, the aberrant conduction of supraventricular impulses was first described by Lewis in 1910.^1,2

Ashman phenomenon and right bundle branch block

The three criteria for the diagnosis of right bundle branch block in adults are:

• A QRS duration of 120 msec or more
• An rsr', rsR', or rSR' in leads V₁ or V₂ (the R' or r' deflection is usually wider than the initial R wave)
• The duration of the S wave in I and V₆ is usually greater than that of the R wave or is greater than 40 msec.³

Variation in the heart rate (due to atrial fibrillation in this patient) affects the width of the QRS interval; the refractory period of a cycle is influenced by the RR interval of the previous cycle. Therefore, if after a long cycle with a consequent long refractory period, a shorter cycle follows, then the beat terminating the short cycle is likely to be aberrantly conducted because one of the bundle branches is still in the refractory period. Because the refractory period for the right bundle branch is longer than that of the left bundle branch, the right bundle branch block pattern is more common.4

In our patient’s tracing (Figure 1), the aberrantly conducted beat has the shortest coupling intervals of any of the conducted beats on the tracing. Although the RR interval preceding the short cycle is not the longest on this tracing, it is moderately long, and so the refractory period of the right bundle branch is moderately long.

The Ashman pattern vs ventricular premature beat

Atrial arrhythmias cause a variation in the refractory period of the bundle branches and the ventricular conduction system, and this explains why the Ashman phenomenon occurs more often in this setting. It is important to distinguish the aberrant conduction seen in the Ashman phenomenon, which electrophysiologically is restricted to the His-Purkinje system, from premature ventricular complexes and ventricular tachycardia.

The current criteria used to distinguish the Ashman phenomenon were described by Fisch^5,6:

• A relatively long cycle immediately preceding the cycle terminated by the aberrant QRS complex: a short-long-short interval is even more likely to initiate aberration. The aberration can be left or right bundle branch block, or both, even in the same patient.
• Right bundle branch block morphology, with normal orientation of the initial QRS vector. Concealed perpetuation of the aberration is possible, and so a series of wide QRS supraventricular beats is possible.
• Irregular coupling of aberrant QRS complexes.
• Lack of a fully compensatory pause.

In Figure 1, the second aberrantly conducted beat is not as aberrant as the first, even though it is even more premature than the first. This can be explained because the refractory period of the right bundle branch has now shortened.

Also, the mechanism of aberrancy of the second beat may be partly the result of concealed perpetuation, ie, incomplete penetration of the His bundle depolarizations in either direction with secondary abnormalities of antegrade or retrograde conduction. This pattern is not directly reflected on the surface electrocardiogram but can be detected on intracardiac electrophysiologic studies.⁷ In concealed perpetuation, instead of inducing tachycardia, the extra stimuli are followed by pauses that exceed the tachycardia cycle length.⁸

Treated by managing the atrial arrhythmia

There is no specific treatment for the aberrant cycles. Rather, treatment is directed at the atrial arrhythmia.⁹ Adequate control of the underlying process and the atrial tachyarrhythmia itself is important. In our patient, control of the exacerbation of chronic obstructive pulmonary disease and of the heart rate improved the ventricular response to atrial fibrillation.

What is the diagnosis? Is a cardiology consult warranted?

AN ABERRANT CONDUCTION PATTERN

The finding seen in this electrocardiogram is known as the Ashman phenomenon, an aberrant conduction pattern seen in atrial dysrhythmias, mainly atrial fibrillation, atrial tachycardia, and atrial ectopy, when a relatively long cycle is followed by a relatively short cycle. The beat terminating the short cycle often has the morphology of right bundle branch block.

This pattern was first described by Gouaux and Ashman in 1947; however, the aberrant conduction of supraventricular impulses was first described by Lewis in 1910.^1,2

Ashman phenomenon and right bundle branch block

The three criteria for the diagnosis of right bundle branch block in adults are:

• A QRS duration of 120 msec or more
• An rsr', rsR', or rSR' in leads V₁ or V₂ (the R' or r' deflection is usually wider than the initial R wave)
• The duration of the S wave in I and V₆ is usually greater than that of the R wave or is greater than 40 msec.³

Variation in the heart rate (due to atrial fibrillation in this patient) affects the width of the QRS interval; the refractory period of a cycle is influenced by the RR interval of the previous cycle. Therefore, if after a long cycle with a consequent long refractory period, a shorter cycle follows, then the beat terminating the short cycle is likely to be aberrantly conducted because one of the bundle branches is still in the refractory period. Because the refractory period for the right bundle branch is longer than that of the left bundle branch, the right bundle branch block pattern is more common.4

In our patient’s tracing (Figure 1), the aberrantly conducted beat has the shortest coupling intervals of any of the conducted beats on the tracing. Although the RR interval preceding the short cycle is not the longest on this tracing, it is moderately long, and so the refractory period of the right bundle branch is moderately long.

The Ashman pattern vs ventricular premature beat

Atrial arrhythmias cause a variation in the refractory period of the bundle branches and the ventricular conduction system, and this explains why the Ashman phenomenon occurs more often in this setting. It is important to distinguish the aberrant conduction seen in the Ashman phenomenon, which electrophysiologically is restricted to the His-Purkinje system, from premature ventricular complexes and ventricular tachycardia.

The current criteria used to distinguish the Ashman phenomenon were described by Fisch^5,6:

• A relatively long cycle immediately preceding the cycle terminated by the aberrant QRS complex: a short-long-short interval is even more likely to initiate aberration. The aberration can be left or right bundle branch block, or both, even in the same patient.
• Right bundle branch block morphology, with normal orientation of the initial QRS vector. Concealed perpetuation of the aberration is possible, and so a series of wide QRS supraventricular beats is possible.
• Irregular coupling of aberrant QRS complexes.
• Lack of a fully compensatory pause.

In Figure 1, the second aberrantly conducted beat is not as aberrant as the first, even though it is even more premature than the first. This can be explained because the refractory period of the right bundle branch has now shortened.

Also, the mechanism of aberrancy of the second beat may be partly the result of concealed perpetuation, ie, incomplete penetration of the His bundle depolarizations in either direction with secondary abnormalities of antegrade or retrograde conduction. This pattern is not directly reflected on the surface electrocardiogram but can be detected on intracardiac electrophysiologic studies.⁷ In concealed perpetuation, instead of inducing tachycardia, the extra stimuli are followed by pauses that exceed the tachycardia cycle length.⁸

Treated by managing the atrial arrhythmia

There is no specific treatment for the aberrant cycles. Rather, treatment is directed at the atrial arrhythmia.⁹ Adequate control of the underlying process and the atrial tachyarrhythmia itself is important. In our patient, control of the exacerbation of chronic obstructive pulmonary disease and of the heart rate improved the ventricular response to atrial fibrillation.

What is the diagnosis? Is a cardiology consult warranted?

AN ABERRANT CONDUCTION PATTERN

The finding seen in this electrocardiogram is known as the Ashman phenomenon, an aberrant conduction pattern seen in atrial dysrhythmias, mainly atrial fibrillation, atrial tachycardia, and atrial ectopy, when a relatively long cycle is followed by a relatively short cycle. The beat terminating the short cycle often has the morphology of right bundle branch block.

This pattern was first described by Gouaux and Ashman in 1947; however, the aberrant conduction of supraventricular impulses was first described by Lewis in 1910.^1,2

Ashman phenomenon and right bundle branch block

The three criteria for the diagnosis of right bundle branch block in adults are:

• A QRS duration of 120 msec or more
• An rsr', rsR', or rSR' in leads V₁ or V₂ (the R' or r' deflection is usually wider than the initial R wave)
• The duration of the S wave in I and V₆ is usually greater than that of the R wave or is greater than 40 msec.³

Variation in the heart rate (due to atrial fibrillation in this patient) affects the width of the QRS interval; the refractory period of a cycle is influenced by the RR interval of the previous cycle. Therefore, if after a long cycle with a consequent long refractory period, a shorter cycle follows, then the beat terminating the short cycle is likely to be aberrantly conducted because one of the bundle branches is still in the refractory period. Because the refractory period for the right bundle branch is longer than that of the left bundle branch, the right bundle branch block pattern is more common.4

In our patient’s tracing (Figure 1), the aberrantly conducted beat has the shortest coupling intervals of any of the conducted beats on the tracing. Although the RR interval preceding the short cycle is not the longest on this tracing, it is moderately long, and so the refractory period of the right bundle branch is moderately long.

The Ashman pattern vs ventricular premature beat

Atrial arrhythmias cause a variation in the refractory period of the bundle branches and the ventricular conduction system, and this explains why the Ashman phenomenon occurs more often in this setting. It is important to distinguish the aberrant conduction seen in the Ashman phenomenon, which electrophysiologically is restricted to the His-Purkinje system, from premature ventricular complexes and ventricular tachycardia.

The current criteria used to distinguish the Ashman phenomenon were described by Fisch^5,6:

• A relatively long cycle immediately preceding the cycle terminated by the aberrant QRS complex: a short-long-short interval is even more likely to initiate aberration. The aberration can be left or right bundle branch block, or both, even in the same patient.
• Right bundle branch block morphology, with normal orientation of the initial QRS vector. Concealed perpetuation of the aberration is possible, and so a series of wide QRS supraventricular beats is possible.
• Irregular coupling of aberrant QRS complexes.
• Lack of a fully compensatory pause.

In Figure 1, the second aberrantly conducted beat is not as aberrant as the first, even though it is even more premature than the first. This can be explained because the refractory period of the right bundle branch has now shortened.

Also, the mechanism of aberrancy of the second beat may be partly the result of concealed perpetuation, ie, incomplete penetration of the His bundle depolarizations in either direction with secondary abnormalities of antegrade or retrograde conduction. This pattern is not directly reflected on the surface electrocardiogram but can be detected on intracardiac electrophysiologic studies.⁷ In concealed perpetuation, instead of inducing tachycardia, the extra stimuli are followed by pauses that exceed the tachycardia cycle length.⁸

Treated by managing the atrial arrhythmia

There is no specific treatment for the aberrant cycles. Rather, treatment is directed at the atrial arrhythmia.⁹ Adequate control of the underlying process and the atrial tachyarrhythmia itself is important. In our patient, control of the exacerbation of chronic obstructive pulmonary disease and of the heart rate improved the ventricular response to atrial fibrillation.

A 48-year-old man reports progressive exercise intolerance, shortness of breath, fatigue, and melena over the past month. He has a long history of Raynaud phenomenon, and 5 months ago he developed severe sclerodactyly in both hands, diagnosed as limited cutaneous systemic sclerosis (scleroderma).

He has no chest pain, swelling of the lower limbs, change in weight, cough, fever, chills, or sick contacts, and he has not traveled recently.

His symptoms began as fatigue and shortness of breath, which worsened until he began having episodes of abdominal pain with melena and dizzy spills, although he never passed out.

He is currently taking long-term low-dose prednisone and mycophenolate mofetil (Cell-Cept) for the systemic sclerosis, and omeprazole (Prilosec) for gastroesophageal reflux. His father had lupus, and his grandmother had colon cancer.

An outpatient workup for sclerosis-related lung and heart involvement is negative. The workup includes computed tomography of the chest, pulmonary function tests, and Doppler echocardiography.

He is afebrile, with a blood pressure of 105/60 mm Hg and a pulse of 98. His cardiopulmonary examination results are normal. He has mild epigastric tenderness without rebound or guarding. His hemoglobin concentration at the time of hospital admission is 7.8 g/dL, down from 14.5 g/dL recorded when limited cutaneous systemic sclerosis was diagnosed. Iron studies reveal iron deficiency.

The antral ectasia is treated with argon plasma coagulation during the endoscopic examination.

Afterward, the patient's hemoglobin stabilizes, and the melena resolves. He is discharged on an oral proton pump inhibitor, with instructions to follow up for another endoscopic session in 1 month.

GASTROINTESTINAL FEATURES OF SYSTEMIC SCLEROSIS

Sclerodermal disorders have diverse manifestations that always include characteristic cutaneous signs. While there are several well-recognized symptomatic conditions commonly associated with scleroderma, attention must also be paid to the less common causes of these symptoms. Scleroderma has gastrointestinal complications that can easily be missed and may not respond to immunomodulatory or proton pump inhibitor therapy: complications can include esophageal dysmotility, hypomotility, gastric paresis, reflux esophagitis, strictures, drug-related ulcer, malabsorption, bacterial overgrowth, and pseudo-obstruction.¹

This patient had an underrecognized cause of dyspnea in the setting of systemic sclerosis. Vascular symptoms of limited cutaneous systemic sclerosis are typically attributed to Raynaud phenomenon; gastrointestinal symptoms are typically attributed to esophageal dysmotility; and associated dyspnea is often considered to represent pulmonary or cardiac involvement of the sclerosis. However, gastric antral vascular ectasia should be considered in any patient with scleroderma and evidence of anemia.

The prevalence of gastric antral vascular ectasia in patients with systemic sclerosis is estimated to be about 6%.^2–4 It is a relatively rare cause of upper gastrointestinal blood loss that can be clinically silent until the patient develops severe iron deficiency anemia and symptoms of dyspnea, fatigue, or congestive heart failure.

Gastric antral vascular ectasia in scleroderma usually presents as iron deficiency anemia, and only presents overtly as hematemesis or melena 10% to 14% of the time.⁴ Because of the often occult nature of the bleeding, the condition may be clinically silent in the early phase. Symptoms of shortness of breath and fatigue may not develop until the anemia worsens rapidly or becomes severe. Anemia is present in almost all cases of gastric antral vascular ectasia (96% to 100%) and should be a strong clinical clue for early endoscopic evaluation in patients with scleroderma, especially if there is already suspicion of upper gastrointestinal bleeding.^2–5

The distinctive endoscopic streaky pattern of ectasia along the stomach antrum seen in gastric antral vascular ectasia is called “watermelon stomach”^4,5 because the striped pattern recalls the stripes of a watermelon. The endoscopic appearance can vary, however, from the watermelon pattern to a coalescence of angiodysplastic lesions termed “honeycomb stomach,” which can easily be mistaken for antral gastritis.^4,5 Therefore, biopsy often serves to confirm the diagnosis, with histologic features including dilated mucosal capillaries with focal fibrin thrombosis and fibromuscular hyperplasia of the lamina propria.

Gastric antral vascular ectasia often requires multiple transfusions of red blood cells, as well as repeated treatments with endoscopic argon plasma coagulation, whereby ionized argon gas is used to conduct an electric current that coagulates the surface of the mucosa to a few millimeters depth.^4–6

A knowledge of the association between scleroderma and gastric antral vascular ectasia can lead to earlier recognition and treatment and can avoid unnecessary testing and complications of severe anemia.

A 48-year-old man reports progressive exercise intolerance, shortness of breath, fatigue, and melena over the past month. He has a long history of Raynaud phenomenon, and 5 months ago he developed severe sclerodactyly in both hands, diagnosed as limited cutaneous systemic sclerosis (scleroderma).

He has no chest pain, swelling of the lower limbs, change in weight, cough, fever, chills, or sick contacts, and he has not traveled recently.

His symptoms began as fatigue and shortness of breath, which worsened until he began having episodes of abdominal pain with melena and dizzy spills, although he never passed out.

He is currently taking long-term low-dose prednisone and mycophenolate mofetil (Cell-Cept) for the systemic sclerosis, and omeprazole (Prilosec) for gastroesophageal reflux. His father had lupus, and his grandmother had colon cancer.

An outpatient workup for sclerosis-related lung and heart involvement is negative. The workup includes computed tomography of the chest, pulmonary function tests, and Doppler echocardiography.

He is afebrile, with a blood pressure of 105/60 mm Hg and a pulse of 98. His cardiopulmonary examination results are normal. He has mild epigastric tenderness without rebound or guarding. His hemoglobin concentration at the time of hospital admission is 7.8 g/dL, down from 14.5 g/dL recorded when limited cutaneous systemic sclerosis was diagnosed. Iron studies reveal iron deficiency.

The antral ectasia is treated with argon plasma coagulation during the endoscopic examination.

Afterward, the patient's hemoglobin stabilizes, and the melena resolves. He is discharged on an oral proton pump inhibitor, with instructions to follow up for another endoscopic session in 1 month.

GASTROINTESTINAL FEATURES OF SYSTEMIC SCLEROSIS

Sclerodermal disorders have diverse manifestations that always include characteristic cutaneous signs. While there are several well-recognized symptomatic conditions commonly associated with scleroderma, attention must also be paid to the less common causes of these symptoms. Scleroderma has gastrointestinal complications that can easily be missed and may not respond to immunomodulatory or proton pump inhibitor therapy: complications can include esophageal dysmotility, hypomotility, gastric paresis, reflux esophagitis, strictures, drug-related ulcer, malabsorption, bacterial overgrowth, and pseudo-obstruction.¹

This patient had an underrecognized cause of dyspnea in the setting of systemic sclerosis. Vascular symptoms of limited cutaneous systemic sclerosis are typically attributed to Raynaud phenomenon; gastrointestinal symptoms are typically attributed to esophageal dysmotility; and associated dyspnea is often considered to represent pulmonary or cardiac involvement of the sclerosis. However, gastric antral vascular ectasia should be considered in any patient with scleroderma and evidence of anemia.

The prevalence of gastric antral vascular ectasia in patients with systemic sclerosis is estimated to be about 6%.^2–4 It is a relatively rare cause of upper gastrointestinal blood loss that can be clinically silent until the patient develops severe iron deficiency anemia and symptoms of dyspnea, fatigue, or congestive heart failure.

Gastric antral vascular ectasia in scleroderma usually presents as iron deficiency anemia, and only presents overtly as hematemesis or melena 10% to 14% of the time.⁴ Because of the often occult nature of the bleeding, the condition may be clinically silent in the early phase. Symptoms of shortness of breath and fatigue may not develop until the anemia worsens rapidly or becomes severe. Anemia is present in almost all cases of gastric antral vascular ectasia (96% to 100%) and should be a strong clinical clue for early endoscopic evaluation in patients with scleroderma, especially if there is already suspicion of upper gastrointestinal bleeding.^2–5

The distinctive endoscopic streaky pattern of ectasia along the stomach antrum seen in gastric antral vascular ectasia is called “watermelon stomach”^4,5 because the striped pattern recalls the stripes of a watermelon. The endoscopic appearance can vary, however, from the watermelon pattern to a coalescence of angiodysplastic lesions termed “honeycomb stomach,” which can easily be mistaken for antral gastritis.^4,5 Therefore, biopsy often serves to confirm the diagnosis, with histologic features including dilated mucosal capillaries with focal fibrin thrombosis and fibromuscular hyperplasia of the lamina propria.

Gastric antral vascular ectasia often requires multiple transfusions of red blood cells, as well as repeated treatments with endoscopic argon plasma coagulation, whereby ionized argon gas is used to conduct an electric current that coagulates the surface of the mucosa to a few millimeters depth.^4–6

A knowledge of the association between scleroderma and gastric antral vascular ectasia can lead to earlier recognition and treatment and can avoid unnecessary testing and complications of severe anemia.

A 48-year-old man reports progressive exercise intolerance, shortness of breath, fatigue, and melena over the past month. He has a long history of Raynaud phenomenon, and 5 months ago he developed severe sclerodactyly in both hands, diagnosed as limited cutaneous systemic sclerosis (scleroderma).

He has no chest pain, swelling of the lower limbs, change in weight, cough, fever, chills, or sick contacts, and he has not traveled recently.

His symptoms began as fatigue and shortness of breath, which worsened until he began having episodes of abdominal pain with melena and dizzy spills, although he never passed out.

He is currently taking long-term low-dose prednisone and mycophenolate mofetil (Cell-Cept) for the systemic sclerosis, and omeprazole (Prilosec) for gastroesophageal reflux. His father had lupus, and his grandmother had colon cancer.

An outpatient workup for sclerosis-related lung and heart involvement is negative. The workup includes computed tomography of the chest, pulmonary function tests, and Doppler echocardiography.

He is afebrile, with a blood pressure of 105/60 mm Hg and a pulse of 98. His cardiopulmonary examination results are normal. He has mild epigastric tenderness without rebound or guarding. His hemoglobin concentration at the time of hospital admission is 7.8 g/dL, down from 14.5 g/dL recorded when limited cutaneous systemic sclerosis was diagnosed. Iron studies reveal iron deficiency.

The antral ectasia is treated with argon plasma coagulation during the endoscopic examination.

Afterward, the patient's hemoglobin stabilizes, and the melena resolves. He is discharged on an oral proton pump inhibitor, with instructions to follow up for another endoscopic session in 1 month.

GASTROINTESTINAL FEATURES OF SYSTEMIC SCLEROSIS

Sclerodermal disorders have diverse manifestations that always include characteristic cutaneous signs. While there are several well-recognized symptomatic conditions commonly associated with scleroderma, attention must also be paid to the less common causes of these symptoms. Scleroderma has gastrointestinal complications that can easily be missed and may not respond to immunomodulatory or proton pump inhibitor therapy: complications can include esophageal dysmotility, hypomotility, gastric paresis, reflux esophagitis, strictures, drug-related ulcer, malabsorption, bacterial overgrowth, and pseudo-obstruction.¹

This patient had an underrecognized cause of dyspnea in the setting of systemic sclerosis. Vascular symptoms of limited cutaneous systemic sclerosis are typically attributed to Raynaud phenomenon; gastrointestinal symptoms are typically attributed to esophageal dysmotility; and associated dyspnea is often considered to represent pulmonary or cardiac involvement of the sclerosis. However, gastric antral vascular ectasia should be considered in any patient with scleroderma and evidence of anemia.

The prevalence of gastric antral vascular ectasia in patients with systemic sclerosis is estimated to be about 6%.^2–4 It is a relatively rare cause of upper gastrointestinal blood loss that can be clinically silent until the patient develops severe iron deficiency anemia and symptoms of dyspnea, fatigue, or congestive heart failure.

Gastric antral vascular ectasia in scleroderma usually presents as iron deficiency anemia, and only presents overtly as hematemesis or melena 10% to 14% of the time.⁴ Because of the often occult nature of the bleeding, the condition may be clinically silent in the early phase. Symptoms of shortness of breath and fatigue may not develop until the anemia worsens rapidly or becomes severe. Anemia is present in almost all cases of gastric antral vascular ectasia (96% to 100%) and should be a strong clinical clue for early endoscopic evaluation in patients with scleroderma, especially if there is already suspicion of upper gastrointestinal bleeding.^2–5

The distinctive endoscopic streaky pattern of ectasia along the stomach antrum seen in gastric antral vascular ectasia is called “watermelon stomach”^4,5 because the striped pattern recalls the stripes of a watermelon. The endoscopic appearance can vary, however, from the watermelon pattern to a coalescence of angiodysplastic lesions termed “honeycomb stomach,” which can easily be mistaken for antral gastritis.^4,5 Therefore, biopsy often serves to confirm the diagnosis, with histologic features including dilated mucosal capillaries with focal fibrin thrombosis and fibromuscular hyperplasia of the lamina propria.

Gastric antral vascular ectasia often requires multiple transfusions of red blood cells, as well as repeated treatments with endoscopic argon plasma coagulation, whereby ionized argon gas is used to conduct an electric current that coagulates the surface of the mucosa to a few millimeters depth.^4–6

A knowledge of the association between scleroderma and gastric antral vascular ectasia can lead to earlier recognition and treatment and can avoid unnecessary testing and complications of severe anemia.

A 25-year-old man presented to his primary care physician with generalized malaise. His symptoms started around 2 months earlier with progressive fatigue, nausea, decreased appetite, and weight loss (15 lb in 2 months). He denied having fever, chills, night sweats, abdominal pain, diarrhea, melena, or hematochezia.

His medical history was remarkable only for depression, well controlled with sertraline (Zoloft), which he started taking 3 years ago. He was not taking any other prescribed, over-the-counter, or herbal medications.

He had no family history of cancer or liver disease. He did not smoke and rarely drank alcohol. He had never used recreational drugs. He was sexually active with one female partner, used condoms for protection, and had never been diagnosed with a sexually transmitted disease. He had not traveled recently and had not been exposed to any pet.

The patient’s laboratory values on admission are shown in Table 1. Of note, his serum alkaline phosphatase level was 1,307 U/L (reference range 40–150 U/L).

LIVER TESTS CAN NARROW THE DIAGNOSIS

The most commonly used laboratory tests of the liver can be classified into those that measure either:

• Liver synthetic function (eg, the serum albumin and bilirubin concentrations and the prothrombin time) or
• Liver damage, as reflected by the serum concentrations of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyltransferase (GGT).^1,2

ALT and AST are normally concentrated in the hepatocytes and thus, when present in the serum in elevated concentrations, are markers of liver cell injury. The serum levels of these enzymes start to increase within a few hours of liver cell injury as they leak out of the cells via the damaged cell membrane. AST is less liver-specific than ALT, since AST levels can be elevated not only in liver injury but also in muscle, cardiac, and red blood cell injury.^3,4

Alkaline phosphatase is actually a heterogeneous group of enzymes found mainly in liver and bone cells. Hepatic alkaline phosphatase is concentrated near the biliary canalicular membrane of the hepatocyte. Accordingly, increased levels of hepatic alkaline phosphatase are mainly seen in liver diseases that predominantly affect the biliary system.³

GGT is also concentrated in hepatic biliary epithelial cells, and thus GGT elevation is another marker of hepatobiliary disease. In fact, measuring the GGT level can help to determine whether an isolated elevation of alkaline phosphatase is due to liver injury.^2,3

Accordingly, liver diseases can be classified into two broad categories:

• Hepatocellular injury, in which the primary injury occurs to the hepatocytes
• Cholestatic injury, in which the primary injury is to the bile ducts.

In the former, elevated levels of ALT and AST predominate, while in the latter, elevated alkaline phosphatase is the main finding.³

WHAT TEST NEXT FOR OUR PATIENT?

1. What is the next most appropriate diagnostic step for our patient?

• Liver biopsy
• Ultrasonography of the liver
• Computed tomography (CT) of the liver
• Observation

Our patient has an elevated GGT level, which suggests that his elevated alkaline phosphatase is of hepatic rather than bony origin. Moreover, a serum alkaline phosphatase level that is elevated out of proportion to the aminotransferase levels reflects cholestatic liver injury.

CASE CONTINUED: ULTRASONOGRAPHY IS MOSTLY NORMAL

Ultrasonography of the right upper quadrant revealed that the liver had normal echogenicity and was mildly enlarged. There was no focal hepatic lesion. The gallbladder appeared normal, with no stones or sludge. No dilated intrahepatic or extrahepatic biliary ducts were seen. The common bile duct measured 4 mm. A small amount of ascites not amenable to paracentesis was present.

Thus, in the absence of biliary dilation on ultrasonography, we are dealing with an intrahepatic cholestatic process.

CAUSES OF CHOLESTATIC LIVER DISEASE

Viral hepatitis

Viral hepatitis most often produces a hepatocellular pattern of injury (ie, AST and ALT elevations predominate). However, in rare cases it can cause a cholestatic pattern of injury.

Our patient subsequently had serologic tests for viral hepatitis, including hepatitis A, B, and C, and the results were negative.

Autoimmune liver disease

The three most common forms of autoimmune liver disease are autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis.

Autoimmune hepatitis is characterized by high serum ALT and AST levels, whereas primary biliary cirrhosis and primary sclerosing cholangitis are associated with predominant elevations of alkaline phosphatase, since they are cholestatic disorders.

Our patient’s alkaline phosphatase level was much higher than his ALT and AST levels, making the latter two diseases more likely.

Primary biliary cirrhosis (and autoimmune hepatitis) are associated with autoantibodies in the serum, such as antinuclear antibody, smooth muscle antibody, and antimitochondrial antibody.

Our patient subsequently was tested for these antibodies, and the results were negative.

Primary sclerosing cholangitis usually affects the extrahepatic biliary system. Thus, if it is present, abnormalities should be seen on imaging.

As mentioned previously, no dilated intrahepatic or extrahepatic biliary ducts were seen on ultrasonography in our patient. Moreover, primary sclerosing cholangitis is associated with inflammatory bowel disease, particularly ulcerative colitis, which our patient did not have.

Drug-induced liver injury

Drug-induced liver injury is a common cause of cholestatic liver disease. However, our patient was not taking any prescribed, over-the-counter, or herbal medications. Additionally, he denied heavy alcohol use.

Infiltrative disorders

Infiltrative disorders such as amyloidosis, sarcoidosis, or lymphoma should be considered in the differential diagnosis of cholestatic liver disease. A clue to a possible infiltrative process is a markedly elevated level of alkaline phosphatase with a mildly increased serum bilirubin concentration, both of which our patient had.

AFTER ULTRASONOGRAPHY, WHAT IS THE NEXT STEP?

2. Which of the following is the next most appropriate diagnostic test for our patient?

• Endoscopic retrograde cholangiopancreatography (ERCP)
• Magnetic resonance cholangiopancreatography (MRCP)
• Liver biopsy
• CT of the abdomen

Figure 1 shows a proposed algorithm for evaluating increased alkaline phosphatase levels.

If there is no biliary duct dilation on ultrasonography, then abnormal levels of alkaline phosphatase most likely represent an intrahepatic pattern of cholestatic liver injury. Therefore, additional imaging with CT or magnetic resonance imaging is of limited diagnostic value. ERCP is used today for therapy rather than diagnosis, so its use is limited to patients known to have dilated biliary ducts on imaging. Liver biopsy, however, can provide useful findings.

Case continued: He undergoes biopsy

Our patient underwent transjugular liver biopsy. During the procedure, transjugular venography showed stenosis in the right, middle, and left hepatic veins and the hepatic portion of the inferior vena cava, consistent with Budd-Chiari syndrome.

The liver biopsy specimen was positive for extensive deposition of slight eosinophilic and amorphous material in a sinusoidal pattern in the liver parenchyma, as well as in the portal tracts, with markedly atrophic hepatocytes. Congo red birefringence confirmed the diagnosis of amyloidosis. The immunohistochemical phenotype was positive for kappa light chains, which is diagnostic for primary-type amyloidosis, also called amyloidosis of light chain composition, or AL.

Bone marrow aspiration and bone marrow biopsy were performed and showed 22% plasma cells, well above the normal range (0–2%), consistent with the diagnosis of multiple myeloma.

BUDD-CHIARI SYNDROME: A CHALLENGING DIAGNOSIS

Budd-Chiari syndrome is a rare condition characterized by obstruction of venous outflow from the liver at a site that may vary from the small hepatic veins up to the inferior vena cava or even the right atrium.^5,6 Obstruction of hepatic venous outflow leads to sinusoidal congestion and hypoxic damage of the hepatocytes.⁷ Hypoxia and necrosis of the hepatocytes result in the release of free radicals. Cirrhosis can eventually occur secondary to ischemic necrosis of hepatocytes and hepatic fibrosis.⁸

The estimated incidence of this syndrome is 1 in 2.5 million persons per year.⁷ It is more prevalent in women and young adults.⁸

Heterogeneous in its causes and manifestations

Budd-Chiari syndrome is also heterogeneous in its manifestations, which depend on the extent of the occlusion, on the acuteness of the obstruction, and on whether venous collateral circulation has developed to decompress the liver sinusoids.^9,12,13 Therefore, on the basis of its clinical manifestations, it can be classified as fulminant, acute, subacute, or chronic.^12–16

The fulminant form presents with hepatic encephalopathy within 8 weeks after the development of jaundice. The subacute form, which is the most common, has a more insidious onset in which hepatic sinusoids are decompressed by portal and hepatic venous collateral circulation. The patient usually presents with abdominal pain, ascites, hepatomegaly, nausea, vomiting, and mild jaundice. Finally the chronic form presents as complications of cirrhosis.^12–16

Imaging plays an important role in diagnosing Budd-Chiari syndrome

Imaging plays an important role in detecting and classifying Budd-Chiari syndrome.

Duplex ultrasonography is useful for detecting this syndrome and has a sensitivity and specificity of 85%.⁹

CT and magnetic resonance imaging can also help in the diagnosis by showing thrombosis, obstruction, or occlusion in the hepatic vein or the inferior vena cava.⁵

Venography is the gold standard for diagnosis. However, it should be performed only if noninvasive tests are negative or nondiagnostic and there is a high clinical suspicion of this disease.¹⁷ Budd-Chiari syndrome has a characteristic pattern on venography known as “spider web,” which is due to the formation of venous collaterals to bypass the occluded hepatic veins.⁹

Liver biopsy is not necessarily required to confirm the diagnosis of Budd-Chiari syndrome, but it can help in diagnosing the acute or subacute forms and also in ruling out other causes. Histologic findings can include centrizonal congestion, loss of hepatocytes, hemorrhage, and fibrosis.^18,19 Regenerative nodules are found in about 25% of patients.¹⁹

TREATING BUDD-CHIARI SYNDROME

The primary goal of treatment is to prevent further extension of the venous thrombosis in the hepatic veins, in their collaterals, and in the intrahepatic and extrahepatic portal venous system. Resolution of hepatic congestion improves liver perfusion and preserves function of the hepatocytes.

Anticoagulation is recommended in the early stages. Heparin therapy should be initiated and subsequently switched to warfarin with the goal of achieving an international normalized ratio of the prothrombin time of 2.0 to 2.5.^8,9,19

Thrombolysis is effective in the acute form.^20,21 Recanalization, including percutaneous or transhepatic angioplasty of localized segments of the narrowed hepatic veins or inferior vena cava, has long-term patency rates of 80% to 90%.²²

If thrombolytic therapy and angioplasty are unsuccessful, a transjugular intrahepatic portosystemic shunt or a surgical procedure (side-to-side portocaval shunt, central splenorenal shunt, or mesocaval shunt) should be considered.⁹

Liver transplantation is another treatment option in those with fulminant Budd-Chiari syndrome or advanced liver cirrhosis.⁸

PROGNOSIS HAS IMPROVED

The prognosis of Budd-Chiari syndrome has improved, thanks to both earlier diagnosis and new treatments. The 1-year survival rate, which was about 60% before 1985, has increased to more than 80% in recent cohort studies.¹⁹

Studies have shown that the Child-Pugh score, which is based on a combination of serum albumin, bilirubin, prothrombin time, encephalopathy, and ascites, can be considered as an independent prognostic factor. A lower Child-Pugh score and a younger age are associated with a good prognosis.^19,23,24 (The Child-Pugh score cannot be applied to our patient because he does not have cirrhosis.)

What happened to our patient?

Our patient was started on anticoagulation for his Budd-Chiari syndrome and on bortezomib (Velcade) and dexamethasone for his multiple myeloma. He achieved remarkable improvement in his liver function tests. Follow-up duplex ultrasonography 1 month after discharge revealed that the stenosis in the hepatic veins had resolved. He is following up with the oncology clinic for management of his multiple myeloma.

A 25-year-old man presented to his primary care physician with generalized malaise. His symptoms started around 2 months earlier with progressive fatigue, nausea, decreased appetite, and weight loss (15 lb in 2 months). He denied having fever, chills, night sweats, abdominal pain, diarrhea, melena, or hematochezia.

His medical history was remarkable only for depression, well controlled with sertraline (Zoloft), which he started taking 3 years ago. He was not taking any other prescribed, over-the-counter, or herbal medications.

He had no family history of cancer or liver disease. He did not smoke and rarely drank alcohol. He had never used recreational drugs. He was sexually active with one female partner, used condoms for protection, and had never been diagnosed with a sexually transmitted disease. He had not traveled recently and had not been exposed to any pet.

The patient’s laboratory values on admission are shown in Table 1. Of note, his serum alkaline phosphatase level was 1,307 U/L (reference range 40–150 U/L).

LIVER TESTS CAN NARROW THE DIAGNOSIS

The most commonly used laboratory tests of the liver can be classified into those that measure either:

• Liver synthetic function (eg, the serum albumin and bilirubin concentrations and the prothrombin time) or
• Liver damage, as reflected by the serum concentrations of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyltransferase (GGT).^1,2

ALT and AST are normally concentrated in the hepatocytes and thus, when present in the serum in elevated concentrations, are markers of liver cell injury. The serum levels of these enzymes start to increase within a few hours of liver cell injury as they leak out of the cells via the damaged cell membrane. AST is less liver-specific than ALT, since AST levels can be elevated not only in liver injury but also in muscle, cardiac, and red blood cell injury.^3,4

Alkaline phosphatase is actually a heterogeneous group of enzymes found mainly in liver and bone cells. Hepatic alkaline phosphatase is concentrated near the biliary canalicular membrane of the hepatocyte. Accordingly, increased levels of hepatic alkaline phosphatase are mainly seen in liver diseases that predominantly affect the biliary system.³

GGT is also concentrated in hepatic biliary epithelial cells, and thus GGT elevation is another marker of hepatobiliary disease. In fact, measuring the GGT level can help to determine whether an isolated elevation of alkaline phosphatase is due to liver injury.^2,3

Accordingly, liver diseases can be classified into two broad categories:

• Hepatocellular injury, in which the primary injury occurs to the hepatocytes
• Cholestatic injury, in which the primary injury is to the bile ducts.

In the former, elevated levels of ALT and AST predominate, while in the latter, elevated alkaline phosphatase is the main finding.³

WHAT TEST NEXT FOR OUR PATIENT?

1. What is the next most appropriate diagnostic step for our patient?

• Liver biopsy
• Ultrasonography of the liver
• Computed tomography (CT) of the liver
• Observation

Our patient has an elevated GGT level, which suggests that his elevated alkaline phosphatase is of hepatic rather than bony origin. Moreover, a serum alkaline phosphatase level that is elevated out of proportion to the aminotransferase levels reflects cholestatic liver injury.

CASE CONTINUED: ULTRASONOGRAPHY IS MOSTLY NORMAL

Ultrasonography of the right upper quadrant revealed that the liver had normal echogenicity and was mildly enlarged. There was no focal hepatic lesion. The gallbladder appeared normal, with no stones or sludge. No dilated intrahepatic or extrahepatic biliary ducts were seen. The common bile duct measured 4 mm. A small amount of ascites not amenable to paracentesis was present.

Thus, in the absence of biliary dilation on ultrasonography, we are dealing with an intrahepatic cholestatic process.

CAUSES OF CHOLESTATIC LIVER DISEASE

Viral hepatitis

Viral hepatitis most often produces a hepatocellular pattern of injury (ie, AST and ALT elevations predominate). However, in rare cases it can cause a cholestatic pattern of injury.

Our patient subsequently had serologic tests for viral hepatitis, including hepatitis A, B, and C, and the results were negative.

Autoimmune liver disease

The three most common forms of autoimmune liver disease are autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis.

Autoimmune hepatitis is characterized by high serum ALT and AST levels, whereas primary biliary cirrhosis and primary sclerosing cholangitis are associated with predominant elevations of alkaline phosphatase, since they are cholestatic disorders.

Our patient’s alkaline phosphatase level was much higher than his ALT and AST levels, making the latter two diseases more likely.

Primary biliary cirrhosis (and autoimmune hepatitis) are associated with autoantibodies in the serum, such as antinuclear antibody, smooth muscle antibody, and antimitochondrial antibody.

Our patient subsequently was tested for these antibodies, and the results were negative.

Primary sclerosing cholangitis usually affects the extrahepatic biliary system. Thus, if it is present, abnormalities should be seen on imaging.

As mentioned previously, no dilated intrahepatic or extrahepatic biliary ducts were seen on ultrasonography in our patient. Moreover, primary sclerosing cholangitis is associated with inflammatory bowel disease, particularly ulcerative colitis, which our patient did not have.

Drug-induced liver injury

Drug-induced liver injury is a common cause of cholestatic liver disease. However, our patient was not taking any prescribed, over-the-counter, or herbal medications. Additionally, he denied heavy alcohol use.

Infiltrative disorders

Infiltrative disorders such as amyloidosis, sarcoidosis, or lymphoma should be considered in the differential diagnosis of cholestatic liver disease. A clue to a possible infiltrative process is a markedly elevated level of alkaline phosphatase with a mildly increased serum bilirubin concentration, both of which our patient had.

AFTER ULTRASONOGRAPHY, WHAT IS THE NEXT STEP?

2. Which of the following is the next most appropriate diagnostic test for our patient?

• Endoscopic retrograde cholangiopancreatography (ERCP)
• Magnetic resonance cholangiopancreatography (MRCP)
• Liver biopsy
• CT of the abdomen

Figure 1 shows a proposed algorithm for evaluating increased alkaline phosphatase levels.

If there is no biliary duct dilation on ultrasonography, then abnormal levels of alkaline phosphatase most likely represent an intrahepatic pattern of cholestatic liver injury. Therefore, additional imaging with CT or magnetic resonance imaging is of limited diagnostic value. ERCP is used today for therapy rather than diagnosis, so its use is limited to patients known to have dilated biliary ducts on imaging. Liver biopsy, however, can provide useful findings.

Case continued: He undergoes biopsy

Our patient underwent transjugular liver biopsy. During the procedure, transjugular venography showed stenosis in the right, middle, and left hepatic veins and the hepatic portion of the inferior vena cava, consistent with Budd-Chiari syndrome.

The liver biopsy specimen was positive for extensive deposition of slight eosinophilic and amorphous material in a sinusoidal pattern in the liver parenchyma, as well as in the portal tracts, with markedly atrophic hepatocytes. Congo red birefringence confirmed the diagnosis of amyloidosis. The immunohistochemical phenotype was positive for kappa light chains, which is diagnostic for primary-type amyloidosis, also called amyloidosis of light chain composition, or AL.

Bone marrow aspiration and bone marrow biopsy were performed and showed 22% plasma cells, well above the normal range (0–2%), consistent with the diagnosis of multiple myeloma.

BUDD-CHIARI SYNDROME: A CHALLENGING DIAGNOSIS

Budd-Chiari syndrome is a rare condition characterized by obstruction of venous outflow from the liver at a site that may vary from the small hepatic veins up to the inferior vena cava or even the right atrium.^5,6 Obstruction of hepatic venous outflow leads to sinusoidal congestion and hypoxic damage of the hepatocytes.⁷ Hypoxia and necrosis of the hepatocytes result in the release of free radicals. Cirrhosis can eventually occur secondary to ischemic necrosis of hepatocytes and hepatic fibrosis.⁸

The estimated incidence of this syndrome is 1 in 2.5 million persons per year.⁷ It is more prevalent in women and young adults.⁸

Heterogeneous in its causes and manifestations

Budd-Chiari syndrome is also heterogeneous in its manifestations, which depend on the extent of the occlusion, on the acuteness of the obstruction, and on whether venous collateral circulation has developed to decompress the liver sinusoids.^9,12,13 Therefore, on the basis of its clinical manifestations, it can be classified as fulminant, acute, subacute, or chronic.^12–16

The fulminant form presents with hepatic encephalopathy within 8 weeks after the development of jaundice. The subacute form, which is the most common, has a more insidious onset in which hepatic sinusoids are decompressed by portal and hepatic venous collateral circulation. The patient usually presents with abdominal pain, ascites, hepatomegaly, nausea, vomiting, and mild jaundice. Finally the chronic form presents as complications of cirrhosis.^12–16

Imaging plays an important role in diagnosing Budd-Chiari syndrome

Imaging plays an important role in detecting and classifying Budd-Chiari syndrome.

Duplex ultrasonography is useful for detecting this syndrome and has a sensitivity and specificity of 85%.⁹

CT and magnetic resonance imaging can also help in the diagnosis by showing thrombosis, obstruction, or occlusion in the hepatic vein or the inferior vena cava.⁵

Venography is the gold standard for diagnosis. However, it should be performed only if noninvasive tests are negative or nondiagnostic and there is a high clinical suspicion of this disease.¹⁷ Budd-Chiari syndrome has a characteristic pattern on venography known as “spider web,” which is due to the formation of venous collaterals to bypass the occluded hepatic veins.⁹

Liver biopsy is not necessarily required to confirm the diagnosis of Budd-Chiari syndrome, but it can help in diagnosing the acute or subacute forms and also in ruling out other causes. Histologic findings can include centrizonal congestion, loss of hepatocytes, hemorrhage, and fibrosis.^18,19 Regenerative nodules are found in about 25% of patients.¹⁹

TREATING BUDD-CHIARI SYNDROME

The primary goal of treatment is to prevent further extension of the venous thrombosis in the hepatic veins, in their collaterals, and in the intrahepatic and extrahepatic portal venous system. Resolution of hepatic congestion improves liver perfusion and preserves function of the hepatocytes.

Anticoagulation is recommended in the early stages. Heparin therapy should be initiated and subsequently switched to warfarin with the goal of achieving an international normalized ratio of the prothrombin time of 2.0 to 2.5.^8,9,19

Thrombolysis is effective in the acute form.^20,21 Recanalization, including percutaneous or transhepatic angioplasty of localized segments of the narrowed hepatic veins or inferior vena cava, has long-term patency rates of 80% to 90%.²²

If thrombolytic therapy and angioplasty are unsuccessful, a transjugular intrahepatic portosystemic shunt or a surgical procedure (side-to-side portocaval shunt, central splenorenal shunt, or mesocaval shunt) should be considered.⁹

Liver transplantation is another treatment option in those with fulminant Budd-Chiari syndrome or advanced liver cirrhosis.⁸

PROGNOSIS HAS IMPROVED

The prognosis of Budd-Chiari syndrome has improved, thanks to both earlier diagnosis and new treatments. The 1-year survival rate, which was about 60% before 1985, has increased to more than 80% in recent cohort studies.¹⁹

Studies have shown that the Child-Pugh score, which is based on a combination of serum albumin, bilirubin, prothrombin time, encephalopathy, and ascites, can be considered as an independent prognostic factor. A lower Child-Pugh score and a younger age are associated with a good prognosis.^19,23,24 (The Child-Pugh score cannot be applied to our patient because he does not have cirrhosis.)

What happened to our patient?

Our patient was started on anticoagulation for his Budd-Chiari syndrome and on bortezomib (Velcade) and dexamethasone for his multiple myeloma. He achieved remarkable improvement in his liver function tests. Follow-up duplex ultrasonography 1 month after discharge revealed that the stenosis in the hepatic veins had resolved. He is following up with the oncology clinic for management of his multiple myeloma.

A 25-year-old man presented to his primary care physician with generalized malaise. His symptoms started around 2 months earlier with progressive fatigue, nausea, decreased appetite, and weight loss (15 lb in 2 months). He denied having fever, chills, night sweats, abdominal pain, diarrhea, melena, or hematochezia.

His medical history was remarkable only for depression, well controlled with sertraline (Zoloft), which he started taking 3 years ago. He was not taking any other prescribed, over-the-counter, or herbal medications.

He had no family history of cancer or liver disease. He did not smoke and rarely drank alcohol. He had never used recreational drugs. He was sexually active with one female partner, used condoms for protection, and had never been diagnosed with a sexually transmitted disease. He had not traveled recently and had not been exposed to any pet.

The patient’s laboratory values on admission are shown in Table 1. Of note, his serum alkaline phosphatase level was 1,307 U/L (reference range 40–150 U/L).

LIVER TESTS CAN NARROW THE DIAGNOSIS

The most commonly used laboratory tests of the liver can be classified into those that measure either:

• Liver synthetic function (eg, the serum albumin and bilirubin concentrations and the prothrombin time) or
• Liver damage, as reflected by the serum concentrations of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyltransferase (GGT).^1,2

ALT and AST are normally concentrated in the hepatocytes and thus, when present in the serum in elevated concentrations, are markers of liver cell injury. The serum levels of these enzymes start to increase within a few hours of liver cell injury as they leak out of the cells via the damaged cell membrane. AST is less liver-specific than ALT, since AST levels can be elevated not only in liver injury but also in muscle, cardiac, and red blood cell injury.^3,4

Alkaline phosphatase is actually a heterogeneous group of enzymes found mainly in liver and bone cells. Hepatic alkaline phosphatase is concentrated near the biliary canalicular membrane of the hepatocyte. Accordingly, increased levels of hepatic alkaline phosphatase are mainly seen in liver diseases that predominantly affect the biliary system.³

GGT is also concentrated in hepatic biliary epithelial cells, and thus GGT elevation is another marker of hepatobiliary disease. In fact, measuring the GGT level can help to determine whether an isolated elevation of alkaline phosphatase is due to liver injury.^2,3

Accordingly, liver diseases can be classified into two broad categories:

• Hepatocellular injury, in which the primary injury occurs to the hepatocytes
• Cholestatic injury, in which the primary injury is to the bile ducts.

In the former, elevated levels of ALT and AST predominate, while in the latter, elevated alkaline phosphatase is the main finding.³

WHAT TEST NEXT FOR OUR PATIENT?

1. What is the next most appropriate diagnostic step for our patient?

• Liver biopsy
• Ultrasonography of the liver
• Computed tomography (CT) of the liver
• Observation

Our patient has an elevated GGT level, which suggests that his elevated alkaline phosphatase is of hepatic rather than bony origin. Moreover, a serum alkaline phosphatase level that is elevated out of proportion to the aminotransferase levels reflects cholestatic liver injury.

CASE CONTINUED: ULTRASONOGRAPHY IS MOSTLY NORMAL

Ultrasonography of the right upper quadrant revealed that the liver had normal echogenicity and was mildly enlarged. There was no focal hepatic lesion. The gallbladder appeared normal, with no stones or sludge. No dilated intrahepatic or extrahepatic biliary ducts were seen. The common bile duct measured 4 mm. A small amount of ascites not amenable to paracentesis was present.

Thus, in the absence of biliary dilation on ultrasonography, we are dealing with an intrahepatic cholestatic process.

CAUSES OF CHOLESTATIC LIVER DISEASE

Viral hepatitis

Viral hepatitis most often produces a hepatocellular pattern of injury (ie, AST and ALT elevations predominate). However, in rare cases it can cause a cholestatic pattern of injury.

Our patient subsequently had serologic tests for viral hepatitis, including hepatitis A, B, and C, and the results were negative.

Autoimmune liver disease

The three most common forms of autoimmune liver disease are autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis.

Autoimmune hepatitis is characterized by high serum ALT and AST levels, whereas primary biliary cirrhosis and primary sclerosing cholangitis are associated with predominant elevations of alkaline phosphatase, since they are cholestatic disorders.

Our patient’s alkaline phosphatase level was much higher than his ALT and AST levels, making the latter two diseases more likely.

Primary biliary cirrhosis (and autoimmune hepatitis) are associated with autoantibodies in the serum, such as antinuclear antibody, smooth muscle antibody, and antimitochondrial antibody.

Our patient subsequently was tested for these antibodies, and the results were negative.

Primary sclerosing cholangitis usually affects the extrahepatic biliary system. Thus, if it is present, abnormalities should be seen on imaging.

As mentioned previously, no dilated intrahepatic or extrahepatic biliary ducts were seen on ultrasonography in our patient. Moreover, primary sclerosing cholangitis is associated with inflammatory bowel disease, particularly ulcerative colitis, which our patient did not have.

Drug-induced liver injury

Drug-induced liver injury is a common cause of cholestatic liver disease. However, our patient was not taking any prescribed, over-the-counter, or herbal medications. Additionally, he denied heavy alcohol use.

Infiltrative disorders

Infiltrative disorders such as amyloidosis, sarcoidosis, or lymphoma should be considered in the differential diagnosis of cholestatic liver disease. A clue to a possible infiltrative process is a markedly elevated level of alkaline phosphatase with a mildly increased serum bilirubin concentration, both of which our patient had.

AFTER ULTRASONOGRAPHY, WHAT IS THE NEXT STEP?

2. Which of the following is the next most appropriate diagnostic test for our patient?

• Endoscopic retrograde cholangiopancreatography (ERCP)
• Magnetic resonance cholangiopancreatography (MRCP)
• Liver biopsy
• CT of the abdomen

Figure 1 shows a proposed algorithm for evaluating increased alkaline phosphatase levels.

If there is no biliary duct dilation on ultrasonography, then abnormal levels of alkaline phosphatase most likely represent an intrahepatic pattern of cholestatic liver injury. Therefore, additional imaging with CT or magnetic resonance imaging is of limited diagnostic value. ERCP is used today for therapy rather than diagnosis, so its use is limited to patients known to have dilated biliary ducts on imaging. Liver biopsy, however, can provide useful findings.

Case continued: He undergoes biopsy

Our patient underwent transjugular liver biopsy. During the procedure, transjugular venography showed stenosis in the right, middle, and left hepatic veins and the hepatic portion of the inferior vena cava, consistent with Budd-Chiari syndrome.

The liver biopsy specimen was positive for extensive deposition of slight eosinophilic and amorphous material in a sinusoidal pattern in the liver parenchyma, as well as in the portal tracts, with markedly atrophic hepatocytes. Congo red birefringence confirmed the diagnosis of amyloidosis. The immunohistochemical phenotype was positive for kappa light chains, which is diagnostic for primary-type amyloidosis, also called amyloidosis of light chain composition, or AL.

Bone marrow aspiration and bone marrow biopsy were performed and showed 22% plasma cells, well above the normal range (0–2%), consistent with the diagnosis of multiple myeloma.

BUDD-CHIARI SYNDROME: A CHALLENGING DIAGNOSIS

Budd-Chiari syndrome is a rare condition characterized by obstruction of venous outflow from the liver at a site that may vary from the small hepatic veins up to the inferior vena cava or even the right atrium.^5,6 Obstruction of hepatic venous outflow leads to sinusoidal congestion and hypoxic damage of the hepatocytes.⁷ Hypoxia and necrosis of the hepatocytes result in the release of free radicals. Cirrhosis can eventually occur secondary to ischemic necrosis of hepatocytes and hepatic fibrosis.⁸

The estimated incidence of this syndrome is 1 in 2.5 million persons per year.⁷ It is more prevalent in women and young adults.⁸

Heterogeneous in its causes and manifestations

Budd-Chiari syndrome is also heterogeneous in its manifestations, which depend on the extent of the occlusion, on the acuteness of the obstruction, and on whether venous collateral circulation has developed to decompress the liver sinusoids.^9,12,13 Therefore, on the basis of its clinical manifestations, it can be classified as fulminant, acute, subacute, or chronic.^12–16

The fulminant form presents with hepatic encephalopathy within 8 weeks after the development of jaundice. The subacute form, which is the most common, has a more insidious onset in which hepatic sinusoids are decompressed by portal and hepatic venous collateral circulation. The patient usually presents with abdominal pain, ascites, hepatomegaly, nausea, vomiting, and mild jaundice. Finally the chronic form presents as complications of cirrhosis.^12–16

Imaging plays an important role in diagnosing Budd-Chiari syndrome

Imaging plays an important role in detecting and classifying Budd-Chiari syndrome.

Duplex ultrasonography is useful for detecting this syndrome and has a sensitivity and specificity of 85%.⁹

CT and magnetic resonance imaging can also help in the diagnosis by showing thrombosis, obstruction, or occlusion in the hepatic vein or the inferior vena cava.⁵

Venography is the gold standard for diagnosis. However, it should be performed only if noninvasive tests are negative or nondiagnostic and there is a high clinical suspicion of this disease.¹⁷ Budd-Chiari syndrome has a characteristic pattern on venography known as “spider web,” which is due to the formation of venous collaterals to bypass the occluded hepatic veins.⁹

Liver biopsy is not necessarily required to confirm the diagnosis of Budd-Chiari syndrome, but it can help in diagnosing the acute or subacute forms and also in ruling out other causes. Histologic findings can include centrizonal congestion, loss of hepatocytes, hemorrhage, and fibrosis.^18,19 Regenerative nodules are found in about 25% of patients.¹⁹

TREATING BUDD-CHIARI SYNDROME

The primary goal of treatment is to prevent further extension of the venous thrombosis in the hepatic veins, in their collaterals, and in the intrahepatic and extrahepatic portal venous system. Resolution of hepatic congestion improves liver perfusion and preserves function of the hepatocytes.

Anticoagulation is recommended in the early stages. Heparin therapy should be initiated and subsequently switched to warfarin with the goal of achieving an international normalized ratio of the prothrombin time of 2.0 to 2.5.^8,9,19

Thrombolysis is effective in the acute form.^20,21 Recanalization, including percutaneous or transhepatic angioplasty of localized segments of the narrowed hepatic veins or inferior vena cava, has long-term patency rates of 80% to 90%.²²

If thrombolytic therapy and angioplasty are unsuccessful, a transjugular intrahepatic portosystemic shunt or a surgical procedure (side-to-side portocaval shunt, central splenorenal shunt, or mesocaval shunt) should be considered.⁹

Liver transplantation is another treatment option in those with fulminant Budd-Chiari syndrome or advanced liver cirrhosis.⁸

PROGNOSIS HAS IMPROVED

The prognosis of Budd-Chiari syndrome has improved, thanks to both earlier diagnosis and new treatments. The 1-year survival rate, which was about 60% before 1985, has increased to more than 80% in recent cohort studies.¹⁹

Studies have shown that the Child-Pugh score, which is based on a combination of serum albumin, bilirubin, prothrombin time, encephalopathy, and ascites, can be considered as an independent prognostic factor. A lower Child-Pugh score and a younger age are associated with a good prognosis.^19,23,24 (The Child-Pugh score cannot be applied to our patient because he does not have cirrhosis.)

What happened to our patient?

Our patient was started on anticoagulation for his Budd-Chiari syndrome and on bortezomib (Velcade) and dexamethasone for his multiple myeloma. He achieved remarkable improvement in his liver function tests. Follow-up duplex ultrasonography 1 month after discharge revealed that the stenosis in the hepatic veins had resolved. He is following up with the oncology clinic for management of his multiple myeloma.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

To the Editor: We thank Drs. Venkatachalam and Rimmerman¹ for their Clinical Picture article, “Electrocardiography in aortic regurgitation: It’s in the details,” in the August 2011 issue. This was very interesting, as usual for the Cleveland Clinic Journal of Medicine.

The maxim that “a negative U wave is never normal,” first noted about 50 years ago, still holds true. However, the authors’ statement on page 506—ie, that a negative U wave indicates structural heart disease—is too restrictive, since ischemia is not always due to a structural problem. Functional ischemia from excess demand, such as from tachycardia, sepsis, or gastrointestinal bleeding, can also cause negative U waves.^2,3 The broader comment in the “sidebar” on page 505 could be considered to include demand ischemia, but for clarity, it would be helpful to state this explicitly.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

In Reply: We appreciate the comments from Drs. Suksaranjit, Cheungpasitporn, Bischof, and Marx on our recent article on the negative U wave in a patient with chronic aortic regurgitation.¹ The clinical data including electrocardiography, echocardiography, and coronary angiography were presented to emphasize the importance of identifying the negative U wave in the setting of valvular heart disease. We outlined the common differential diagnosis for a negative U wave (page 506). We believe that in the appropriate clinical setting the presence of a negative U wave provides diagnostic utility.

Several published reports to date have described the occurrence of the negative U wave in the setting of obstructive coronary artery disease^2–5 or coronary artery vasospasm.⁶ We were unable to find similar data in the setting of demand ischemia in the presence of normal coronary arteries (functional ischemia), but we fully recognize its likely occurrence, and we value the helpful insight.

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Congestive heart failure, as noted in the review by Samala et al in this issue of the Journal, is more prevalent in the elderly. Particularly in the frail elderly, managing severe congestive heart failure poses ethical, socioeconomic, and medical challenges. The presence of even subtle cognitive impairment requires detailed dialogue with family and caregivers about medications and about symptoms that warrant a trip to the emergency room. Patients on a fixed income may not be able to afford their medications and thus may use them sporadically. And the preprepared foods they often eat are laden with sodium.

The symptoms of congestive heart failure may easily go unrecognized or be attributed to other common problems. Sorting out the reasons for exertional fatigue, especially a generalized sense of fatigue, can be particularly vexing. Anemia and sarcopenia can directly cause exertional fatigue or “weakness” but may also exacerbate heart failure and cause similar symptoms. Pharmacologic and dietary causes for volume overload must be sought. Even intermittent use of over-the-counter nonsteroidal anti-inflammatory drugs can be problematic.

Severe congestive heart failure is a lethal disease. Current quality guidelines for its treatment emphasize the use of multiple drugs and devices. Yet vasoactive drugs may not be well tolerated in frail patients, who are particularly vulnerable to orthostatic hypotension and cerebral hypoperfusion. Digoxin, of marginal benefit in younger patients without tachyarrhythmias, has an even more tenuous risk-benefit ratio in the frail elderly. Beta-blockers may cause fatigue and depression, and even low-dose diuretics can exacerbate symptoms of bladder dysfunction. Previously implanted defibrillators may be inconsistent with the patient’s current end-of-life desires.

Ideal management of the genuinely frail elderly patient with severe congestive heart failure is not always a matter of ventricular assist devices, biventricular pacers, or angiotensin-converting enzyme inhibitors. At some point, referral to palliative care resources, guided by informed input from the patient, family members, and caregivers, may be the most appropriate high-quality care that we can (and should) offer.

Mr. R. is an 85-year-old with congestive heart failure; the last time his ejection fraction was measured it was 30%. He also has hypertension, coronary artery disease (for which he underwent triple-vessel coronary artery bypass grafting), osteoarthritis, hyperlipidemia, and chronic obstructive pulmonary disease. He currently takes lisinopril (Zestril), carvedilol (Coreg), aspirin, clopidogrel (Plavix), digoxin, simvastatin (Zocor), furosemide (Lasix), an albuterol inhaler (Proventil), and over-the-counter naproxen (Naprosyn), the last two taken as needed.

Accompanied by his daughter, Mr. R. comes to see his primary care physician for a routine follow-up visit. He says he feels fine and has no shortness of breath or chest pain, but he feels light-headed at times, especially when he gets out of bed. He also mentions that he is bothered with having to get up three to four times at night to urinate.

On further questioning, he relates that he uses a cane to walk around the house and gets short of breath when walking from his bed to the bathroom and from one room to the next. He can feed himself, but he needs assistance with bathing and getting dressed.

Mr. R. admits that he has been feeling lonely since his wife died about a year ago. He now lives with his daughter and her family, and they all get along well. His daughter mentions that over the last 6 months he has not been eating well, that he appears to have lost interest in doing some of the things that he used to enjoy, and that he has lost weight. She adds that he has fallen twice in the last month.

On physical examination, Mr. R. is without distress but appears weak. He answers all questions appropriately, although his affect is flat and his daughter fills in some of the details.

Supine, his blood pressure is 160/90 mm Hg and his heart rate is 75; immediately after standing up he feels dizzy and his blood pressure drops to 120/60 mm Hg with a heart rate of 110. Three months ago he weighed 155 pounds (70.3 kg); today he weighs 145 pounds (65.9 kg).

His neck veins are not distended. On chest auscultation, bibasilar coarse crackles are heard, as well as a systolic murmur (grade 2 on a scale of 6), loudest in the second intercostal space at the right parasternal border. No peripheral edema is detected. His Mini-Mental State Exam score is 22 out of 30.

What changes, if any, should be made in Mr. R.’s management? What advice should the primary care physician give Mr. R. and his daughter about the course of his heart failure?

THE IMPORTANCE OF COMPLETE CARE

Mr. R. has multiple convoluted medical issues that plague many elderly patients with heart failure. To provide optimal care to patients like him, physicians need to draw on knowledge from the fields of internal medicine, geriatrics, and cardiology.

In this paper, we discuss how diagnosing and managing heart failure is different in elderly patients. We emphasize the importance of complete care of frail elderly patients, highlighting the pharmacologic and nonpharmacologic interventions that are available. Finally, we will return to Mr. R. and discuss a comprehensive plan for him.

HEART FAILURE, FRAILTY, DISABILITY ARE ALL CONNECTED

The ability to bounce back from physical insults, chiefly medical illnesses, sharply declines in old age. As various stressors accumulate, physical deterioration becomes inevitable. While some older adults can avoid going down this path of morbidity, in an increasing number of frail elderly patients, congestive heart failure inescapably assumes a complicated course.

Frailty is a state of increased vulnerability to stressors due to age-related declines in physiologic reserve.¹ Two elements intimately related to frailty are comorbidity and disability.

Fried et al² analyzed data from more than 5,000 older men and women in the Cardiovascular Health Study and concluded that comorbidity (ie, having two or more chronic diseases) is a risk factor for frailty, which in turn results in disability, falls, hospitalizations, and death.

The relationship between congestive heart failure and frailty is complex. Not only does heart failure itself result in frailty, but its multiple therapies can put additional stress on a frail patient. In addition, the heart failure and its treatments can negatively affect coexisting disorders (Figure 1).

BY THE NUMBERS

Heart failure is largely a disorder of the elderly, and as the US population ages, heart failure is rising in prevalence to epidemic numbers.³ The median age of patients admitted to the hospital because of heart failure is 75,⁴ and patients age 65 and older account for more than 75% of heart failure hospitalizations.⁵ Every year, in every 1,000 people over age 65, nearly 10 new cases of heart failure are diagnosed.⁶

Before age 70, men are affected more than women, but the opposite is true at age 70 and beyond. The reason for this reversal is that women live longer and have a better prognosis, as the cause of heart failure in most women is diastolic dysfunction secondary to hypertension rather than systolic dysfunction due to coronary artery disease, as in most men.⁷

Heart failure is costly and generally has a poor prognosis. The total cost of treating it reached a staggering $37.2 billion in 2009, and it was the leading cause of Medicare hospital admissions.⁶ Heart failure is the primary cause or a contributory cause of death in about 290,000 patients each year, and the rate of death at 1 year is an astonishing 1 in 5.⁶ The median survival time after diagnosis is 2.3 to 3.6 years in patients ages 67 to 74, and it is considerably shorter—1.1 to 1.6 years—in patients age 85 and older.⁸

THE BROKEN HEART

In 2005, the American College of Cardiology and the American Heart Association defined congestive heart failure as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”⁹ This characterization captures the intricate nature of the disease: its spectrum of symptoms, its many causes (eg, coronary artery disease, hypertension, nonischemic or idiopathic cardiomyopathy, and valvular heart disease), and the dual pathophysiologic features of systolic and diastolic impairment.

Systolic vs diastolic failure

Of the various ways of classifying heart failure, the most important is systolic vs diastolic.

The hallmark of systolic heart failure is a decreased left ventricular ejection fraction, and it is characterized by a large thin-walled ventricle that is weak and unable to eject enough blood to generate a normal cardiac output.

In contrast, the ejection fraction is normal or nearly normal in diastolic heart failure, but the end-diastolic volume is decreased because the ventricle is hypertrophied and thick-walled. The resultant chamber has become small and stiff and does not have enough volume for sufficient cardiac output.

QUIRKS IN THE HISTORY AND PHYSICAL EXAMINATION

The combination of inactivity and coexisting illnesses in a frail older adult may obscure some of the usual clinical manifestations of heart failure. While shortness of breath on mild exertion, easy fatigability, and leg swelling are common in younger heart failure patients, these symptoms may be due to normal aging in a much older patient. Let us consider some important aspects of the common signs and symptoms associated with heart failure.

Dyspnea on exertion is one of the earliest and most prominent symptoms. The usual question asked of patients to elicit whether this key manifestation is present is, “Do you get short of breath after walking a block?” However, this question may not be appropriate for a frail elderly person whose activity is restricted by comorbidities such as severe arthritis, coronary artery disease, or peripheral arterial disease. For a patient like this, ask instead if he or she gets short of breath after milder forms of exertion, such as making the bed, walking to the bathroom, or changing clothes.¹⁰ Also, keep in mind that dyspnea on exertion may be due to other conditions, such as renal failure, lung disease, depression, anemia, or deconditioning.

Orthopnea and paroxysmal nocturnal dyspnea may not be volunteered or elicited if a patient is sleeping in a chair or a recliner.

Leg swelling is less specific in older adults than in younger patients because chronic venous insufficiency is common in older people.

Weight gain almost always accompanies symptomatic heart failure but may also be due to increased appetite secondary to depression.

A change in mental status is common in elderly people with heart failure, especially those with vascular dementia with extensive cerebrovascular atherosclerosis or those who have latent Alzheimer disease.¹⁰

Cough, a symptom of a multitude of disorders, may be an early or the only manifestation of heart failure.

Pulmonary crackles are typically detected in most heart failure patients, but they may not be as characteristic in older adults, as they may also be noted in bronchitis, pneumonia, and other chronic lung diseases.

Additional symptoms to watch for include fatigue, syncope, angina, nocturia, and oliguria.

The bottom line is to integrate individual findings with other elements of the history and physical examination in diagnosing heart failure and tracking its progression.

CLINCHING THE DIAGNOSIS

Congestive heart failure is essentially a clinical diagnosis best established even before ordering tests, especially during times and situations in which these tests are not always readily available, such as outside office hours and in a long-term care setting.

A reliable and thorough history and physical examination is the most important component of the diagnostic process.

An echocardiogram is obtained next to measure the ejection fraction, which has both prognostic and therapeutic significance. Echocardiography can also uncover potential contributory cardiac structural abnormalities.

A chest radiograph is also typically obtained to look for pulmonary congestion, but in older adults its interpretation may be skewed by chronic lung disease or spinal deformities such as scoliosis and kyphosis.

The B-type natriuretic peptide (BNP) level is a popular blood test. BNP is commonly elevated in patients with heart failure. However, an elevated level in older adults should always be evaluated within the context of other clinical findings, as it can also result from advancing age and diseases other than heart failure, such as coronary artery disease, chronic pulmonary disease, pulmonary embolism, and renal insufficiency.^11,12

PHARMACOTHERAPY PEARLS

Drug treatment for heart failure has evolved rapidly. Robust and sophisticated clinical trials have led to guidelines that call for specific medications. Unfortunately, older patients, particularly the very old and frail, have been poorly represented in these studies.⁹ Nonetheless, the type and choice of drugs for the young and old are similar.

Take into account age-associated changes in pharmacokinetics

Age-associated changes in pharmacokinetics must be taken into account when prescribing drugs for heart failure.¹³

Oral absorption of cardiovascular drugs is not significantly affected by the various changes that occur in older adults (eg, reduced gastric acid production, gastric emptying rate, gastrointestinal blood flow, and mobility). However, reductions in both lean body mass and total body water that come with aging result in lower volumes of distribution and higher plasma concentrations of hydrophilic drugs, most notably angiotensin-converting enzyme (ACE) inhibitors and digoxin. In contrast, the plasma concentrations of lipophilic drugs such as beta-blockers and central alpha-agonists tend to decrease as the proportion of body fat increases in older adults.

As the plasma albumin level diminishes with age, the free-drug concentration of salicylates and warfarin (Coumadin), which are extensively albumin-bound, may increase.

The serum concentrations of cardiovascular drugs metabolized in the liver—eg, propranolol (Inderal), lidocaine, labetalol (Trandate), verapamil (Calan), diltiazem (Cardizem), nitrates, and warfarin—may be elevated due to reduced hepatic blood flow, mass, volume, and overall metabolic capacity.

Declines in renal blood flow, glomerular filtration, and tubular function may cause accumulation of drugs that are excreted through the kidneys.

Beware of toxicities

Table 1 lists some of the drugs used in treating heart failure, common adverse affects to watch for, and recommendations for their use.

WIELDING THE SCALPEL

A tenet of heart failure management is to correct the underlying cardiac structural abnormality. This often calls for invasive intervention along with optimization of drug therapy.

For example:

• Diseased coronary arteries may be amenable to revascularization, either by percutaneous coronary intervention or by the much more involved coronary artery bypass grafting, with the aim of enhancing cardiac function.
• Valves can be repaired or replaced in patients with valvular heart disease.
• A pacemaker can be implanted to remedy sick sinus syndrome, especially with concurrent use of heart-rate-lowering agents such as beta-blockers.
• Placement of an implantable cardioverter-defibrillator has been found to be effective in preventing death due to ventricular tachyarrhythmias in patients with an ejection fraction of less than 30%.⁹
• Cardiac resynchronization with a biventricular pacemaker may increase the ejection fraction and cardiac output by eliminating dyssynchronous contraction of the left and right ventricles.¹⁴

In frail older adults, consideration of these invasive therapies must be individualized. While procedures such as percutaneous coronary intervention and pacemaker placement may not be as physically taxing as bypass grafting or valve replacement, the potential for surgical complications must be seriously considered, particularly if the patient has diminished physiologic reserve. Case-to-case consideration is also crucial in cardioverter-defibrillator insertion, as the survival benefit may be diminished in older adults, who likely have coexisting illnesses that predispose them to die of a noncardiac cause.^15,16

The bottom line is to contemplate multiple factors—severity of the heart failure, comorbidities, baseline functional status, and social support—when assessing the appropriateness of an invasive intervention.

BEYOND DRUGS AND DEVICES: WE CAN DO ‘MORE’

Much of the spotlight has been on the various drugs and devices used to treat heart failure, but of equal importance for frail elderly patients are complementary approaches that can be used to ease disease progression and boost the quality of life. The acronym MORE highlights these strategies.

M: Multidisciplinary management programs

Heart failure disease-management programs are designed to provide comprehensive multidisciplinary care across different settings (ie, home, outpatient, and inpatient) to high-risk patients who often have multiple medical, social, and behavioral issues.⁹ Interventions usually include intensive patient education, encouraging patients to be more aggressive participants in their care, closely monitoring patients through telephone follow-up or home nursing, carefully reviewing medications to improve adherence to evidence-based guidelines, and multidisciplinary care with nurse case management directed by a physician.

Studies have shown that management programs, which were largely nurse-directed and targeted at older adults and patients with advanced disease, can improve quality of life and functional status, decrease hospitalizations for both heart failure and other causes, and decrease medical costs.^17–19

O: Other diseases

R: Restrictions

Specific limitations in the intake of certain dietary elements are a valuable adjunct in heart failure management.

Sodium intake should be restricted to less than 3 g/day by not adding salt to meals and by avoiding salt-rich foods (eg, canned and processed foods).²⁴ During times of distressing volume overload, a tighter sodium limit of 2 g/day is necessary, and diuretics may be less effective if this restriction is not implemented.

Fluid restriction depends on the patient’s clinical status.²⁵ While it is not necessary to limit fluid intake in the absence of retention, a limit of 2 L/day is recommended if edema is detected. If volume overload is severe, the limit should be 1 L/day.

Alcohol is a myocardial depressant that reduces the left ventricular ejection fraction.²⁶ Abstinence is a must for patients with alcohol-induced heart failure; otherwise, a limit of 1 drink (8 oz of beer, 4 oz of wine, or 1 oz of hard liquor) per day is suggested.²⁴

Calories and fat intake are both important to watch, particularly in patients with obesity, hyperlipidemia, hypertension, or coronary artery disease.

Usual causes of death in patients with heart failure include sudden cardiac death, arrhythmias, hypotension, end-organ hypoperfusion, and metabolic derangement.^27,28

Given the life-limiting nature of the disease in frail older adults, it is very important for clinicians to discuss end-of-life matters with patients and their families as early as possible. Needed are effective communication skills that foster respect, empathy, and mutual understanding.

Advance directives. The primary task is to encourage patients to develop advance health directives. These are legal documents that represent patients’ preferences about interventions available toward the end of life such as do-not-resuscitate orders, appointment of surrogate decision-makers, and use of life-sustaining interventions (eg, a feeding tube, dialysis, blood transfusions). Establishing these directives early on will help ease the transition from one mode of care to another (eg, from acute care to hospice care), prevent pointless use of resources (eg, emergency room visits, hospital admissions), and ensure that the patient’s wishes are carried out.

Palliative measures that aim to alleviate suffering and promote quality of life and dignity are available for patients with severe symptoms. For varying degrees of dyspnea, diuretics, nitrates, morphine, and positive inotropic agents such as dobutamine (Dobutrex) and milrinone (Primacor) can be tried. Thoracentesis is done in patients with extensive pleural effusion. Fatigue and anorexia are due to a combination of factors, namely, decreased cardiac output, increased neurohormone levels, deconditioning, depression, decreased sleep, and anxiety.²⁹ Opioids, caffeine, exercise, oxygen, fluid and salt restriction, and correction of anemia and depression may help ease these symptoms.

For patients with an implantable cardioverter-defibrillator, deactivation is an important matter that needs to be addressed. Deactivation can be carried out with certainty once the goal of care has shifted away from curative efforts and either the patient or a surrogate decision-maker has made the informed decision to turn the device off. Berger³⁰ raised three points that the clinician and decision-maker can discuss in trying to achieve a resolution during times of doubt and indecision:

• The patient may no longer value continued survival
• The device may no longer offer the prospect of increased survival
• The device may impede active dying.

The idea of hospice care should be gradually and gently explored to ensure a prompt and seamless transition when the time comes. The patient and family need to know that the goal of hospice care is to ensure comfort and that they can benefit the most by enrolling early during the course of the terminal illness.

The Medicare hospice benefit is granted to patients who have been certified by two physicians to have a life expectancy of 6 months or less if their terminal illness runs its natural course. The criteria for determining that heart failure is terminal are:

• New York Heart Association class III (symptomatic with less than ordinary activities) or IV (symptomatic at rest)
• Left ventricular ejection fraction less than or equal to 20%
• Persistent symptoms despite optimal medical management
• Inability to tolerate optional management due to hypotension with or without renal failure.³¹

WHAT CAN WE DO FOR MR. R.?

Mr. R. has systolic heart failure stemming from coronary artery disease, and his symptoms put him in New York Heart Association class III. He is well managed with drugs of different appropriate classes: an ACE inhibitor, a beta-blocker, digoxin, an aldosterone antagonist, and a diuretic. His other drugs all have well-defined indications.

Since he does not have fluid overload, his furosemide can be stopped, and this change will likely relieve his orthostatic hypotension and nocturia. His systolic blood pressure target can be liberalized to 150 mm Hg or less, as tighter control might exacerbate orthostatic hypotension. This change, along with having him start using a walker instead of a cane, will hopefully prevent future falls. Furthermore, his naproxen should be discontinued, as it can worsen heart failure.

Mr. R. has symptoms of depression and thus needs to be started on an antidepressant and encouraged to engage in social activities as much as he can tolerate. These interventions may also help with his mild dementia, which is evidenced by a Mini-Mental State Exam score of 22. He will not benefit from sodium and fat restriction, as he has actually been losing weight.

To keep Mr. R.’s cognitive impairment and overall decline in function from compromising his compliance with his treatment, he will need a substantial amount of assistance, which his daughter alone may not be able to provide. To tackle this concern, a discussion about participating in a heart failure management program can be started with Mr. R. and his family.

More importantly, his advanced directives, including delegating a surrogate decision-maker and deciding on do-not-resuscitate status, have to be clarified. Finally, it would be prudent to introduce the concept of hospice care to the patient and his daughter while he is still coherent and able to state his preferences.

Mr. R. is an 85-year-old with congestive heart failure; the last time his ejection fraction was measured it was 30%. He also has hypertension, coronary artery disease (for which he underwent triple-vessel coronary artery bypass grafting), osteoarthritis, hyperlipidemia, and chronic obstructive pulmonary disease. He currently takes lisinopril (Zestril), carvedilol (Coreg), aspirin, clopidogrel (Plavix), digoxin, simvastatin (Zocor), furosemide (Lasix), an albuterol inhaler (Proventil), and over-the-counter naproxen (Naprosyn), the last two taken as needed.

Accompanied by his daughter, Mr. R. comes to see his primary care physician for a routine follow-up visit. He says he feels fine and has no shortness of breath or chest pain, but he feels light-headed at times, especially when he gets out of bed. He also mentions that he is bothered with having to get up three to four times at night to urinate.

On further questioning, he relates that he uses a cane to walk around the house and gets short of breath when walking from his bed to the bathroom and from one room to the next. He can feed himself, but he needs assistance with bathing and getting dressed.

Mr. R. admits that he has been feeling lonely since his wife died about a year ago. He now lives with his daughter and her family, and they all get along well. His daughter mentions that over the last 6 months he has not been eating well, that he appears to have lost interest in doing some of the things that he used to enjoy, and that he has lost weight. She adds that he has fallen twice in the last month.

On physical examination, Mr. R. is without distress but appears weak. He answers all questions appropriately, although his affect is flat and his daughter fills in some of the details.

Supine, his blood pressure is 160/90 mm Hg and his heart rate is 75; immediately after standing up he feels dizzy and his blood pressure drops to 120/60 mm Hg with a heart rate of 110. Three months ago he weighed 155 pounds (70.3 kg); today he weighs 145 pounds (65.9 kg).

His neck veins are not distended. On chest auscultation, bibasilar coarse crackles are heard, as well as a systolic murmur (grade 2 on a scale of 6), loudest in the second intercostal space at the right parasternal border. No peripheral edema is detected. His Mini-Mental State Exam score is 22 out of 30.

What changes, if any, should be made in Mr. R.’s management? What advice should the primary care physician give Mr. R. and his daughter about the course of his heart failure?

THE IMPORTANCE OF COMPLETE CARE

Mr. R. has multiple convoluted medical issues that plague many elderly patients with heart failure. To provide optimal care to patients like him, physicians need to draw on knowledge from the fields of internal medicine, geriatrics, and cardiology.

In this paper, we discuss how diagnosing and managing heart failure is different in elderly patients. We emphasize the importance of complete care of frail elderly patients, highlighting the pharmacologic and nonpharmacologic interventions that are available. Finally, we will return to Mr. R. and discuss a comprehensive plan for him.

HEART FAILURE, FRAILTY, DISABILITY ARE ALL CONNECTED

The ability to bounce back from physical insults, chiefly medical illnesses, sharply declines in old age. As various stressors accumulate, physical deterioration becomes inevitable. While some older adults can avoid going down this path of morbidity, in an increasing number of frail elderly patients, congestive heart failure inescapably assumes a complicated course.

Frailty is a state of increased vulnerability to stressors due to age-related declines in physiologic reserve.¹ Two elements intimately related to frailty are comorbidity and disability.

Fried et al² analyzed data from more than 5,000 older men and women in the Cardiovascular Health Study and concluded that comorbidity (ie, having two or more chronic diseases) is a risk factor for frailty, which in turn results in disability, falls, hospitalizations, and death.

The relationship between congestive heart failure and frailty is complex. Not only does heart failure itself result in frailty, but its multiple therapies can put additional stress on a frail patient. In addition, the heart failure and its treatments can negatively affect coexisting disorders (Figure 1).

BY THE NUMBERS

Heart failure is largely a disorder of the elderly, and as the US population ages, heart failure is rising in prevalence to epidemic numbers.³ The median age of patients admitted to the hospital because of heart failure is 75,⁴ and patients age 65 and older account for more than 75% of heart failure hospitalizations.⁵ Every year, in every 1,000 people over age 65, nearly 10 new cases of heart failure are diagnosed.⁶

Before age 70, men are affected more than women, but the opposite is true at age 70 and beyond. The reason for this reversal is that women live longer and have a better prognosis, as the cause of heart failure in most women is diastolic dysfunction secondary to hypertension rather than systolic dysfunction due to coronary artery disease, as in most men.⁷

Heart failure is costly and generally has a poor prognosis. The total cost of treating it reached a staggering $37.2 billion in 2009, and it was the leading cause of Medicare hospital admissions.⁶ Heart failure is the primary cause or a contributory cause of death in about 290,000 patients each year, and the rate of death at 1 year is an astonishing 1 in 5.⁶ The median survival time after diagnosis is 2.3 to 3.6 years in patients ages 67 to 74, and it is considerably shorter—1.1 to 1.6 years—in patients age 85 and older.⁸

THE BROKEN HEART

In 2005, the American College of Cardiology and the American Heart Association defined congestive heart failure as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”⁹ This characterization captures the intricate nature of the disease: its spectrum of symptoms, its many causes (eg, coronary artery disease, hypertension, nonischemic or idiopathic cardiomyopathy, and valvular heart disease), and the dual pathophysiologic features of systolic and diastolic impairment.

Systolic vs diastolic failure

Of the various ways of classifying heart failure, the most important is systolic vs diastolic.

The hallmark of systolic heart failure is a decreased left ventricular ejection fraction, and it is characterized by a large thin-walled ventricle that is weak and unable to eject enough blood to generate a normal cardiac output.

In contrast, the ejection fraction is normal or nearly normal in diastolic heart failure, but the end-diastolic volume is decreased because the ventricle is hypertrophied and thick-walled. The resultant chamber has become small and stiff and does not have enough volume for sufficient cardiac output.

QUIRKS IN THE HISTORY AND PHYSICAL EXAMINATION

The combination of inactivity and coexisting illnesses in a frail older adult may obscure some of the usual clinical manifestations of heart failure. While shortness of breath on mild exertion, easy fatigability, and leg swelling are common in younger heart failure patients, these symptoms may be due to normal aging in a much older patient. Let us consider some important aspects of the common signs and symptoms associated with heart failure.

Dyspnea on exertion is one of the earliest and most prominent symptoms. The usual question asked of patients to elicit whether this key manifestation is present is, “Do you get short of breath after walking a block?” However, this question may not be appropriate for a frail elderly person whose activity is restricted by comorbidities such as severe arthritis, coronary artery disease, or peripheral arterial disease. For a patient like this, ask instead if he or she gets short of breath after milder forms of exertion, such as making the bed, walking to the bathroom, or changing clothes.¹⁰ Also, keep in mind that dyspnea on exertion may be due to other conditions, such as renal failure, lung disease, depression, anemia, or deconditioning.

Orthopnea and paroxysmal nocturnal dyspnea may not be volunteered or elicited if a patient is sleeping in a chair or a recliner.

Leg swelling is less specific in older adults than in younger patients because chronic venous insufficiency is common in older people.

Weight gain almost always accompanies symptomatic heart failure but may also be due to increased appetite secondary to depression.

A change in mental status is common in elderly people with heart failure, especially those with vascular dementia with extensive cerebrovascular atherosclerosis or those who have latent Alzheimer disease.¹⁰

Cough, a symptom of a multitude of disorders, may be an early or the only manifestation of heart failure.

Pulmonary crackles are typically detected in most heart failure patients, but they may not be as characteristic in older adults, as they may also be noted in bronchitis, pneumonia, and other chronic lung diseases.

Additional symptoms to watch for include fatigue, syncope, angina, nocturia, and oliguria.

The bottom line is to integrate individual findings with other elements of the history and physical examination in diagnosing heart failure and tracking its progression.

CLINCHING THE DIAGNOSIS

Congestive heart failure is essentially a clinical diagnosis best established even before ordering tests, especially during times and situations in which these tests are not always readily available, such as outside office hours and in a long-term care setting.

A reliable and thorough history and physical examination is the most important component of the diagnostic process.

An echocardiogram is obtained next to measure the ejection fraction, which has both prognostic and therapeutic significance. Echocardiography can also uncover potential contributory cardiac structural abnormalities.

A chest radiograph is also typically obtained to look for pulmonary congestion, but in older adults its interpretation may be skewed by chronic lung disease or spinal deformities such as scoliosis and kyphosis.

The B-type natriuretic peptide (BNP) level is a popular blood test. BNP is commonly elevated in patients with heart failure. However, an elevated level in older adults should always be evaluated within the context of other clinical findings, as it can also result from advancing age and diseases other than heart failure, such as coronary artery disease, chronic pulmonary disease, pulmonary embolism, and renal insufficiency.^11,12

PHARMACOTHERAPY PEARLS

Drug treatment for heart failure has evolved rapidly. Robust and sophisticated clinical trials have led to guidelines that call for specific medications. Unfortunately, older patients, particularly the very old and frail, have been poorly represented in these studies.⁹ Nonetheless, the type and choice of drugs for the young and old are similar.

Take into account age-associated changes in pharmacokinetics

Age-associated changes in pharmacokinetics must be taken into account when prescribing drugs for heart failure.¹³

Oral absorption of cardiovascular drugs is not significantly affected by the various changes that occur in older adults (eg, reduced gastric acid production, gastric emptying rate, gastrointestinal blood flow, and mobility). However, reductions in both lean body mass and total body water that come with aging result in lower volumes of distribution and higher plasma concentrations of hydrophilic drugs, most notably angiotensin-converting enzyme (ACE) inhibitors and digoxin. In contrast, the plasma concentrations of lipophilic drugs such as beta-blockers and central alpha-agonists tend to decrease as the proportion of body fat increases in older adults.

As the plasma albumin level diminishes with age, the free-drug concentration of salicylates and warfarin (Coumadin), which are extensively albumin-bound, may increase.

The serum concentrations of cardiovascular drugs metabolized in the liver—eg, propranolol (Inderal), lidocaine, labetalol (Trandate), verapamil (Calan), diltiazem (Cardizem), nitrates, and warfarin—may be elevated due to reduced hepatic blood flow, mass, volume, and overall metabolic capacity.

Declines in renal blood flow, glomerular filtration, and tubular function may cause accumulation of drugs that are excreted through the kidneys.

Beware of toxicities

Table 1 lists some of the drugs used in treating heart failure, common adverse affects to watch for, and recommendations for their use.

WIELDING THE SCALPEL

A tenet of heart failure management is to correct the underlying cardiac structural abnormality. This often calls for invasive intervention along with optimization of drug therapy.

For example:

• Diseased coronary arteries may be amenable to revascularization, either by percutaneous coronary intervention or by the much more involved coronary artery bypass grafting, with the aim of enhancing cardiac function.
• Valves can be repaired or replaced in patients with valvular heart disease.
• A pacemaker can be implanted to remedy sick sinus syndrome, especially with concurrent use of heart-rate-lowering agents such as beta-blockers.
• Placement of an implantable cardioverter-defibrillator has been found to be effective in preventing death due to ventricular tachyarrhythmias in patients with an ejection fraction of less than 30%.⁹
• Cardiac resynchronization with a biventricular pacemaker may increase the ejection fraction and cardiac output by eliminating dyssynchronous contraction of the left and right ventricles.¹⁴

In frail older adults, consideration of these invasive therapies must be individualized. While procedures such as percutaneous coronary intervention and pacemaker placement may not be as physically taxing as bypass grafting or valve replacement, the potential for surgical complications must be seriously considered, particularly if the patient has diminished physiologic reserve. Case-to-case consideration is also crucial in cardioverter-defibrillator insertion, as the survival benefit may be diminished in older adults, who likely have coexisting illnesses that predispose them to die of a noncardiac cause.^15,16

The bottom line is to contemplate multiple factors—severity of the heart failure, comorbidities, baseline functional status, and social support—when assessing the appropriateness of an invasive intervention.

BEYOND DRUGS AND DEVICES: WE CAN DO ‘MORE’

Much of the spotlight has been on the various drugs and devices used to treat heart failure, but of equal importance for frail elderly patients are complementary approaches that can be used to ease disease progression and boost the quality of life. The acronym MORE highlights these strategies.

M: Multidisciplinary management programs

Heart failure disease-management programs are designed to provide comprehensive multidisciplinary care across different settings (ie, home, outpatient, and inpatient) to high-risk patients who often have multiple medical, social, and behavioral issues.⁹ Interventions usually include intensive patient education, encouraging patients to be more aggressive participants in their care, closely monitoring patients through telephone follow-up or home nursing, carefully reviewing medications to improve adherence to evidence-based guidelines, and multidisciplinary care with nurse case management directed by a physician.

Studies have shown that management programs, which were largely nurse-directed and targeted at older adults and patients with advanced disease, can improve quality of life and functional status, decrease hospitalizations for both heart failure and other causes, and decrease medical costs.^17–19

O: Other diseases

R: Restrictions

Specific limitations in the intake of certain dietary elements are a valuable adjunct in heart failure management.

Sodium intake should be restricted to less than 3 g/day by not adding salt to meals and by avoiding salt-rich foods (eg, canned and processed foods).²⁴ During times of distressing volume overload, a tighter sodium limit of 2 g/day is necessary, and diuretics may be less effective if this restriction is not implemented.

Fluid restriction depends on the patient’s clinical status.²⁵ While it is not necessary to limit fluid intake in the absence of retention, a limit of 2 L/day is recommended if edema is detected. If volume overload is severe, the limit should be 1 L/day.

Alcohol is a myocardial depressant that reduces the left ventricular ejection fraction.²⁶ Abstinence is a must for patients with alcohol-induced heart failure; otherwise, a limit of 1 drink (8 oz of beer, 4 oz of wine, or 1 oz of hard liquor) per day is suggested.²⁴

Calories and fat intake are both important to watch, particularly in patients with obesity, hyperlipidemia, hypertension, or coronary artery disease.

Usual causes of death in patients with heart failure include sudden cardiac death, arrhythmias, hypotension, end-organ hypoperfusion, and metabolic derangement.^27,28

Given the life-limiting nature of the disease in frail older adults, it is very important for clinicians to discuss end-of-life matters with patients and their families as early as possible. Needed are effective communication skills that foster respect, empathy, and mutual understanding.

Advance directives. The primary task is to encourage patients to develop advance health directives. These are legal documents that represent patients’ preferences about interventions available toward the end of life such as do-not-resuscitate orders, appointment of surrogate decision-makers, and use of life-sustaining interventions (eg, a feeding tube, dialysis, blood transfusions). Establishing these directives early on will help ease the transition from one mode of care to another (eg, from acute care to hospice care), prevent pointless use of resources (eg, emergency room visits, hospital admissions), and ensure that the patient’s wishes are carried out.

Palliative measures that aim to alleviate suffering and promote quality of life and dignity are available for patients with severe symptoms. For varying degrees of dyspnea, diuretics, nitrates, morphine, and positive inotropic agents such as dobutamine (Dobutrex) and milrinone (Primacor) can be tried. Thoracentesis is done in patients with extensive pleural effusion. Fatigue and anorexia are due to a combination of factors, namely, decreased cardiac output, increased neurohormone levels, deconditioning, depression, decreased sleep, and anxiety.²⁹ Opioids, caffeine, exercise, oxygen, fluid and salt restriction, and correction of anemia and depression may help ease these symptoms.

For patients with an implantable cardioverter-defibrillator, deactivation is an important matter that needs to be addressed. Deactivation can be carried out with certainty once the goal of care has shifted away from curative efforts and either the patient or a surrogate decision-maker has made the informed decision to turn the device off. Berger³⁰ raised three points that the clinician and decision-maker can discuss in trying to achieve a resolution during times of doubt and indecision:

• The patient may no longer value continued survival
• The device may no longer offer the prospect of increased survival
• The device may impede active dying.

The idea of hospice care should be gradually and gently explored to ensure a prompt and seamless transition when the time comes. The patient and family need to know that the goal of hospice care is to ensure comfort and that they can benefit the most by enrolling early during the course of the terminal illness.

The Medicare hospice benefit is granted to patients who have been certified by two physicians to have a life expectancy of 6 months or less if their terminal illness runs its natural course. The criteria for determining that heart failure is terminal are:

• New York Heart Association class III (symptomatic with less than ordinary activities) or IV (symptomatic at rest)
• Left ventricular ejection fraction less than or equal to 20%
• Persistent symptoms despite optimal medical management
• Inability to tolerate optional management due to hypotension with or without renal failure.³¹

WHAT CAN WE DO FOR MR. R.?

Mr. R. has systolic heart failure stemming from coronary artery disease, and his symptoms put him in New York Heart Association class III. He is well managed with drugs of different appropriate classes: an ACE inhibitor, a beta-blocker, digoxin, an aldosterone antagonist, and a diuretic. His other drugs all have well-defined indications.

Since he does not have fluid overload, his furosemide can be stopped, and this change will likely relieve his orthostatic hypotension and nocturia. His systolic blood pressure target can be liberalized to 150 mm Hg or less, as tighter control might exacerbate orthostatic hypotension. This change, along with having him start using a walker instead of a cane, will hopefully prevent future falls. Furthermore, his naproxen should be discontinued, as it can worsen heart failure.

Mr. R. has symptoms of depression and thus needs to be started on an antidepressant and encouraged to engage in social activities as much as he can tolerate. These interventions may also help with his mild dementia, which is evidenced by a Mini-Mental State Exam score of 22. He will not benefit from sodium and fat restriction, as he has actually been losing weight.

To keep Mr. R.’s cognitive impairment and overall decline in function from compromising his compliance with his treatment, he will need a substantial amount of assistance, which his daughter alone may not be able to provide. To tackle this concern, a discussion about participating in a heart failure management program can be started with Mr. R. and his family.

More importantly, his advanced directives, including delegating a surrogate decision-maker and deciding on do-not-resuscitate status, have to be clarified. Finally, it would be prudent to introduce the concept of hospice care to the patient and his daughter while he is still coherent and able to state his preferences.

Mr. R. is an 85-year-old with congestive heart failure; the last time his ejection fraction was measured it was 30%. He also has hypertension, coronary artery disease (for which he underwent triple-vessel coronary artery bypass grafting), osteoarthritis, hyperlipidemia, and chronic obstructive pulmonary disease. He currently takes lisinopril (Zestril), carvedilol (Coreg), aspirin, clopidogrel (Plavix), digoxin, simvastatin (Zocor), furosemide (Lasix), an albuterol inhaler (Proventil), and over-the-counter naproxen (Naprosyn), the last two taken as needed.

Accompanied by his daughter, Mr. R. comes to see his primary care physician for a routine follow-up visit. He says he feels fine and has no shortness of breath or chest pain, but he feels light-headed at times, especially when he gets out of bed. He also mentions that he is bothered with having to get up three to four times at night to urinate.

On further questioning, he relates that he uses a cane to walk around the house and gets short of breath when walking from his bed to the bathroom and from one room to the next. He can feed himself, but he needs assistance with bathing and getting dressed.

Mr. R. admits that he has been feeling lonely since his wife died about a year ago. He now lives with his daughter and her family, and they all get along well. His daughter mentions that over the last 6 months he has not been eating well, that he appears to have lost interest in doing some of the things that he used to enjoy, and that he has lost weight. She adds that he has fallen twice in the last month.

On physical examination, Mr. R. is without distress but appears weak. He answers all questions appropriately, although his affect is flat and his daughter fills in some of the details.

Supine, his blood pressure is 160/90 mm Hg and his heart rate is 75; immediately after standing up he feels dizzy and his blood pressure drops to 120/60 mm Hg with a heart rate of 110. Three months ago he weighed 155 pounds (70.3 kg); today he weighs 145 pounds (65.9 kg).

His neck veins are not distended. On chest auscultation, bibasilar coarse crackles are heard, as well as a systolic murmur (grade 2 on a scale of 6), loudest in the second intercostal space at the right parasternal border. No peripheral edema is detected. His Mini-Mental State Exam score is 22 out of 30.

What changes, if any, should be made in Mr. R.’s management? What advice should the primary care physician give Mr. R. and his daughter about the course of his heart failure?

THE IMPORTANCE OF COMPLETE CARE

Mr. R. has multiple convoluted medical issues that plague many elderly patients with heart failure. To provide optimal care to patients like him, physicians need to draw on knowledge from the fields of internal medicine, geriatrics, and cardiology.

In this paper, we discuss how diagnosing and managing heart failure is different in elderly patients. We emphasize the importance of complete care of frail elderly patients, highlighting the pharmacologic and nonpharmacologic interventions that are available. Finally, we will return to Mr. R. and discuss a comprehensive plan for him.

HEART FAILURE, FRAILTY, DISABILITY ARE ALL CONNECTED

The ability to bounce back from physical insults, chiefly medical illnesses, sharply declines in old age. As various stressors accumulate, physical deterioration becomes inevitable. While some older adults can avoid going down this path of morbidity, in an increasing number of frail elderly patients, congestive heart failure inescapably assumes a complicated course.

Frailty is a state of increased vulnerability to stressors due to age-related declines in physiologic reserve.¹ Two elements intimately related to frailty are comorbidity and disability.

Fried et al² analyzed data from more than 5,000 older men and women in the Cardiovascular Health Study and concluded that comorbidity (ie, having two or more chronic diseases) is a risk factor for frailty, which in turn results in disability, falls, hospitalizations, and death.

The relationship between congestive heart failure and frailty is complex. Not only does heart failure itself result in frailty, but its multiple therapies can put additional stress on a frail patient. In addition, the heart failure and its treatments can negatively affect coexisting disorders (Figure 1).

BY THE NUMBERS

Heart failure is largely a disorder of the elderly, and as the US population ages, heart failure is rising in prevalence to epidemic numbers.³ The median age of patients admitted to the hospital because of heart failure is 75,⁴ and patients age 65 and older account for more than 75% of heart failure hospitalizations.⁵ Every year, in every 1,000 people over age 65, nearly 10 new cases of heart failure are diagnosed.⁶

Before age 70, men are affected more than women, but the opposite is true at age 70 and beyond. The reason for this reversal is that women live longer and have a better prognosis, as the cause of heart failure in most women is diastolic dysfunction secondary to hypertension rather than systolic dysfunction due to coronary artery disease, as in most men.⁷

Heart failure is costly and generally has a poor prognosis. The total cost of treating it reached a staggering $37.2 billion in 2009, and it was the leading cause of Medicare hospital admissions.⁶ Heart failure is the primary cause or a contributory cause of death in about 290,000 patients each year, and the rate of death at 1 year is an astonishing 1 in 5.⁶ The median survival time after diagnosis is 2.3 to 3.6 years in patients ages 67 to 74, and it is considerably shorter—1.1 to 1.6 years—in patients age 85 and older.⁸

THE BROKEN HEART

In 2005, the American College of Cardiology and the American Heart Association defined congestive heart failure as “a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.”⁹ This characterization captures the intricate nature of the disease: its spectrum of symptoms, its many causes (eg, coronary artery disease, hypertension, nonischemic or idiopathic cardiomyopathy, and valvular heart disease), and the dual pathophysiologic features of systolic and diastolic impairment.

Systolic vs diastolic failure

Of the various ways of classifying heart failure, the most important is systolic vs diastolic.

The hallmark of systolic heart failure is a decreased left ventricular ejection fraction, and it is characterized by a large thin-walled ventricle that is weak and unable to eject enough blood to generate a normal cardiac output.

In contrast, the ejection fraction is normal or nearly normal in diastolic heart failure, but the end-diastolic volume is decreased because the ventricle is hypertrophied and thick-walled. The resultant chamber has become small and stiff and does not have enough volume for sufficient cardiac output.

QUIRKS IN THE HISTORY AND PHYSICAL EXAMINATION

The combination of inactivity and coexisting illnesses in a frail older adult may obscure some of the usual clinical manifestations of heart failure. While shortness of breath on mild exertion, easy fatigability, and leg swelling are common in younger heart failure patients, these symptoms may be due to normal aging in a much older patient. Let us consider some important aspects of the common signs and symptoms associated with heart failure.

Dyspnea on exertion is one of the earliest and most prominent symptoms. The usual question asked of patients to elicit whether this key manifestation is present is, “Do you get short of breath after walking a block?” However, this question may not be appropriate for a frail elderly person whose activity is restricted by comorbidities such as severe arthritis, coronary artery disease, or peripheral arterial disease. For a patient like this, ask instead if he or she gets short of breath after milder forms of exertion, such as making the bed, walking to the bathroom, or changing clothes.¹⁰ Also, keep in mind that dyspnea on exertion may be due to other conditions, such as renal failure, lung disease, depression, anemia, or deconditioning.

Orthopnea and paroxysmal nocturnal dyspnea may not be volunteered or elicited if a patient is sleeping in a chair or a recliner.

Leg swelling is less specific in older adults than in younger patients because chronic venous insufficiency is common in older people.

Weight gain almost always accompanies symptomatic heart failure but may also be due to increased appetite secondary to depression.

A change in mental status is common in elderly people with heart failure, especially those with vascular dementia with extensive cerebrovascular atherosclerosis or those who have latent Alzheimer disease.¹⁰

Cough, a symptom of a multitude of disorders, may be an early or the only manifestation of heart failure.

Pulmonary crackles are typically detected in most heart failure patients, but they may not be as characteristic in older adults, as they may also be noted in bronchitis, pneumonia, and other chronic lung diseases.

Additional symptoms to watch for include fatigue, syncope, angina, nocturia, and oliguria.

The bottom line is to integrate individual findings with other elements of the history and physical examination in diagnosing heart failure and tracking its progression.

CLINCHING THE DIAGNOSIS

Congestive heart failure is essentially a clinical diagnosis best established even before ordering tests, especially during times and situations in which these tests are not always readily available, such as outside office hours and in a long-term care setting.

A reliable and thorough history and physical examination is the most important component of the diagnostic process.

An echocardiogram is obtained next to measure the ejection fraction, which has both prognostic and therapeutic significance. Echocardiography can also uncover potential contributory cardiac structural abnormalities.

A chest radiograph is also typically obtained to look for pulmonary congestion, but in older adults its interpretation may be skewed by chronic lung disease or spinal deformities such as scoliosis and kyphosis.

The B-type natriuretic peptide (BNP) level is a popular blood test. BNP is commonly elevated in patients with heart failure. However, an elevated level in older adults should always be evaluated within the context of other clinical findings, as it can also result from advancing age and diseases other than heart failure, such as coronary artery disease, chronic pulmonary disease, pulmonary embolism, and renal insufficiency.^11,12

PHARMACOTHERAPY PEARLS

Drug treatment for heart failure has evolved rapidly. Robust and sophisticated clinical trials have led to guidelines that call for specific medications. Unfortunately, older patients, particularly the very old and frail, have been poorly represented in these studies.⁹ Nonetheless, the type and choice of drugs for the young and old are similar.

Take into account age-associated changes in pharmacokinetics

Age-associated changes in pharmacokinetics must be taken into account when prescribing drugs for heart failure.¹³

Oral absorption of cardiovascular drugs is not significantly affected by the various changes that occur in older adults (eg, reduced gastric acid production, gastric emptying rate, gastrointestinal blood flow, and mobility). However, reductions in both lean body mass and total body water that come with aging result in lower volumes of distribution and higher plasma concentrations of hydrophilic drugs, most notably angiotensin-converting enzyme (ACE) inhibitors and digoxin. In contrast, the plasma concentrations of lipophilic drugs such as beta-blockers and central alpha-agonists tend to decrease as the proportion of body fat increases in older adults.

As the plasma albumin level diminishes with age, the free-drug concentration of salicylates and warfarin (Coumadin), which are extensively albumin-bound, may increase.

The serum concentrations of cardiovascular drugs metabolized in the liver—eg, propranolol (Inderal), lidocaine, labetalol (Trandate), verapamil (Calan), diltiazem (Cardizem), nitrates, and warfarin—may be elevated due to reduced hepatic blood flow, mass, volume, and overall metabolic capacity.

Declines in renal blood flow, glomerular filtration, and tubular function may cause accumulation of drugs that are excreted through the kidneys.

Beware of toxicities

Table 1 lists some of the drugs used in treating heart failure, common adverse affects to watch for, and recommendations for their use.

WIELDING THE SCALPEL

A tenet of heart failure management is to correct the underlying cardiac structural abnormality. This often calls for invasive intervention along with optimization of drug therapy.

For example:

• Diseased coronary arteries may be amenable to revascularization, either by percutaneous coronary intervention or by the much more involved coronary artery bypass grafting, with the aim of enhancing cardiac function.
• Valves can be repaired or replaced in patients with valvular heart disease.
• A pacemaker can be implanted to remedy sick sinus syndrome, especially with concurrent use of heart-rate-lowering agents such as beta-blockers.
• Placement of an implantable cardioverter-defibrillator has been found to be effective in preventing death due to ventricular tachyarrhythmias in patients with an ejection fraction of less than 30%.⁹
• Cardiac resynchronization with a biventricular pacemaker may increase the ejection fraction and cardiac output by eliminating dyssynchronous contraction of the left and right ventricles.¹⁴

In frail older adults, consideration of these invasive therapies must be individualized. While procedures such as percutaneous coronary intervention and pacemaker placement may not be as physically taxing as bypass grafting or valve replacement, the potential for surgical complications must be seriously considered, particularly if the patient has diminished physiologic reserve. Case-to-case consideration is also crucial in cardioverter-defibrillator insertion, as the survival benefit may be diminished in older adults, who likely have coexisting illnesses that predispose them to die of a noncardiac cause.^15,16

The bottom line is to contemplate multiple factors—severity of the heart failure, comorbidities, baseline functional status, and social support—when assessing the appropriateness of an invasive intervention.

BEYOND DRUGS AND DEVICES: WE CAN DO ‘MORE’

Much of the spotlight has been on the various drugs and devices used to treat heart failure, but of equal importance for frail elderly patients are complementary approaches that can be used to ease disease progression and boost the quality of life. The acronym MORE highlights these strategies.

M: Multidisciplinary management programs

Heart failure disease-management programs are designed to provide comprehensive multidisciplinary care across different settings (ie, home, outpatient, and inpatient) to high-risk patients who often have multiple medical, social, and behavioral issues.⁹ Interventions usually include intensive patient education, encouraging patients to be more aggressive participants in their care, closely monitoring patients through telephone follow-up or home nursing, carefully reviewing medications to improve adherence to evidence-based guidelines, and multidisciplinary care with nurse case management directed by a physician.

Studies have shown that management programs, which were largely nurse-directed and targeted at older adults and patients with advanced disease, can improve quality of life and functional status, decrease hospitalizations for both heart failure and other causes, and decrease medical costs.^17–19

O: Other diseases

R: Restrictions

Specific limitations in the intake of certain dietary elements are a valuable adjunct in heart failure management.

Sodium intake should be restricted to less than 3 g/day by not adding salt to meals and by avoiding salt-rich foods (eg, canned and processed foods).²⁴ During times of distressing volume overload, a tighter sodium limit of 2 g/day is necessary, and diuretics may be less effective if this restriction is not implemented.

Fluid restriction depends on the patient’s clinical status.²⁵ While it is not necessary to limit fluid intake in the absence of retention, a limit of 2 L/day is recommended if edema is detected. If volume overload is severe, the limit should be 1 L/day.

Alcohol is a myocardial depressant that reduces the left ventricular ejection fraction.²⁶ Abstinence is a must for patients with alcohol-induced heart failure; otherwise, a limit of 1 drink (8 oz of beer, 4 oz of wine, or 1 oz of hard liquor) per day is suggested.²⁴

Calories and fat intake are both important to watch, particularly in patients with obesity, hyperlipidemia, hypertension, or coronary artery disease.

Usual causes of death in patients with heart failure include sudden cardiac death, arrhythmias, hypotension, end-organ hypoperfusion, and metabolic derangement.^27,28

Given the life-limiting nature of the disease in frail older adults, it is very important for clinicians to discuss end-of-life matters with patients and their families as early as possible. Needed are effective communication skills that foster respect, empathy, and mutual understanding.

Advance directives. The primary task is to encourage patients to develop advance health directives. These are legal documents that represent patients’ preferences about interventions available toward the end of life such as do-not-resuscitate orders, appointment of surrogate decision-makers, and use of life-sustaining interventions (eg, a feeding tube, dialysis, blood transfusions). Establishing these directives early on will help ease the transition from one mode of care to another (eg, from acute care to hospice care), prevent pointless use of resources (eg, emergency room visits, hospital admissions), and ensure that the patient’s wishes are carried out.

Palliative measures that aim to alleviate suffering and promote quality of life and dignity are available for patients with severe symptoms. For varying degrees of dyspnea, diuretics, nitrates, morphine, and positive inotropic agents such as dobutamine (Dobutrex) and milrinone (Primacor) can be tried. Thoracentesis is done in patients with extensive pleural effusion. Fatigue and anorexia are due to a combination of factors, namely, decreased cardiac output, increased neurohormone levels, deconditioning, depression, decreased sleep, and anxiety.²⁹ Opioids, caffeine, exercise, oxygen, fluid and salt restriction, and correction of anemia and depression may help ease these symptoms.

For patients with an implantable cardioverter-defibrillator, deactivation is an important matter that needs to be addressed. Deactivation can be carried out with certainty once the goal of care has shifted away from curative efforts and either the patient or a surrogate decision-maker has made the informed decision to turn the device off. Berger³⁰ raised three points that the clinician and decision-maker can discuss in trying to achieve a resolution during times of doubt and indecision:

• The patient may no longer value continued survival
• The device may no longer offer the prospect of increased survival
• The device may impede active dying.

The idea of hospice care should be gradually and gently explored to ensure a prompt and seamless transition when the time comes. The patient and family need to know that the goal of hospice care is to ensure comfort and that they can benefit the most by enrolling early during the course of the terminal illness.

The Medicare hospice benefit is granted to patients who have been certified by two physicians to have a life expectancy of 6 months or less if their terminal illness runs its natural course. The criteria for determining that heart failure is terminal are:

• New York Heart Association class III (symptomatic with less than ordinary activities) or IV (symptomatic at rest)
• Left ventricular ejection fraction less than or equal to 20%
• Persistent symptoms despite optimal medical management
• Inability to tolerate optional management due to hypotension with or without renal failure.³¹

WHAT CAN WE DO FOR MR. R.?

Mr. R. has systolic heart failure stemming from coronary artery disease, and his symptoms put him in New York Heart Association class III. He is well managed with drugs of different appropriate classes: an ACE inhibitor, a beta-blocker, digoxin, an aldosterone antagonist, and a diuretic. His other drugs all have well-defined indications.

Since he does not have fluid overload, his furosemide can be stopped, and this change will likely relieve his orthostatic hypotension and nocturia. His systolic blood pressure target can be liberalized to 150 mm Hg or less, as tighter control might exacerbate orthostatic hypotension. This change, along with having him start using a walker instead of a cane, will hopefully prevent future falls. Furthermore, his naproxen should be discontinued, as it can worsen heart failure.

Mr. R. has symptoms of depression and thus needs to be started on an antidepressant and encouraged to engage in social activities as much as he can tolerate. These interventions may also help with his mild dementia, which is evidenced by a Mini-Mental State Exam score of 22. He will not benefit from sodium and fat restriction, as he has actually been losing weight.

To keep Mr. R.’s cognitive impairment and overall decline in function from compromising his compliance with his treatment, he will need a substantial amount of assistance, which his daughter alone may not be able to provide. To tackle this concern, a discussion about participating in a heart failure management program can be started with Mr. R. and his family.

More importantly, his advanced directives, including delegating a surrogate decision-maker and deciding on do-not-resuscitate status, have to be clarified. Finally, it would be prudent to introduce the concept of hospice care to the patient and his daughter while he is still coherent and able to state his preferences.

Researchers have found that having a transient ischemic attack (TIA) can reduce a person’s life expectancy up to 20%, according to a study published online November 10 in Stroke. “There is a lack of modern-day data quantifying the effect of TIA on survival, and recent data do not take into account expected survival,” the researchers commented. To investigate the impact of a TIA on survival, the investigators analyzed data from 22,157 patients hospitalized with a TIA, then estimated survival relative to the age- and sex-matched general population up to nine years after hospitalization. At one-year follow-up, 91.5% of TIA patients survived, compared with 95.0% expected survival in the general population; by nine-years follow-up, observed survival was 20% lower than expected. Older age, prior hospitalization for stroke (but not TIA), atrial fibrillation, and congestive heart failure significantly increased the risk of excess death in these patients.
Higher levels of urinary sodium excretion were associated with an increased risk of cardiovascular events, while lower levels were associated with cardiovascular death and hospitalization for congestive heart failure, according to a study published in the November 23 JAMA. “[Our objective was] to determine the association between estimated urinary sodium and potassium excretion (surrogates for intake) and cardiovascular events in patients with established cardiovascular disease or diabetes mellitus,” stated the researchers. The results of their observational analyses revealed that “compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all cardiovascular events.” In addition, a sodium excretion of less than 3 g per day was associated with increased risk of cardiovascular mortality and hospitalization for congestive heart failure, and a higher estimated potassium excretion was associated with a reduced risk of stroke.
Serum vitamin D levels are significantly lower in patients with recurrent inflammatory spinal cord disease, according to the results of a study published online November 14 in Archives of Neurology. The study authors performed a retrospective analysis evaluating vitamin D levels of 77 patients with monophasic and recurrent inflammatory spinal cord diseases. “Vitamin D levels are significantly lower in patients who developed recurrent spinal cord disease, adjusting for season, age, sex, and race,” the investigators concluded. “This study provides a basis for a prospective trial of measuring 25-hydroxyvitamin D levels in these patient populations and assessing the influence of vitamin D supplementation on the frequency of relapses in those with recurrent inflammatory spinal cord disease.”
The FDA has approved AdaptiveStim with RestoreSensor neurostimulation system for the management of chronic pain. Unlike other implantable neurostimulation devices that require frequent manual adjustments with changes in body positions, the AdaptiveStim system (Medtronic, Inc; Minneapolis) automatically adapts stimulation levels to the needs of people with chronic back and/or leg pain by recognizing and remembering the correlation between a change in body position and the level of stimulation needed. The FDA’s approval was based on data from a clinical trial in which 86.5% of study participants with chronic pain experienced better pain relief and convenience when the system was turned on, compared with a control period when the participants manually adjusted neurostimulation settings; 80.3% of study participants also reported functional improvements, including improved comfort during position changes. The AdaptiveStim system was also approved for use in MRI head scans if recommended by a physician.
Brain overgrowth in boys with autism involves an abnormal excess number of neurons, according to the results of a small preliminary study published in the November 9 JAMA. “Autism often involves early brain overgrowth, including the prefrontal cortex,” the investigators stated. “Although prefrontal abnormality has been theorized to underlie some autistic symptoms, the cellular defects that cause abnormal overgrowth remain unknown.” To investigate whether this overgrowth in children with autism involves excess neuron numbers, the researchers compared postmortem tissue from the prefrontal cortex of seven boys (age range, 2 to 16) who had autism with postmortem tissue of six typically developing boys. They found that children with autism had 67% more neurons in the prefrontal cortex. “Brain weight in the autistic case differed from normative mean weight for age by a mean of 17.6%, while brains in controls differed by a mean of 0.2%,” the researchers reported.
A person’s stroke risk profile may also be helpful in predicting whether a person will develop memory problems and cognitive impairment later in life, according to a study published in the November 8 Neurology. “Participants included subjects without stroke at baseline … with at least two cognitive function assessments during the follow-up,” the researchers explained. “During a mean follow-up of 4.1 years, 1,907 participants met criteria for incident cognitive impairment.” The researchers determined that male sex, black race, less education, older age, and presence of left ventricular hypertrophy were related to the development of cognitive impairment. “Total Framingham Stroke Risk Profile score, elevated blood pressure, and left ventricular hypertrophy predict development of clinically significant cognitive dysfunction,” the investigators concluded. “Prevention and treatment of high blood pressure may be effective in preserving cognitive health.”
The FDA has approved Xarelto (rivaroxaban) to reduce the risk of stroke in people who have nonvalvular atrial fibrillation. Xarelto (Janssen Pharmaceuticals Inc; Titusville, New Jersey) is an oral anti-clotting drug that has also been approved to reduce the risk of blood clots, deep vein thrombosis, and pulmonary embolism following knee or hip replacement surgery. The FDA’s approval was based on the results of a clinical trial with more than 14,000 patients that compared Xarelto with the anti-clotting drug warfarin; Xarelto proved similar to warfarin in its ability to prevent stroke. Bleeding was the most common adverse event reported by patients treated with Xarelto in this clinical trial, and the risk of bleeding was similar to the risk of bleeding associated with warfarin.
Patients with dementia who have a stroke have a higher likelihood of becoming disabled and being institutionalized, compared with patients who did not have dementia at the time of their stroke, according to a report in the November 1 Neurology. Investigators conducted a retrospective cohort study that included 9,304 patients with an acute ischemic stroke, 702 of whom had a history of dementia. “Patients with dementia were older (mean age, 81 vs 70), had more severe strokes, and were more likely to have atrial fibrillation than those without dementia,” the investigators determined. They also found that patients with dementia were slightly less likely to be admitted to a stroke unit, had a higher disability at discharge, and were less likely to be discharged to their prestroke place of residence. “In patients with stroke, preexisting dementia is associated with high rates of disability and institutionalization, representing an increasing challenge for the health care system,” the researchers concluded.

Researchers have found that having a transient ischemic attack (TIA) can reduce a person’s life expectancy up to 20%, according to a study published online November 10 in Stroke. “There is a lack of modern-day data quantifying the effect of TIA on survival, and recent data do not take into account expected survival,” the researchers commented. To investigate the impact of a TIA on survival, the investigators analyzed data from 22,157 patients hospitalized with a TIA, then estimated survival relative to the age- and sex-matched general population up to nine years after hospitalization. At one-year follow-up, 91.5% of TIA patients survived, compared with 95.0% expected survival in the general population; by nine-years follow-up, observed survival was 20% lower than expected. Older age, prior hospitalization for stroke (but not TIA), atrial fibrillation, and congestive heart failure significantly increased the risk of excess death in these patients.
Higher levels of urinary sodium excretion were associated with an increased risk of cardiovascular events, while lower levels were associated with cardiovascular death and hospitalization for congestive heart failure, according to a study published in the November 23 JAMA. “[Our objective was] to determine the association between estimated urinary sodium and potassium excretion (surrogates for intake) and cardiovascular events in patients with established cardiovascular disease or diabetes mellitus,” stated the researchers. The results of their observational analyses revealed that “compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all cardiovascular events.” In addition, a sodium excretion of less than 3 g per day was associated with increased risk of cardiovascular mortality and hospitalization for congestive heart failure, and a higher estimated potassium excretion was associated with a reduced risk of stroke.
Serum vitamin D levels are significantly lower in patients with recurrent inflammatory spinal cord disease, according to the results of a study published online November 14 in Archives of Neurology. The study authors performed a retrospective analysis evaluating vitamin D levels of 77 patients with monophasic and recurrent inflammatory spinal cord diseases. “Vitamin D levels are significantly lower in patients who developed recurrent spinal cord disease, adjusting for season, age, sex, and race,” the investigators concluded. “This study provides a basis for a prospective trial of measuring 25-hydroxyvitamin D levels in these patient populations and assessing the influence of vitamin D supplementation on the frequency of relapses in those with recurrent inflammatory spinal cord disease.”
The FDA has approved AdaptiveStim with RestoreSensor neurostimulation system for the management of chronic pain. Unlike other implantable neurostimulation devices that require frequent manual adjustments with changes in body positions, the AdaptiveStim system (Medtronic, Inc; Minneapolis) automatically adapts stimulation levels to the needs of people with chronic back and/or leg pain by recognizing and remembering the correlation between a change in body position and the level of stimulation needed. The FDA’s approval was based on data from a clinical trial in which 86.5% of study participants with chronic pain experienced better pain relief and convenience when the system was turned on, compared with a control period when the participants manually adjusted neurostimulation settings; 80.3% of study participants also reported functional improvements, including improved comfort during position changes. The AdaptiveStim system was also approved for use in MRI head scans if recommended by a physician.
Brain overgrowth in boys with autism involves an abnormal excess number of neurons, according to the results of a small preliminary study published in the November 9 JAMA. “Autism often involves early brain overgrowth, including the prefrontal cortex,” the investigators stated. “Although prefrontal abnormality has been theorized to underlie some autistic symptoms, the cellular defects that cause abnormal overgrowth remain unknown.” To investigate whether this overgrowth in children with autism involves excess neuron numbers, the researchers compared postmortem tissue from the prefrontal cortex of seven boys (age range, 2 to 16) who had autism with postmortem tissue of six typically developing boys. They found that children with autism had 67% more neurons in the prefrontal cortex. “Brain weight in the autistic case differed from normative mean weight for age by a mean of 17.6%, while brains in controls differed by a mean of 0.2%,” the researchers reported.
A person’s stroke risk profile may also be helpful in predicting whether a person will develop memory problems and cognitive impairment later in life, according to a study published in the November 8 Neurology. “Participants included subjects without stroke at baseline … with at least two cognitive function assessments during the follow-up,” the researchers explained. “During a mean follow-up of 4.1 years, 1,907 participants met criteria for incident cognitive impairment.” The researchers determined that male sex, black race, less education, older age, and presence of left ventricular hypertrophy were related to the development of cognitive impairment. “Total Framingham Stroke Risk Profile score, elevated blood pressure, and left ventricular hypertrophy predict development of clinically significant cognitive dysfunction,” the investigators concluded. “Prevention and treatment of high blood pressure may be effective in preserving cognitive health.”
The FDA has approved Xarelto (rivaroxaban) to reduce the risk of stroke in people who have nonvalvular atrial fibrillation. Xarelto (Janssen Pharmaceuticals Inc; Titusville, New Jersey) is an oral anti-clotting drug that has also been approved to reduce the risk of blood clots, deep vein thrombosis, and pulmonary embolism following knee or hip replacement surgery. The FDA’s approval was based on the results of a clinical trial with more than 14,000 patients that compared Xarelto with the anti-clotting drug warfarin; Xarelto proved similar to warfarin in its ability to prevent stroke. Bleeding was the most common adverse event reported by patients treated with Xarelto in this clinical trial, and the risk of bleeding was similar to the risk of bleeding associated with warfarin.
Patients with dementia who have a stroke have a higher likelihood of becoming disabled and being institutionalized, compared with patients who did not have dementia at the time of their stroke, according to a report in the November 1 Neurology. Investigators conducted a retrospective cohort study that included 9,304 patients with an acute ischemic stroke, 702 of whom had a history of dementia. “Patients with dementia were older (mean age, 81 vs 70), had more severe strokes, and were more likely to have atrial fibrillation than those without dementia,” the investigators determined. They also found that patients with dementia were slightly less likely to be admitted to a stroke unit, had a higher disability at discharge, and were less likely to be discharged to their prestroke place of residence. “In patients with stroke, preexisting dementia is associated with high rates of disability and institutionalization, representing an increasing challenge for the health care system,” the researchers concluded.

Researchers have found that having a transient ischemic attack (TIA) can reduce a person’s life expectancy up to 20%, according to a study published online November 10 in Stroke. “There is a lack of modern-day data quantifying the effect of TIA on survival, and recent data do not take into account expected survival,” the researchers commented. To investigate the impact of a TIA on survival, the investigators analyzed data from 22,157 patients hospitalized with a TIA, then estimated survival relative to the age- and sex-matched general population up to nine years after hospitalization. At one-year follow-up, 91.5% of TIA patients survived, compared with 95.0% expected survival in the general population; by nine-years follow-up, observed survival was 20% lower than expected. Older age, prior hospitalization for stroke (but not TIA), atrial fibrillation, and congestive heart failure significantly increased the risk of excess death in these patients.
Higher levels of urinary sodium excretion were associated with an increased risk of cardiovascular events, while lower levels were associated with cardiovascular death and hospitalization for congestive heart failure, according to a study published in the November 23 JAMA. “[Our objective was] to determine the association between estimated urinary sodium and potassium excretion (surrogates for intake) and cardiovascular events in patients with established cardiovascular disease or diabetes mellitus,” stated the researchers. The results of their observational analyses revealed that “compared with baseline sodium excretion of 4 to 5.99 g per day, sodium excretion of greater than 7 g per day was associated with an increased risk of all cardiovascular events.” In addition, a sodium excretion of less than 3 g per day was associated with increased risk of cardiovascular mortality and hospitalization for congestive heart failure, and a higher estimated potassium excretion was associated with a reduced risk of stroke.
Serum vitamin D levels are significantly lower in patients with recurrent inflammatory spinal cord disease, according to the results of a study published online November 14 in Archives of Neurology. The study authors performed a retrospective analysis evaluating vitamin D levels of 77 patients with monophasic and recurrent inflammatory spinal cord diseases. “Vitamin D levels are significantly lower in patients who developed recurrent spinal cord disease, adjusting for season, age, sex, and race,” the investigators concluded. “This study provides a basis for a prospective trial of measuring 25-hydroxyvitamin D levels in these patient populations and assessing the influence of vitamin D supplementation on the frequency of relapses in those with recurrent inflammatory spinal cord disease.”
The FDA has approved AdaptiveStim with RestoreSensor neurostimulation system for the management of chronic pain. Unlike other implantable neurostimulation devices that require frequent manual adjustments with changes in body positions, the AdaptiveStim system (Medtronic, Inc; Minneapolis) automatically adapts stimulation levels to the needs of people with chronic back and/or leg pain by recognizing and remembering the correlation between a change in body position and the level of stimulation needed. The FDA’s approval was based on data from a clinical trial in which 86.5% of study participants with chronic pain experienced better pain relief and convenience when the system was turned on, compared with a control period when the participants manually adjusted neurostimulation settings; 80.3% of study participants also reported functional improvements, including improved comfort during position changes. The AdaptiveStim system was also approved for use in MRI head scans if recommended by a physician.
Brain overgrowth in boys with autism involves an abnormal excess number of neurons, according to the results of a small preliminary study published in the November 9 JAMA. “Autism often involves early brain overgrowth, including the prefrontal cortex,” the investigators stated. “Although prefrontal abnormality has been theorized to underlie some autistic symptoms, the cellular defects that cause abnormal overgrowth remain unknown.” To investigate whether this overgrowth in children with autism involves excess neuron numbers, the researchers compared postmortem tissue from the prefrontal cortex of seven boys (age range, 2 to 16) who had autism with postmortem tissue of six typically developing boys. They found that children with autism had 67% more neurons in the prefrontal cortex. “Brain weight in the autistic case differed from normative mean weight for age by a mean of 17.6%, while brains in controls differed by a mean of 0.2%,” the researchers reported.
A person’s stroke risk profile may also be helpful in predicting whether a person will develop memory problems and cognitive impairment later in life, according to a study published in the November 8 Neurology. “Participants included subjects without stroke at baseline … with at least two cognitive function assessments during the follow-up,” the researchers explained. “During a mean follow-up of 4.1 years, 1,907 participants met criteria for incident cognitive impairment.” The researchers determined that male sex, black race, less education, older age, and presence of left ventricular hypertrophy were related to the development of cognitive impairment. “Total Framingham Stroke Risk Profile score, elevated blood pressure, and left ventricular hypertrophy predict development of clinically significant cognitive dysfunction,” the investigators concluded. “Prevention and treatment of high blood pressure may be effective in preserving cognitive health.”
The FDA has approved Xarelto (rivaroxaban) to reduce the risk of stroke in people who have nonvalvular atrial fibrillation. Xarelto (Janssen Pharmaceuticals Inc; Titusville, New Jersey) is an oral anti-clotting drug that has also been approved to reduce the risk of blood clots, deep vein thrombosis, and pulmonary embolism following knee or hip replacement surgery. The FDA’s approval was based on the results of a clinical trial with more than 14,000 patients that compared Xarelto with the anti-clotting drug warfarin; Xarelto proved similar to warfarin in its ability to prevent stroke. Bleeding was the most common adverse event reported by patients treated with Xarelto in this clinical trial, and the risk of bleeding was similar to the risk of bleeding associated with warfarin.
Patients with dementia who have a stroke have a higher likelihood of becoming disabled and being institutionalized, compared with patients who did not have dementia at the time of their stroke, according to a report in the November 1 Neurology. Investigators conducted a retrospective cohort study that included 9,304 patients with an acute ischemic stroke, 702 of whom had a history of dementia. “Patients with dementia were older (mean age, 81 vs 70), had more severe strokes, and were more likely to have atrial fibrillation than those without dementia,” the investigators determined. They also found that patients with dementia were slightly less likely to be admitted to a stroke unit, had a higher disability at discharge, and were less likely to be discharged to their prestroke place of residence. “In patients with stroke, preexisting dementia is associated with high rates of disability and institutionalization, representing an increasing challenge for the health care system,” the researchers concluded.