Cleveland Clinic Journal of Medicine

A 20-year-old woman presents to the emergency department with postprandial epigastric and right-upper-quadrant pain, sometimes associated with nausea. She has been having six to eight loose bowel movements every day, with no blood or mucus, and she has lost about 20 lb despite a good appetite. The diarrhea did not improve when she tried omitting milk products and carbohydrates.

Her symptoms began several months ago, but she says that 3 days ago the pain worsened steadily, radiating to the middle of her back, with associated episodes of nonbloody, nonbilious emesis. She cannot keep down liquids or solids. She says she has never had such episodes in the past.

She reports no oral ulcers, urinary symptoms, skin rashes, musculoskeletal pain, or neurologic symptoms, and she denies being anxious or depressed.

She has no history of serious illness, surgery, or hospitalization. She smokes a half pack of cigarettes a day, drinks alcohol occasionally, and smokes marijuana occasionally. She is employed as a certified nursing assistant.

She is taking ethinyl estradiol-levonorgestrel pills for birth control and takes calcium carbonate as needed for abdominal discomfort. She is taking no other medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).

Her maternal uncle died of colon cancer at age 32, and her mother had colon polyps on colonoscopy. There is no family history of inflammatory bowel disease or celiac sprue. Her father committed suicide.

Her laboratory values

• White blood cell count 10.2 × 10⁹/L (normal range 4–11)
• Red blood cell count 4.71 × 10¹²/L (3.9–5.5)
• Hemoglobin 14.4 g/dL (12–16)
• Hematocrit 42.4% (37%–47%)
• Mean corpuscular volume 90 fL (83–99)
• Mean corpuscular hemoglobin 30.6 pg (27–33)
• Platelet count 230 × 10⁹/L (150–400)
• Red cell distribution width 13.3% (11.5%–14.5%)
• Sodium 140 mmol/L (132–148)
• Potassium 3.3 mmol/L (3.5–5.0)
• Chloride 104 mmol/L (98–111)
• Bicarbonate 28 mmol/L (23–32)
• Blood urea nitrogen 9 mg/dL (8–25)
• Creatinine 0.8 mg/dL (0.7–1.4)
• Glucose 87 mg/dL (65–100)
• Alanine aminotransferase 26 U/L (0–45)
• Aspartate aminotransferase 21 U/L (7–40)
• Alkaline phosphatase 101 U/L (40–150)
• Total bilirubin 0.8 mg/dL (0–1.5)
• Albumin 3.5 g/dL (3.5–5)
• Pregnancy screen negative
• Urine toxicology screen negative.

Physical examination

The patient is very thin and appears quite uncomfortable. Her temperature is 99.7°F (37.6°C), pulse rate 101, respiratory rate 18, blood pressure 111/67 mm Hg, and oxygen saturation 96% on room air. Her skin is warm and dry. Her height is 66 inches, weight 116 lb, and body mass index 18.7.

Examination of the head and neck shows normal dentition, dry mucus membranes, and no oral exudates. The thyroid is normal, and no masses or lymphadenopathy are noted.

Heart sounds and rhythm are normal, and the lungs are clear with no crackles or rubs. The abdomen is scaphoid and soft, with no distention. She has epigastric tenderness but no rebound, guarding, rigidity, palpable mass, or costovertebral angle tenderness. Bowel sounds are normal. The neurologic examination is normal.

NARROWING THE DIAGNOSIS

1. Given the history and findings so far, which is the least likely cause of her symptoms?

• Lactose intolerance
• Celiac disease
• Crohn disease
• Duodenal ulcer
• Eating disorder

This young woman’s presentation has some features found in all of these conditions. However, the least likely is lactose intolerance.

Lactose intolerance results from a shortage of the enzyme lactase, which is normally produced by the cells that line the small intestine. Close to 50 million American adults have lactose intolerance. Common symptoms include nausea, cramps, bloating, gas, and diarrhea, which begin about 30 minutes to 2 hours after eating or drinking foods containing lactose.

Since the patient’s symptoms did not improve when she tried omitting milk products, and since lactose intolerance is rarely associated with pain radiating to the back and with severe vomiting, this is the least likely cause of her symptoms.

Celiac disease presents with a myriad of symptoms—sometimes without gastrointestinal (GI) symptoms. Anemia is the most common laboratory finding, due most often to iron deficiency, but also due to deficiencies of vitamin B₁₂ and folate as a result of malabsorption.¹

Our patient’s laboratory values—especially her red cell indices—do not confirm this finding. One must also remember, however, that hemoglobin tends to be falsely elevated in patients who are dehydrated.

Crohn disease often presents with occult blood loss, low-grade fever, weight loss, and anemia. Though the condition is most often ileocolic, it can affect any part of the gastrointestinal tract. Nevertheless, most patients with gastroduodenal involvement have previously been diagnosed with ileocolic disease, and gastroduodenal involvement manifests later. Nonradiating epigastric pain is very common. Obstructive symptoms due to gastroduodenal strictures (eg, postprandial vomiting, epigastric pain, weight loss, bloating) are also common. ²

Duodenal ulcer. The most important factors responsible for duodenal ulcers are NSAID use and Helicobacter pylori infection.³ Duodenal ulcers have a variety of clinical presentations, ranging from no symptoms to severe pain. Epigastric pain can be sharp, dull, burning, or penetrating. Many patients complain of a feeling of hunger and weight gain—as opposed to gastric ulcer, in which patients experience anorexia and weight loss. Abdominal pain generally occurs several hours after meals and often awakens the patient at night. Pain is often relieved by food, but this phenomenon is present in only 20% to 60% of patients and probably is not specific for duodenal ulcer.

Our patient does not use NSAIDs, but some of her symptoms, such as postprandial pain, epigastric pain radiating to the back, and nausea and vomiting are seen with duodenal ulcer.

Eating disorders. The two main types of eating disorders—anorexia nervosa and bulimia nervosa—have a significant diagnostic overlap,⁴ and a third type, binge-eating disorder, is currently being investigated and defined. Girls and women are 10 times as likely as boys and men to develop an eating disorder.

People with anorexia have a distorted view of their bodies. Even when they are extremely thin, they see themselves as too fat.

Bulimia is characterized by binge-eating, purging, and overexercising to compensate for the excess calories. Patients are often close to normal weight.

Binge-eating disorder involves the consumption of very large amounts of food in a short period of time. About 2% of all young adults in the United States struggle with bingeeating. They are either overweight or obese.

These disorders tend to be associated with other psychiatric disorders such as depression or obsessive-compulsive disorder. Our patient sought medical attention and was appropriately concerned about her weight loss, which make an eating disorder unlikely.

CASE CONTINUED: SHE UNDERGOES CT

2. Which of the following is the most likely diagnosis at this point?

• SMA syndrome
• Chronic mesenteric ischemia involving the SMA
• Megaduodenum due to a connective tissue disorder

SMA syndrome is the most likely diagnosis. Despite its name, this syndrome is not a vascular condition. It is an uncommon cause of proximal intestinal obstruction in which the duodenum is compressed between the SMA and the aorta. First described in 1861, it has also been known as cast syndrome, Wilkie syndrome, and arteriomesenteric duodenal obstruction.⁵

To date, more than 400 cases of this syndrome have been reported, twice as many in women as in men. Most patients are between 20 and 40 years of age at the time of diagnosis. Common presenting symptoms include postprandial abdominal pain, nausea, vomiting, and weight loss, which may further reduce the angle between the SMA and the aorta. Diarrhea is not generally associated with this syndrome, and in our patient’s case the diarrhea was thought to be unrelated to the SMA syndrome, since it subsided spontaneously.

Conditions and events that cause, contribute to, or worsen SMA syndrome include:

• Rapid weight loss (as in cancer or burns) or lean body habitus
• Prolonged bed rest
• Use of a body cast
• Malabsorption
• Spinal disease, deformity, or trauma
• Scoliosis surgery
• Rapid linear growth without compensatory weight gain
• Abnormally high and fixed position of the ligament of Treitz
• Abdominal surgery
• Cardiac cachexia
• Unusually low origin of the SMA.⁷

More common causes of mechanical smallbowel obstruction are adhesions, hernias, and tumors.⁸ Hyperactive, high-pitched peristalsis with rushes coinciding with cramps is typical. Abdominal cramps are centered around the umbilicus or in the epigastrium and are associated with vomiting; obstipation develops in patients with complete obstruction. Patients with partial obstruction may develop diarrhea. Paralytic ileus secondary to hypokalemia is an important consideration in partial obstruction. However, abdominal radiography and CT did not confirm an obstruction, and her symptoms persisted despite correction of the potassium level.

Chronic mesenteric ischemia can be caused by vasculitis, nonocclusive conditions that cause prolonged vasoconstriction (eg, cocaine ingestion), or reduced cardiac output.⁹ Symptoms are due to the gradual reduction in blood flow to the intestine that occurs during eating. Our patient’s toxicology report did not suggest cocaine abuse, and her history and the workup thus far do not suggest heart failure. A workup for vasculitis was negative.

Megaduodenum, SMA-like syndrome. In rare cases, dilation of the duodenum at the level of the SMA may be part of a generalized duodenal dilation caused by something other than obstruction due to mechanical compression. There are conditions, as described below, that cause an SMA-like syndrome.

A compression defect of the duodenum at the site where the SMA crossed the duodenum was found in a series of 11 cases of systemic sclerosis.¹⁰ These patients had definite dilation of the duodenum, but it was a result of atrophy of the muscle layers and replacement by collagenous tissue, changes that result in diminished peristalsis, loss of muscle tone, and dilation. The duodenum yields to pressure in its third portion under the SMA.

Several pathologic conditions, particularly connective tissue disorders, may predispose to the development of a megaduodenum that may result in an imprint on the duodenum at the level of the SMA. The most noteworthy of these conditions is scleroderma. Other conditions that can cause reduced duodenal peristalsis include diabetes, pancreatitis, dermatomyositis, lupus erythematosus, myxedema, and amyloidosis.¹¹

It is important to distinguish SMA syndrome from SMA-like syndromes for several reasons.¹² SMA-like syndromes result in loss of normal peristalsis. Further, the conditions have different outcomes, even though they are managed similarly initially, ie, with rehydration and parenteral nutrition. Surgery is to be avoided if possible in conditions that affect widespread areas of the intestine, such as scleroderma or diabetic neuropathy.

3. Which of the following is helpful in confirming SMA syndrome?

• CT of the abdomen
• Upper GI radiography series
• Upper GI endoscopy

All three can help confirm the diagnosis.

CT of the abdomen is a convenient, safe, rapid, readily available, and relatively noninvasive way to evaluate the aortomesenteric angle and to view retroperitoneal and mesenteric fat.¹³ Rehydration before injecting intravenous dye is important to avoid precipitating renal failure. In this patient, CT findings that helped make the diagnosis included a narrow aortomesenteric angle, compression of the duodenum, and a paucity of fat around the SMA.

An upper GI series can reveal dilation of the first and second portions of the duodenum and abrupt compression of the duodenal mucosal folds. Other findings can include a delay of 4 to 6 hours in gastroduodenal transit and relief of the obstruction when the patient is in the left lateral decubitus position. The Hayes maneuver refers to the disappearance of these radiologic features in the knee-chest position on cinefluoroscopy.¹⁴ The findings mentioned above are best noted in the supine position on both radiography and CT.

Endoscopy is necessary to rule out mechanical causes of duodenal obstruction. A pulsatile extrinsic compression suggests this condition but is found only occasionally.

Other imaging studies, such as ultrasonography, arteriography, and hypotonic duodenography, are used less often.

4. At this time, which of the following would be the most appropriate initial treatment in this patient?

• Conservative treatment
• Narcotics
• Duodenojejunostomy

Conservative treatment is indicated initially in all cases of SMA syndrome.¹⁵ This involves reversing precipitating factors and replacing fluid, electrolytes, and nutrition via total parenteral nutrition and nasogastric decompression.

To avoid keeping the patient on intravenous therapy for a prolonged time, it is important to start enteral feeding once the pain has subsided and the patient can tolerate it. A double-lumen nasojejunal tube is passed distal to the obstruction under fluoroscopic guidance. During feedings, the patient should be in the modified knee-chest, prone, or leftside-down position, all of which increase the aortomesenteric angle.

Delaying the treatment of SMA syndrome can increase the risk of morbidity and mortality by progressive malnutrition, dehydration, oliguria, electrolyte abnormalities (eg, hypokalemia), or intestinal perforation from prolonged ischemia.^16,17

Narcotics and other drugs known to slow gut motility should be avoided.

Symptoms typically improve after restoration of normal body weight. If conservative treatment fails, or if the case is severe or chronic, surgery is required.¹⁸ Fortunately, this is not required often.

Duodenojejunostomy is the most common surgical treatment and involves creation of an alternate route between the duodenum and the jejunum, bypassing the compression between the aorta and the SMA. Other procedures include gastrojejunostomy, laparoscopic duodenojejunostomy, ¹⁹ a Roux-en-Y procedure, robotically assisted duodenojejunostomy, and anterior transposition of the third portion of the duodenum. Cleavage of the ligament of Treitz is another option, enabling the duodenum to drop away from the apex of the sharpened aortomesenteric angle.

WHEN TO CONSIDER SMA SYNDROME

The SMA syndrome is an uncommon cause of a very common presenting symptom, ie, abdominal pain. Nevertheless, it should be considered in the differential diagnosis of abdominal pain, especially in patients who have conditions that cause significant weight loss, such as anorexia nervosa, malabsorption, or hypercatabolic states such as burns, major surgery, severe injuries, or malignancies. The diagnosis is based on a thorough history and on supportive findings from CT and endoscopy.

In our patient, weight loss began with nonspecific diarrhea but perpetuated itself as SMA syndrome occurred.

Appropriate management consists of interrupting the cycle of weight loss and secondary upper gut obstruction. For patients in whom more definitive therapy is not feasible, a gastrostomy tube for decompression with a jejunal extension available for feeding appears to be a reasonable and safe treatment option. Duodenojejunostomy is considered the procedure of choice in severe cases.

CASE CONCLUDED

Fortunately, our patient responded well to conservative management. She was treated with intravenous hydration and correction of electrolytes and 10 days later was able to tolerate a soft diet. She was discharged in stable condition. At a follow-up visit 2 weeks later, she reported minimal abdominal discomfort, was able to tolerate meals, and had gained a few pounds. She continues to do well.

A 20-year-old woman presents to the emergency department with postprandial epigastric and right-upper-quadrant pain, sometimes associated with nausea. She has been having six to eight loose bowel movements every day, with no blood or mucus, and she has lost about 20 lb despite a good appetite. The diarrhea did not improve when she tried omitting milk products and carbohydrates.

Her symptoms began several months ago, but she says that 3 days ago the pain worsened steadily, radiating to the middle of her back, with associated episodes of nonbloody, nonbilious emesis. She cannot keep down liquids or solids. She says she has never had such episodes in the past.

She reports no oral ulcers, urinary symptoms, skin rashes, musculoskeletal pain, or neurologic symptoms, and she denies being anxious or depressed.

She has no history of serious illness, surgery, or hospitalization. She smokes a half pack of cigarettes a day, drinks alcohol occasionally, and smokes marijuana occasionally. She is employed as a certified nursing assistant.

She is taking ethinyl estradiol-levonorgestrel pills for birth control and takes calcium carbonate as needed for abdominal discomfort. She is taking no other medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).

Her maternal uncle died of colon cancer at age 32, and her mother had colon polyps on colonoscopy. There is no family history of inflammatory bowel disease or celiac sprue. Her father committed suicide.

Her laboratory values

• White blood cell count 10.2 × 10⁹/L (normal range 4–11)
• Red blood cell count 4.71 × 10¹²/L (3.9–5.5)
• Hemoglobin 14.4 g/dL (12–16)
• Hematocrit 42.4% (37%–47%)
• Mean corpuscular volume 90 fL (83–99)
• Mean corpuscular hemoglobin 30.6 pg (27–33)
• Platelet count 230 × 10⁹/L (150–400)
• Red cell distribution width 13.3% (11.5%–14.5%)
• Sodium 140 mmol/L (132–148)
• Potassium 3.3 mmol/L (3.5–5.0)
• Chloride 104 mmol/L (98–111)
• Bicarbonate 28 mmol/L (23–32)
• Blood urea nitrogen 9 mg/dL (8–25)
• Creatinine 0.8 mg/dL (0.7–1.4)
• Glucose 87 mg/dL (65–100)
• Alanine aminotransferase 26 U/L (0–45)
• Aspartate aminotransferase 21 U/L (7–40)
• Alkaline phosphatase 101 U/L (40–150)
• Total bilirubin 0.8 mg/dL (0–1.5)
• Albumin 3.5 g/dL (3.5–5)
• Pregnancy screen negative
• Urine toxicology screen negative.

Physical examination

The patient is very thin and appears quite uncomfortable. Her temperature is 99.7°F (37.6°C), pulse rate 101, respiratory rate 18, blood pressure 111/67 mm Hg, and oxygen saturation 96% on room air. Her skin is warm and dry. Her height is 66 inches, weight 116 lb, and body mass index 18.7.

Examination of the head and neck shows normal dentition, dry mucus membranes, and no oral exudates. The thyroid is normal, and no masses or lymphadenopathy are noted.

Heart sounds and rhythm are normal, and the lungs are clear with no crackles or rubs. The abdomen is scaphoid and soft, with no distention. She has epigastric tenderness but no rebound, guarding, rigidity, palpable mass, or costovertebral angle tenderness. Bowel sounds are normal. The neurologic examination is normal.

NARROWING THE DIAGNOSIS

1. Given the history and findings so far, which is the least likely cause of her symptoms?

• Lactose intolerance
• Celiac disease
• Crohn disease
• Duodenal ulcer
• Eating disorder

This young woman’s presentation has some features found in all of these conditions. However, the least likely is lactose intolerance.

Lactose intolerance results from a shortage of the enzyme lactase, which is normally produced by the cells that line the small intestine. Close to 50 million American adults have lactose intolerance. Common symptoms include nausea, cramps, bloating, gas, and diarrhea, which begin about 30 minutes to 2 hours after eating or drinking foods containing lactose.

Since the patient’s symptoms did not improve when she tried omitting milk products, and since lactose intolerance is rarely associated with pain radiating to the back and with severe vomiting, this is the least likely cause of her symptoms.

Celiac disease presents with a myriad of symptoms—sometimes without gastrointestinal (GI) symptoms. Anemia is the most common laboratory finding, due most often to iron deficiency, but also due to deficiencies of vitamin B₁₂ and folate as a result of malabsorption.¹

Our patient’s laboratory values—especially her red cell indices—do not confirm this finding. One must also remember, however, that hemoglobin tends to be falsely elevated in patients who are dehydrated.

Crohn disease often presents with occult blood loss, low-grade fever, weight loss, and anemia. Though the condition is most often ileocolic, it can affect any part of the gastrointestinal tract. Nevertheless, most patients with gastroduodenal involvement have previously been diagnosed with ileocolic disease, and gastroduodenal involvement manifests later. Nonradiating epigastric pain is very common. Obstructive symptoms due to gastroduodenal strictures (eg, postprandial vomiting, epigastric pain, weight loss, bloating) are also common. ²

Duodenal ulcer. The most important factors responsible for duodenal ulcers are NSAID use and Helicobacter pylori infection.³ Duodenal ulcers have a variety of clinical presentations, ranging from no symptoms to severe pain. Epigastric pain can be sharp, dull, burning, or penetrating. Many patients complain of a feeling of hunger and weight gain—as opposed to gastric ulcer, in which patients experience anorexia and weight loss. Abdominal pain generally occurs several hours after meals and often awakens the patient at night. Pain is often relieved by food, but this phenomenon is present in only 20% to 60% of patients and probably is not specific for duodenal ulcer.

Our patient does not use NSAIDs, but some of her symptoms, such as postprandial pain, epigastric pain radiating to the back, and nausea and vomiting are seen with duodenal ulcer.

Eating disorders. The two main types of eating disorders—anorexia nervosa and bulimia nervosa—have a significant diagnostic overlap,⁴ and a third type, binge-eating disorder, is currently being investigated and defined. Girls and women are 10 times as likely as boys and men to develop an eating disorder.

People with anorexia have a distorted view of their bodies. Even when they are extremely thin, they see themselves as too fat.

Bulimia is characterized by binge-eating, purging, and overexercising to compensate for the excess calories. Patients are often close to normal weight.

Binge-eating disorder involves the consumption of very large amounts of food in a short period of time. About 2% of all young adults in the United States struggle with bingeeating. They are either overweight or obese.

These disorders tend to be associated with other psychiatric disorders such as depression or obsessive-compulsive disorder. Our patient sought medical attention and was appropriately concerned about her weight loss, which make an eating disorder unlikely.

CASE CONTINUED: SHE UNDERGOES CT

2. Which of the following is the most likely diagnosis at this point?

• SMA syndrome
• Chronic mesenteric ischemia involving the SMA
• Megaduodenum due to a connective tissue disorder

SMA syndrome is the most likely diagnosis. Despite its name, this syndrome is not a vascular condition. It is an uncommon cause of proximal intestinal obstruction in which the duodenum is compressed between the SMA and the aorta. First described in 1861, it has also been known as cast syndrome, Wilkie syndrome, and arteriomesenteric duodenal obstruction.⁵

To date, more than 400 cases of this syndrome have been reported, twice as many in women as in men. Most patients are between 20 and 40 years of age at the time of diagnosis. Common presenting symptoms include postprandial abdominal pain, nausea, vomiting, and weight loss, which may further reduce the angle between the SMA and the aorta. Diarrhea is not generally associated with this syndrome, and in our patient’s case the diarrhea was thought to be unrelated to the SMA syndrome, since it subsided spontaneously.

Conditions and events that cause, contribute to, or worsen SMA syndrome include:

• Rapid weight loss (as in cancer or burns) or lean body habitus
• Prolonged bed rest
• Use of a body cast
• Malabsorption
• Spinal disease, deformity, or trauma
• Scoliosis surgery
• Rapid linear growth without compensatory weight gain
• Abnormally high and fixed position of the ligament of Treitz
• Abdominal surgery
• Cardiac cachexia
• Unusually low origin of the SMA.⁷

More common causes of mechanical smallbowel obstruction are adhesions, hernias, and tumors.⁸ Hyperactive, high-pitched peristalsis with rushes coinciding with cramps is typical. Abdominal cramps are centered around the umbilicus or in the epigastrium and are associated with vomiting; obstipation develops in patients with complete obstruction. Patients with partial obstruction may develop diarrhea. Paralytic ileus secondary to hypokalemia is an important consideration in partial obstruction. However, abdominal radiography and CT did not confirm an obstruction, and her symptoms persisted despite correction of the potassium level.

Chronic mesenteric ischemia can be caused by vasculitis, nonocclusive conditions that cause prolonged vasoconstriction (eg, cocaine ingestion), or reduced cardiac output.⁹ Symptoms are due to the gradual reduction in blood flow to the intestine that occurs during eating. Our patient’s toxicology report did not suggest cocaine abuse, and her history and the workup thus far do not suggest heart failure. A workup for vasculitis was negative.

Megaduodenum, SMA-like syndrome. In rare cases, dilation of the duodenum at the level of the SMA may be part of a generalized duodenal dilation caused by something other than obstruction due to mechanical compression. There are conditions, as described below, that cause an SMA-like syndrome.

A compression defect of the duodenum at the site where the SMA crossed the duodenum was found in a series of 11 cases of systemic sclerosis.¹⁰ These patients had definite dilation of the duodenum, but it was a result of atrophy of the muscle layers and replacement by collagenous tissue, changes that result in diminished peristalsis, loss of muscle tone, and dilation. The duodenum yields to pressure in its third portion under the SMA.

Several pathologic conditions, particularly connective tissue disorders, may predispose to the development of a megaduodenum that may result in an imprint on the duodenum at the level of the SMA. The most noteworthy of these conditions is scleroderma. Other conditions that can cause reduced duodenal peristalsis include diabetes, pancreatitis, dermatomyositis, lupus erythematosus, myxedema, and amyloidosis.¹¹

It is important to distinguish SMA syndrome from SMA-like syndromes for several reasons.¹² SMA-like syndromes result in loss of normal peristalsis. Further, the conditions have different outcomes, even though they are managed similarly initially, ie, with rehydration and parenteral nutrition. Surgery is to be avoided if possible in conditions that affect widespread areas of the intestine, such as scleroderma or diabetic neuropathy.

3. Which of the following is helpful in confirming SMA syndrome?

• CT of the abdomen
• Upper GI radiography series
• Upper GI endoscopy

All three can help confirm the diagnosis.

CT of the abdomen is a convenient, safe, rapid, readily available, and relatively noninvasive way to evaluate the aortomesenteric angle and to view retroperitoneal and mesenteric fat.¹³ Rehydration before injecting intravenous dye is important to avoid precipitating renal failure. In this patient, CT findings that helped make the diagnosis included a narrow aortomesenteric angle, compression of the duodenum, and a paucity of fat around the SMA.

An upper GI series can reveal dilation of the first and second portions of the duodenum and abrupt compression of the duodenal mucosal folds. Other findings can include a delay of 4 to 6 hours in gastroduodenal transit and relief of the obstruction when the patient is in the left lateral decubitus position. The Hayes maneuver refers to the disappearance of these radiologic features in the knee-chest position on cinefluoroscopy.¹⁴ The findings mentioned above are best noted in the supine position on both radiography and CT.

Endoscopy is necessary to rule out mechanical causes of duodenal obstruction. A pulsatile extrinsic compression suggests this condition but is found only occasionally.

Other imaging studies, such as ultrasonography, arteriography, and hypotonic duodenography, are used less often.

4. At this time, which of the following would be the most appropriate initial treatment in this patient?

• Conservative treatment
• Narcotics
• Duodenojejunostomy

Conservative treatment is indicated initially in all cases of SMA syndrome.¹⁵ This involves reversing precipitating factors and replacing fluid, electrolytes, and nutrition via total parenteral nutrition and nasogastric decompression.

To avoid keeping the patient on intravenous therapy for a prolonged time, it is important to start enteral feeding once the pain has subsided and the patient can tolerate it. A double-lumen nasojejunal tube is passed distal to the obstruction under fluoroscopic guidance. During feedings, the patient should be in the modified knee-chest, prone, or leftside-down position, all of which increase the aortomesenteric angle.

Delaying the treatment of SMA syndrome can increase the risk of morbidity and mortality by progressive malnutrition, dehydration, oliguria, electrolyte abnormalities (eg, hypokalemia), or intestinal perforation from prolonged ischemia.^16,17

Narcotics and other drugs known to slow gut motility should be avoided.

Symptoms typically improve after restoration of normal body weight. If conservative treatment fails, or if the case is severe or chronic, surgery is required.¹⁸ Fortunately, this is not required often.

Duodenojejunostomy is the most common surgical treatment and involves creation of an alternate route between the duodenum and the jejunum, bypassing the compression between the aorta and the SMA. Other procedures include gastrojejunostomy, laparoscopic duodenojejunostomy, ¹⁹ a Roux-en-Y procedure, robotically assisted duodenojejunostomy, and anterior transposition of the third portion of the duodenum. Cleavage of the ligament of Treitz is another option, enabling the duodenum to drop away from the apex of the sharpened aortomesenteric angle.

WHEN TO CONSIDER SMA SYNDROME

The SMA syndrome is an uncommon cause of a very common presenting symptom, ie, abdominal pain. Nevertheless, it should be considered in the differential diagnosis of abdominal pain, especially in patients who have conditions that cause significant weight loss, such as anorexia nervosa, malabsorption, or hypercatabolic states such as burns, major surgery, severe injuries, or malignancies. The diagnosis is based on a thorough history and on supportive findings from CT and endoscopy.

In our patient, weight loss began with nonspecific diarrhea but perpetuated itself as SMA syndrome occurred.

Appropriate management consists of interrupting the cycle of weight loss and secondary upper gut obstruction. For patients in whom more definitive therapy is not feasible, a gastrostomy tube for decompression with a jejunal extension available for feeding appears to be a reasonable and safe treatment option. Duodenojejunostomy is considered the procedure of choice in severe cases.

CASE CONCLUDED

Fortunately, our patient responded well to conservative management. She was treated with intravenous hydration and correction of electrolytes and 10 days later was able to tolerate a soft diet. She was discharged in stable condition. At a follow-up visit 2 weeks later, she reported minimal abdominal discomfort, was able to tolerate meals, and had gained a few pounds. She continues to do well.

A 20-year-old woman presents to the emergency department with postprandial epigastric and right-upper-quadrant pain, sometimes associated with nausea. She has been having six to eight loose bowel movements every day, with no blood or mucus, and she has lost about 20 lb despite a good appetite. The diarrhea did not improve when she tried omitting milk products and carbohydrates.

Her symptoms began several months ago, but she says that 3 days ago the pain worsened steadily, radiating to the middle of her back, with associated episodes of nonbloody, nonbilious emesis. She cannot keep down liquids or solids. She says she has never had such episodes in the past.

She reports no oral ulcers, urinary symptoms, skin rashes, musculoskeletal pain, or neurologic symptoms, and she denies being anxious or depressed.

She has no history of serious illness, surgery, or hospitalization. She smokes a half pack of cigarettes a day, drinks alcohol occasionally, and smokes marijuana occasionally. She is employed as a certified nursing assistant.

She is taking ethinyl estradiol-levonorgestrel pills for birth control and takes calcium carbonate as needed for abdominal discomfort. She is taking no other medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).

Her maternal uncle died of colon cancer at age 32, and her mother had colon polyps on colonoscopy. There is no family history of inflammatory bowel disease or celiac sprue. Her father committed suicide.

Her laboratory values

• White blood cell count 10.2 × 10⁹/L (normal range 4–11)
• Red blood cell count 4.71 × 10¹²/L (3.9–5.5)
• Hemoglobin 14.4 g/dL (12–16)
• Hematocrit 42.4% (37%–47%)
• Mean corpuscular volume 90 fL (83–99)
• Mean corpuscular hemoglobin 30.6 pg (27–33)
• Platelet count 230 × 10⁹/L (150–400)
• Red cell distribution width 13.3% (11.5%–14.5%)
• Sodium 140 mmol/L (132–148)
• Potassium 3.3 mmol/L (3.5–5.0)
• Chloride 104 mmol/L (98–111)
• Bicarbonate 28 mmol/L (23–32)
• Blood urea nitrogen 9 mg/dL (8–25)
• Creatinine 0.8 mg/dL (0.7–1.4)
• Glucose 87 mg/dL (65–100)
• Alanine aminotransferase 26 U/L (0–45)
• Aspartate aminotransferase 21 U/L (7–40)
• Alkaline phosphatase 101 U/L (40–150)
• Total bilirubin 0.8 mg/dL (0–1.5)
• Albumin 3.5 g/dL (3.5–5)
• Pregnancy screen negative
• Urine toxicology screen negative.

Physical examination

The patient is very thin and appears quite uncomfortable. Her temperature is 99.7°F (37.6°C), pulse rate 101, respiratory rate 18, blood pressure 111/67 mm Hg, and oxygen saturation 96% on room air. Her skin is warm and dry. Her height is 66 inches, weight 116 lb, and body mass index 18.7.

Examination of the head and neck shows normal dentition, dry mucus membranes, and no oral exudates. The thyroid is normal, and no masses or lymphadenopathy are noted.

Heart sounds and rhythm are normal, and the lungs are clear with no crackles or rubs. The abdomen is scaphoid and soft, with no distention. She has epigastric tenderness but no rebound, guarding, rigidity, palpable mass, or costovertebral angle tenderness. Bowel sounds are normal. The neurologic examination is normal.

NARROWING THE DIAGNOSIS

1. Given the history and findings so far, which is the least likely cause of her symptoms?

• Lactose intolerance
• Celiac disease
• Crohn disease
• Duodenal ulcer
• Eating disorder

This young woman’s presentation has some features found in all of these conditions. However, the least likely is lactose intolerance.

Lactose intolerance results from a shortage of the enzyme lactase, which is normally produced by the cells that line the small intestine. Close to 50 million American adults have lactose intolerance. Common symptoms include nausea, cramps, bloating, gas, and diarrhea, which begin about 30 minutes to 2 hours after eating or drinking foods containing lactose.

Since the patient’s symptoms did not improve when she tried omitting milk products, and since lactose intolerance is rarely associated with pain radiating to the back and with severe vomiting, this is the least likely cause of her symptoms.

Celiac disease presents with a myriad of symptoms—sometimes without gastrointestinal (GI) symptoms. Anemia is the most common laboratory finding, due most often to iron deficiency, but also due to deficiencies of vitamin B₁₂ and folate as a result of malabsorption.¹

Our patient’s laboratory values—especially her red cell indices—do not confirm this finding. One must also remember, however, that hemoglobin tends to be falsely elevated in patients who are dehydrated.

Crohn disease often presents with occult blood loss, low-grade fever, weight loss, and anemia. Though the condition is most often ileocolic, it can affect any part of the gastrointestinal tract. Nevertheless, most patients with gastroduodenal involvement have previously been diagnosed with ileocolic disease, and gastroduodenal involvement manifests later. Nonradiating epigastric pain is very common. Obstructive symptoms due to gastroduodenal strictures (eg, postprandial vomiting, epigastric pain, weight loss, bloating) are also common. ²

Duodenal ulcer. The most important factors responsible for duodenal ulcers are NSAID use and Helicobacter pylori infection.³ Duodenal ulcers have a variety of clinical presentations, ranging from no symptoms to severe pain. Epigastric pain can be sharp, dull, burning, or penetrating. Many patients complain of a feeling of hunger and weight gain—as opposed to gastric ulcer, in which patients experience anorexia and weight loss. Abdominal pain generally occurs several hours after meals and often awakens the patient at night. Pain is often relieved by food, but this phenomenon is present in only 20% to 60% of patients and probably is not specific for duodenal ulcer.

Our patient does not use NSAIDs, but some of her symptoms, such as postprandial pain, epigastric pain radiating to the back, and nausea and vomiting are seen with duodenal ulcer.

Eating disorders. The two main types of eating disorders—anorexia nervosa and bulimia nervosa—have a significant diagnostic overlap,⁴ and a third type, binge-eating disorder, is currently being investigated and defined. Girls and women are 10 times as likely as boys and men to develop an eating disorder.

People with anorexia have a distorted view of their bodies. Even when they are extremely thin, they see themselves as too fat.

Bulimia is characterized by binge-eating, purging, and overexercising to compensate for the excess calories. Patients are often close to normal weight.

Binge-eating disorder involves the consumption of very large amounts of food in a short period of time. About 2% of all young adults in the United States struggle with bingeeating. They are either overweight or obese.

These disorders tend to be associated with other psychiatric disorders such as depression or obsessive-compulsive disorder. Our patient sought medical attention and was appropriately concerned about her weight loss, which make an eating disorder unlikely.

CASE CONTINUED: SHE UNDERGOES CT

2. Which of the following is the most likely diagnosis at this point?

• SMA syndrome
• Chronic mesenteric ischemia involving the SMA
• Megaduodenum due to a connective tissue disorder

SMA syndrome is the most likely diagnosis. Despite its name, this syndrome is not a vascular condition. It is an uncommon cause of proximal intestinal obstruction in which the duodenum is compressed between the SMA and the aorta. First described in 1861, it has also been known as cast syndrome, Wilkie syndrome, and arteriomesenteric duodenal obstruction.⁵

To date, more than 400 cases of this syndrome have been reported, twice as many in women as in men. Most patients are between 20 and 40 years of age at the time of diagnosis. Common presenting symptoms include postprandial abdominal pain, nausea, vomiting, and weight loss, which may further reduce the angle between the SMA and the aorta. Diarrhea is not generally associated with this syndrome, and in our patient’s case the diarrhea was thought to be unrelated to the SMA syndrome, since it subsided spontaneously.

Conditions and events that cause, contribute to, or worsen SMA syndrome include:

• Rapid weight loss (as in cancer or burns) or lean body habitus
• Prolonged bed rest
• Use of a body cast
• Malabsorption
• Spinal disease, deformity, or trauma
• Scoliosis surgery
• Rapid linear growth without compensatory weight gain
• Abnormally high and fixed position of the ligament of Treitz
• Abdominal surgery
• Cardiac cachexia
• Unusually low origin of the SMA.⁷

More common causes of mechanical smallbowel obstruction are adhesions, hernias, and tumors.⁸ Hyperactive, high-pitched peristalsis with rushes coinciding with cramps is typical. Abdominal cramps are centered around the umbilicus or in the epigastrium and are associated with vomiting; obstipation develops in patients with complete obstruction. Patients with partial obstruction may develop diarrhea. Paralytic ileus secondary to hypokalemia is an important consideration in partial obstruction. However, abdominal radiography and CT did not confirm an obstruction, and her symptoms persisted despite correction of the potassium level.

Chronic mesenteric ischemia can be caused by vasculitis, nonocclusive conditions that cause prolonged vasoconstriction (eg, cocaine ingestion), or reduced cardiac output.⁹ Symptoms are due to the gradual reduction in blood flow to the intestine that occurs during eating. Our patient’s toxicology report did not suggest cocaine abuse, and her history and the workup thus far do not suggest heart failure. A workup for vasculitis was negative.

Megaduodenum, SMA-like syndrome. In rare cases, dilation of the duodenum at the level of the SMA may be part of a generalized duodenal dilation caused by something other than obstruction due to mechanical compression. There are conditions, as described below, that cause an SMA-like syndrome.

A compression defect of the duodenum at the site where the SMA crossed the duodenum was found in a series of 11 cases of systemic sclerosis.¹⁰ These patients had definite dilation of the duodenum, but it was a result of atrophy of the muscle layers and replacement by collagenous tissue, changes that result in diminished peristalsis, loss of muscle tone, and dilation. The duodenum yields to pressure in its third portion under the SMA.

Several pathologic conditions, particularly connective tissue disorders, may predispose to the development of a megaduodenum that may result in an imprint on the duodenum at the level of the SMA. The most noteworthy of these conditions is scleroderma. Other conditions that can cause reduced duodenal peristalsis include diabetes, pancreatitis, dermatomyositis, lupus erythematosus, myxedema, and amyloidosis.¹¹

It is important to distinguish SMA syndrome from SMA-like syndromes for several reasons.¹² SMA-like syndromes result in loss of normal peristalsis. Further, the conditions have different outcomes, even though they are managed similarly initially, ie, with rehydration and parenteral nutrition. Surgery is to be avoided if possible in conditions that affect widespread areas of the intestine, such as scleroderma or diabetic neuropathy.

3. Which of the following is helpful in confirming SMA syndrome?

• CT of the abdomen
• Upper GI radiography series
• Upper GI endoscopy

All three can help confirm the diagnosis.

CT of the abdomen is a convenient, safe, rapid, readily available, and relatively noninvasive way to evaluate the aortomesenteric angle and to view retroperitoneal and mesenteric fat.¹³ Rehydration before injecting intravenous dye is important to avoid precipitating renal failure. In this patient, CT findings that helped make the diagnosis included a narrow aortomesenteric angle, compression of the duodenum, and a paucity of fat around the SMA.

An upper GI series can reveal dilation of the first and second portions of the duodenum and abrupt compression of the duodenal mucosal folds. Other findings can include a delay of 4 to 6 hours in gastroduodenal transit and relief of the obstruction when the patient is in the left lateral decubitus position. The Hayes maneuver refers to the disappearance of these radiologic features in the knee-chest position on cinefluoroscopy.¹⁴ The findings mentioned above are best noted in the supine position on both radiography and CT.

Endoscopy is necessary to rule out mechanical causes of duodenal obstruction. A pulsatile extrinsic compression suggests this condition but is found only occasionally.

Other imaging studies, such as ultrasonography, arteriography, and hypotonic duodenography, are used less often.

4. At this time, which of the following would be the most appropriate initial treatment in this patient?

• Conservative treatment
• Narcotics
• Duodenojejunostomy

Conservative treatment is indicated initially in all cases of SMA syndrome.¹⁵ This involves reversing precipitating factors and replacing fluid, electrolytes, and nutrition via total parenteral nutrition and nasogastric decompression.

To avoid keeping the patient on intravenous therapy for a prolonged time, it is important to start enteral feeding once the pain has subsided and the patient can tolerate it. A double-lumen nasojejunal tube is passed distal to the obstruction under fluoroscopic guidance. During feedings, the patient should be in the modified knee-chest, prone, or leftside-down position, all of which increase the aortomesenteric angle.

Delaying the treatment of SMA syndrome can increase the risk of morbidity and mortality by progressive malnutrition, dehydration, oliguria, electrolyte abnormalities (eg, hypokalemia), or intestinal perforation from prolonged ischemia.^16,17

Narcotics and other drugs known to slow gut motility should be avoided.

Symptoms typically improve after restoration of normal body weight. If conservative treatment fails, or if the case is severe or chronic, surgery is required.¹⁸ Fortunately, this is not required often.

Duodenojejunostomy is the most common surgical treatment and involves creation of an alternate route between the duodenum and the jejunum, bypassing the compression between the aorta and the SMA. Other procedures include gastrojejunostomy, laparoscopic duodenojejunostomy, ¹⁹ a Roux-en-Y procedure, robotically assisted duodenojejunostomy, and anterior transposition of the third portion of the duodenum. Cleavage of the ligament of Treitz is another option, enabling the duodenum to drop away from the apex of the sharpened aortomesenteric angle.

WHEN TO CONSIDER SMA SYNDROME

The SMA syndrome is an uncommon cause of a very common presenting symptom, ie, abdominal pain. Nevertheless, it should be considered in the differential diagnosis of abdominal pain, especially in patients who have conditions that cause significant weight loss, such as anorexia nervosa, malabsorption, or hypercatabolic states such as burns, major surgery, severe injuries, or malignancies. The diagnosis is based on a thorough history and on supportive findings from CT and endoscopy.

In our patient, weight loss began with nonspecific diarrhea but perpetuated itself as SMA syndrome occurred.

Appropriate management consists of interrupting the cycle of weight loss and secondary upper gut obstruction. For patients in whom more definitive therapy is not feasible, a gastrostomy tube for decompression with a jejunal extension available for feeding appears to be a reasonable and safe treatment option. Duodenojejunostomy is considered the procedure of choice in severe cases.

CASE CONCLUDED

Fortunately, our patient responded well to conservative management. She was treated with intravenous hydration and correction of electrolytes and 10 days later was able to tolerate a soft diet. She was discharged in stable condition. At a follow-up visit 2 weeks later, she reported minimal abdominal discomfort, was able to tolerate meals, and had gained a few pounds. She continues to do well.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders of blood cell production in the bone marrow that can transform into acute myeloid leukemia (AML).^1,2 They are diagnosed most often in the elderly.

Primary care physicians and geriatricians tend to be the first to identify the problem, as they recognize that cytopenias are not simply a normal consequence of aging.

MDS are considered to be cancers, akin to chronic leukemia or acute leukemia, with epidemiologic data tracked by national cancer registries and the US Centers for Disease Control and Prevention, under the auspices of the Surveillance, Epidemiology, and End Results (SEER) program.³

In this article, we briefly review the classification of MDS, current epidemiologic data, key diagnostic features, and current management options.

WHEN TO SUSPECT MDS

In many patients, MDS are asymptomatic and appear as an abnormality on a routine complete blood cell count (CBC) or as part of a workup for anemia. Symptoms develop as the bone marrow’s ability to produce normal-functioning blood cells is more and more compromised. The range of symptoms depends on the bone marrow cell type affected.

Patients with MDS typically have some degree of anemia, often detected incidentally on a routine CBC, or they have symptoms stemming from anemia or thrombocytopenia, or have recurrent infections.

Subtypes of MDS have different pathologic and clinical presentations and different prognoses. They are often categorized as lower-risk or higher-risk, depending on the likelihood of transforming to AML. Patients with lower-risk MDS survive a median of 3 to 7 years. Higher-risk types are pathobiologically similar to AML in older adults, and patients either develop AML or die of complications of MDS, on average within 1.5 years.

Several classification schemes and prognostic models guide the selection of the most appropriate therapy.

Older age and comorbidities such as coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease make MDS more difficult to manage and worsen the prognosis.⁴

MOST PATIENTS ARE OLDER

Only since 2001, when MDS became reportable to SEER,^3,5 has the epidemiology of MDS been reported in the United States.

MDS are currently diagnosed in an estimated 3.4 per 100,000 US citizens yearly.

The incidence rate increased from 3.28 per 100,000 per year in 2001 to 3.56 per 100,000 in 2004.⁵ The increase has been attributed to enhanced awareness of the disease and to the aging of the population, with the number of people age 65 or older in the United States expected to double from the year 2000 to 2030. Another factor is that effective therapies are now available, possibly making hematologists and oncologists more likely to pursue the diagnosis.

These numbers translate to 10,000 to 15,000 new cases annually, and given the life expectancy of patients affected by this disease (and the life-extending treatments for it), an estimated 30,000 to 60,000 Americans living with MDS.^6,7

Even though MDS can occur at any age, most patients are older. The median age at diagnosis is 71 years,^3,5,8 and 72% of patients are age 70 or older.³ The prevalence increases with age, to a rate of 36 per 100,000 in those age 80 and older.⁹ However, in areas of East Asia, it occurs at ages almost 2 decades younger than in the rest of the world.⁵

MDS are more common in men than in women and in whites than in blacks. Smoking appears to increase the risk, but alcohol consumption does not.¹⁰

About 10% of cases of MDS are secondary, most often due to radiation treatment or chemotherapy (particularly with alkylating agents and topoisomerase inhibitors) for cancer. The time from treatment of a primary malignancy (most often prostate, breast, bladder, lung, or non-Hodgkin lymphoma) to the development of MDS is about 5 years.⁵ A small number of cases are due to occupational exposure to radiation or benzene or other organic solvents, as might occur in the rubber industry (see below). Secondary MDS have a worse prognosis than primary (de novo) MDS.

GENETIC AND ENVIRONMENTAL FACTORS

The cause of de novo MDS is not known. Genetic and environmental factors probably both play a role. The lower median age at diagnosis in Eastern countries such as Japan than in the United States suggests that environmental factors¹¹ such as smoking, ionizing radiation, and benzene exposure play a role.^12,13 Some epidemiologic evidence suggests a higher incidence of MDS after exposure to solvents, hair dyes, and pesticides.¹³

Congenital conditions such as Down syndrome, Fanconi anemia, and Bloom syndrome are associated with MDS. Those affected usually present at an earlier age,¹³ suggesting a “multiple-hit” mechanism of cancer development with genetic and environmental factors. MDS rarely run in families.

SYMPTOMS ARE OFTEN NONSPECIFIC

Symptoms of MDS are often vague and nonspecific, and the diagnosis is often made during a workup for anemia, thrombocytopenia, or neutropenia discovered on a CBC. If present, signs and symptoms depend on the blood and bone marrow cell types that are affected.

When erythrocytes are affected (the most common situation), patients present with signs of anemia, including pallor, pale conjunctiva, tachycardia, hypotension, fatigue, headache, and exercise intolerance, or with signs and symptoms of a worsening underlying condition such as angina pectoris, heart failure, or emphysema.

When platelets or neutrophils are affected. Fewer than 20% of patients present with symptoms of isolated thrombocytopenia such as minor bleeding (eg, mucosal bleeding, petechiae, easy bruising, epistaxis) or major bleeding (eg, gastrointestinal bleeding, intracranial hemorrhage) or of isolated neutropenia (eg, fatigue, frequent bacterial infections of different organs systems).

Splenomegaly and lymphadenopathy are uncommon in MDS and, if detected, should raise suspicion of a myeloproliferative or lymphoproliferative neoplasm.

LABORATORY TESTS NEEDED

Complete blood cell count

Once the common causes of patient’s symptoms are evaluated, a CBC is needed to look for a hematologic cause. If a patient is ultimately determined to have MDS, anemia is the most common finding on the CBC: about 80% of patients with MDS are anemic at presentation. ⁶

Anemia associated with MDS can be microcytic, normocytic, or, most commonly, macrocytic. ¹⁴ Thrombocytopenia and neutropenia can be solitary or associated with anemia, and they are seen in about 40% of patients at the time of diagnosis.⁶ As the disease progresses, the degree of cytopenia worsens and, in most cases, preserved cell lineages are eventually affected.

Once cytopenia is discovered, a workup for the cause is needed. We emphasize a workup first for anemia, as it is the most common form of cytopenia in MDS. A workup for isolated thrombocytopenia or neutropenia usually requires a bone marrow examination earlier in the course, and we will discuss it only briefly here. Multilineage cytopenia almost always suggests abnormal bone marrow function and can be the basis for referral to a hematologist or oncologist.

Evaluation of anemia

If anemia is detected, it is reasonable to look for nonhematologic causes such as gastrointestinal bleeding, a cardiac cause, or a nutritional deficiency.

Anemia has a variety of possible hematologic causes, as shown in a study in the United States.¹⁵ When blood samples were collected from more than 2,000 people age 65 and older, 10.6% were found to have anemia, categorized as follows:

• Nutrient-deficiency anemia, related to low levels of vitamin B₁₂, folate, or more commonly iron
• Anemia of chronic inflammation (formerly anemia of chronic disease, associated with a major medical disorder)
• Unexplained anemia (of those with unexplained anemia, 17.4% had blood findings compatible with MDS).¹⁵

• Tests for nutrient deficiencies such as iron, vitamin B₁₂, and folate levels. Subsequent tests can include assessment for copper deficiencies. Vitamin B₁₂ and copper deficiency can mimic MDS.
• Fecal occult blood testing, and, if positive, further evaluation for a source of gastrointestinal bleeding.
• Liver function tests, renal function tests, and tests for endocrine disorders, such as thyroid function tests.
• Review of drugs that can cause megaloblastoid erythropoiesis, such as methotrexate (Trexall), valproic acid (Depakote), phenytoin (Dilantin), phenobarbital (Luminal), sulfasalazine (Sulfazine), and zidovudine (Retrovir).
• Assesment of the responsiveness of the bone marrow to anemia, via a reticulocyte count or an erythropoietin level, or both, prior to any blood transfusion.
• Screening for relevant infections, including human immunodeficiency virus (HIV), hepatitis, or, in rare cases, parvovirus.
• Screening for lifestyle factors that may result in bone marrow suppression, such as excessive alcohol intake.

Evaluation of other cytopenias

In cases of isolated thrombocytopenia or combined bicytopenia (eg, anemia and thrombocytopenia), abdominal ultrasonography should be done to evaluate for splenomegaly.

Blood tests to evaluate for immune-mediated cytopenias, including idiopathic thrombocytopenic purpura and hemolytic anemia, include the direct and indirect Coombs antiglobulin tests, the lactate dehydrogenase level, the reticulocyte count, and the haptoglobin level. Other immune-mediated causes of cytopenia include connective tissue disorders and vasculitides, and an antinuclear antibody titer and rheumatoid factor level can also be considered.

Referral if tests are negative

If all these tests are negative, the next step is referral to a hematologist-oncologist for further workup, which may include a review of the peripheral blood smear; bone marrow aspiration and biopsy for evaluation of iron stores and bone marrow cellularity; and specialized tests such as assessment of antiplatelet antibodies, protein electrophoresis, or fluorescence in situ hybridization to evaluate for specific clonal disorders. The purpose of bone marrow aspiration and biopsy in MDS is to evaluate the morphology of the bone marrow and the patient’s cytogenetic profile. Each has its prognostic and therapeutic implications.

SCORING SYSTEMS FOR MDS, RATHER THAN STAGING SYSTEMS

The purpose of classification systems for any medical condition is to uniformly evaluate and group patients with a disease subtype to compare patient populations similarly throughout the world, to predict prognosis, and to dictate therapeutic directions.

MDS have two main classification systems, the FAB (French-American-British) and the WHO (World Health Organization). Revised in 2008,¹⁶ the WHO classification (Table 2, not available online)¹⁷ is widely accepted because it incorporates morphologic and cytogenetic factors and correlates with prognosis.¹⁸ The categories are distinguished by specific characteristics of peripheral blood and bone marrow.

Unlike many other cancers, MDS are not “staged.” Rather, prognostic systems have been devised to predict the risk of transformation to AML and to predict overall survival. These systems are based on:

• The number of myeloblasts in the bone marrow (the higher the count, the worse the prognosis)
• The number or degree of cytopenias
• Cytogenetic abnormalities (acquired genetic abnormalities in the neoplastic clone), found in about half of patients with MDS.¹⁹

The most widely used prognostic systems are the International Prognostic Scoring System (Table 3, not available online)² and the WPSS (WHO Classification-based Prognostic Scoring System¹). The latter system encorporates transfusion burden.

Supportive care includes transfusion of blood products to minimize complications of cytopenias and to improve quality of life, as well as antibiotics to treat active infections.

Transfusions

Almost all patients with MDS need red cell transfusions at some point, while fewer need platelets. The frequency of transfusion depends on the extent of the disease and on comorbidities.

Red blood cells typically are given when the hemoglobin level falls below 8.5 g/dL, and platelets are given when the platelet count is below 100 × 10⁹/L, in the absence of symptoms. Patients with symptomatic anemia should receive transfusion to relieve their symptoms. Some patients need transfusions occasionally, while others are transfusion-dependent.

Iron chelation

Blood product transfusions can lead to iron overload, particularly with a lifetime administration of more than 20 units, or with a year of continuous transfusions, and this is associated with diminished survival.²⁰

However, considering the short survival of patients with MDS, the benefit of iron chelation is debatable. This intervention should be reserved for patients with lower-risk disease who are expected to survive more than 1 year and who have received more than 25 units of packed red blood cells.²¹

Antibiotics

Neutropenia is defined as an absolute neutrophil count less than 1.5 × 10⁹/L. The risk of infection, particularly bacterial infection, is significantly increased when the neutrophil count is below 0.5 × 10⁹/L. Fever (temperature > 100.4°F or 38.0°C) in neutropenic patients is an emergency, requiring hospitalization and immediate initiation of broad-spectrum antibiotics along with a workup for the cause of the fever.²² Prophylactic antibiotics have no proven role in MDS patients with neutropenia.

TREATMENT OF LOWER-RISK DISEASE

Erythropoiesis-stimulating agents

Once a patient starts to require red blood cell transfusions, an erythropoiesis-stimulating agent (EPA) can be considered.^23,24 These include recombinant agents such as erythropoietin (Procrit) and darbepoetin alfa (Aranesp).

Response is measured as an improvement in hemoglobin or as independence from transfusions in those previously dependent on them. Patients most likely to respond are those whose pretransfusion erythropoietin level is below 100 IU/L and who have minimal transfusion needs.^25,26 Addition of a colony-stimulating factor can be considered for patients with neutropenia. On average, about 40% of patients ultimately respond to an EPA, but those who respond eventually develop resistance to the agent. Retrospective data indicate that use of EPAs may improve survival in MDS.^23,24

The recommended threshold hemoglobin level for starting an EPA is less than 10 g/dL. Patients need to be monitored with a CBC every time they receive treatment. The agent should be stopped once the hemoglobin level reaches 12 g/dL. A number of studies have shown lower survival rates when ESAs are used in nonhematologic malignancies, particularly if the malignancy is advanced and when the ESA is used to achieve a goal hemoglobin above 12 g/dL. There are no data to suggest a higher death rate in patients with hematologic malignancies who take ESAs. The use of ESAs in MDS patients should be judicious, however, and titrated to a goal hemoglobin level no higher than 12 g/dL.²⁷

Other treatments

If ESA treatment is ineffective, other treatments may be considered, usually initiated by a hematologist or medical oncologist.

Immunosuppressive therapy with antithymocyte globulin (Thymoglobulin)²⁸ is an option for patients with hypocellular or immune-mediated MDS. This treatment may decrease the need for transfusion and may improve the blood count.

Lenalidomide (Revlimid) for MDS with isolated chromosome 5q deletion²⁹ can decrease the need for blood transfusion in approximately two-thirds of these patients.

Azacitidine (Vidaza) or decitabine (Dacogen), in patients with more advanced subtypes of MDS (eg, those with excess blasts) or with pancytopenia unresponsive to other therapies, can induce hematologic improvement and decrease transfusion dependence, as well as prolong survival.

Stem cell transplantation, for patients with more advanced subtypes of MDS and who have an appropriately matched donor, has the potential of being curative.

Experimental treatments are available in clinical trials.

TREATMENT OF HIGHER-RISK DISEASE

About 25% of patients with newly diagnosed MDS and 15% to 20% of patients with established MDS have higher-risk disease.³⁰ These patients should almost always be followed by a hematologist or medical oncologist, with therapy initiated immediately, regardless of blood counts, given the high likelihood of transformation to AML or death within 1.5 years.

The treatment options for higher-risk disease include:

• Methyltransferase inhibitors such as azacitidine and decitabine^31–34
• Cytotoxic chemotherapy (similar to treatment of acute myeloid leukemia)
• Bone marrow-hematopoeitic stem cell transplantation^35,36
• Experimental treatments in clinical trials.

As mentioned earlier, outside of transplantation, only azacitidine has been shown to improve overall survival (with a doubling of survival at 2 years, to 50%), and no drug therapy is curative. Managing patient expectations for treatment outcome is thus crucial in higher-risk disease, and ongoing assessments of quality of life, both on or off therapy, should be considered obligatory.

Stem cell transplantation cures MDS

MDS are complex and heterogeneous, so treatment options range from supportive care to chemotherapy and allogeneic stem cell transplantation.⁶ The choice depends on the severity of disease, ie, lower-risk or higherrisk (Table 3, not available online), as well as on the prognosis, the availability of therapeutic options, and the patient’s expectations.

Hematopoietic stem cell transplantation is the only curative treatment for MDS. However, it is performed in fewer than 5% of patients,³⁰ usually younger patients with few comorbidities, because the rate of transplantrelated death is high. Therefore, most treatments are palliative, aimed at improving the quality of life and prolonging survival.

The balance between risks and benefits of these treatments must be justifiable.³⁰ Further, patients who have no symptoms or who have lower-risk disease need no treatment and may not for years. However, they do need close follow-up, because their symptoms will worsen and will eventually require treatment.

TAKE-HOME POINTS

• Myelodysplastic syndromes are more prevalent than previously realized. Mainly a disease of older adults, they should be suspected in any patient with unexplained cytopenia.
• Life expectancy at the time of diagnosis depends on the types of cells affected.
• Supportive and disease-altering options are available.
• Prompt referral to a hematologist or oncologist is important for confirmation of the diagnosis and initiation of an appropriate treatment plan. Patients with lower-risk disease can continue follow-up with their primary care provider once treatment goals and plans are established.

ACKNOWLEDGMENT

We thank Dr. Karl Theil of the Cleveland Clinic Department of Clinical Pathology for the photomicrographs used on the cover.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders of blood cell production in the bone marrow that can transform into acute myeloid leukemia (AML).^1,2 They are diagnosed most often in the elderly.

Primary care physicians and geriatricians tend to be the first to identify the problem, as they recognize that cytopenias are not simply a normal consequence of aging.

MDS are considered to be cancers, akin to chronic leukemia or acute leukemia, with epidemiologic data tracked by national cancer registries and the US Centers for Disease Control and Prevention, under the auspices of the Surveillance, Epidemiology, and End Results (SEER) program.³

In this article, we briefly review the classification of MDS, current epidemiologic data, key diagnostic features, and current management options.

WHEN TO SUSPECT MDS

In many patients, MDS are asymptomatic and appear as an abnormality on a routine complete blood cell count (CBC) or as part of a workup for anemia. Symptoms develop as the bone marrow’s ability to produce normal-functioning blood cells is more and more compromised. The range of symptoms depends on the bone marrow cell type affected.

Patients with MDS typically have some degree of anemia, often detected incidentally on a routine CBC, or they have symptoms stemming from anemia or thrombocytopenia, or have recurrent infections.

Subtypes of MDS have different pathologic and clinical presentations and different prognoses. They are often categorized as lower-risk or higher-risk, depending on the likelihood of transforming to AML. Patients with lower-risk MDS survive a median of 3 to 7 years. Higher-risk types are pathobiologically similar to AML in older adults, and patients either develop AML or die of complications of MDS, on average within 1.5 years.

Several classification schemes and prognostic models guide the selection of the most appropriate therapy.

Older age and comorbidities such as coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease make MDS more difficult to manage and worsen the prognosis.⁴

MOST PATIENTS ARE OLDER

Only since 2001, when MDS became reportable to SEER,^3,5 has the epidemiology of MDS been reported in the United States.

MDS are currently diagnosed in an estimated 3.4 per 100,000 US citizens yearly.

The incidence rate increased from 3.28 per 100,000 per year in 2001 to 3.56 per 100,000 in 2004.⁵ The increase has been attributed to enhanced awareness of the disease and to the aging of the population, with the number of people age 65 or older in the United States expected to double from the year 2000 to 2030. Another factor is that effective therapies are now available, possibly making hematologists and oncologists more likely to pursue the diagnosis.

These numbers translate to 10,000 to 15,000 new cases annually, and given the life expectancy of patients affected by this disease (and the life-extending treatments for it), an estimated 30,000 to 60,000 Americans living with MDS.^6,7

Even though MDS can occur at any age, most patients are older. The median age at diagnosis is 71 years,^3,5,8 and 72% of patients are age 70 or older.³ The prevalence increases with age, to a rate of 36 per 100,000 in those age 80 and older.⁹ However, in areas of East Asia, it occurs at ages almost 2 decades younger than in the rest of the world.⁵

MDS are more common in men than in women and in whites than in blacks. Smoking appears to increase the risk, but alcohol consumption does not.¹⁰

About 10% of cases of MDS are secondary, most often due to radiation treatment or chemotherapy (particularly with alkylating agents and topoisomerase inhibitors) for cancer. The time from treatment of a primary malignancy (most often prostate, breast, bladder, lung, or non-Hodgkin lymphoma) to the development of MDS is about 5 years.⁵ A small number of cases are due to occupational exposure to radiation or benzene or other organic solvents, as might occur in the rubber industry (see below). Secondary MDS have a worse prognosis than primary (de novo) MDS.

GENETIC AND ENVIRONMENTAL FACTORS

The cause of de novo MDS is not known. Genetic and environmental factors probably both play a role. The lower median age at diagnosis in Eastern countries such as Japan than in the United States suggests that environmental factors¹¹ such as smoking, ionizing radiation, and benzene exposure play a role.^12,13 Some epidemiologic evidence suggests a higher incidence of MDS after exposure to solvents, hair dyes, and pesticides.¹³

Congenital conditions such as Down syndrome, Fanconi anemia, and Bloom syndrome are associated with MDS. Those affected usually present at an earlier age,¹³ suggesting a “multiple-hit” mechanism of cancer development with genetic and environmental factors. MDS rarely run in families.

SYMPTOMS ARE OFTEN NONSPECIFIC

Symptoms of MDS are often vague and nonspecific, and the diagnosis is often made during a workup for anemia, thrombocytopenia, or neutropenia discovered on a CBC. If present, signs and symptoms depend on the blood and bone marrow cell types that are affected.

When erythrocytes are affected (the most common situation), patients present with signs of anemia, including pallor, pale conjunctiva, tachycardia, hypotension, fatigue, headache, and exercise intolerance, or with signs and symptoms of a worsening underlying condition such as angina pectoris, heart failure, or emphysema.

When platelets or neutrophils are affected. Fewer than 20% of patients present with symptoms of isolated thrombocytopenia such as minor bleeding (eg, mucosal bleeding, petechiae, easy bruising, epistaxis) or major bleeding (eg, gastrointestinal bleeding, intracranial hemorrhage) or of isolated neutropenia (eg, fatigue, frequent bacterial infections of different organs systems).

Splenomegaly and lymphadenopathy are uncommon in MDS and, if detected, should raise suspicion of a myeloproliferative or lymphoproliferative neoplasm.

LABORATORY TESTS NEEDED

Complete blood cell count

Once the common causes of patient’s symptoms are evaluated, a CBC is needed to look for a hematologic cause. If a patient is ultimately determined to have MDS, anemia is the most common finding on the CBC: about 80% of patients with MDS are anemic at presentation. ⁶

Anemia associated with MDS can be microcytic, normocytic, or, most commonly, macrocytic. ¹⁴ Thrombocytopenia and neutropenia can be solitary or associated with anemia, and they are seen in about 40% of patients at the time of diagnosis.⁶ As the disease progresses, the degree of cytopenia worsens and, in most cases, preserved cell lineages are eventually affected.

Once cytopenia is discovered, a workup for the cause is needed. We emphasize a workup first for anemia, as it is the most common form of cytopenia in MDS. A workup for isolated thrombocytopenia or neutropenia usually requires a bone marrow examination earlier in the course, and we will discuss it only briefly here. Multilineage cytopenia almost always suggests abnormal bone marrow function and can be the basis for referral to a hematologist or oncologist.

Evaluation of anemia

If anemia is detected, it is reasonable to look for nonhematologic causes such as gastrointestinal bleeding, a cardiac cause, or a nutritional deficiency.

Anemia has a variety of possible hematologic causes, as shown in a study in the United States.¹⁵ When blood samples were collected from more than 2,000 people age 65 and older, 10.6% were found to have anemia, categorized as follows:

• Nutrient-deficiency anemia, related to low levels of vitamin B₁₂, folate, or more commonly iron
• Anemia of chronic inflammation (formerly anemia of chronic disease, associated with a major medical disorder)
• Unexplained anemia (of those with unexplained anemia, 17.4% had blood findings compatible with MDS).¹⁵

• Tests for nutrient deficiencies such as iron, vitamin B₁₂, and folate levels. Subsequent tests can include assessment for copper deficiencies. Vitamin B₁₂ and copper deficiency can mimic MDS.
• Fecal occult blood testing, and, if positive, further evaluation for a source of gastrointestinal bleeding.
• Liver function tests, renal function tests, and tests for endocrine disorders, such as thyroid function tests.
• Review of drugs that can cause megaloblastoid erythropoiesis, such as methotrexate (Trexall), valproic acid (Depakote), phenytoin (Dilantin), phenobarbital (Luminal), sulfasalazine (Sulfazine), and zidovudine (Retrovir).
• Assesment of the responsiveness of the bone marrow to anemia, via a reticulocyte count or an erythropoietin level, or both, prior to any blood transfusion.
• Screening for relevant infections, including human immunodeficiency virus (HIV), hepatitis, or, in rare cases, parvovirus.
• Screening for lifestyle factors that may result in bone marrow suppression, such as excessive alcohol intake.

Evaluation of other cytopenias

In cases of isolated thrombocytopenia or combined bicytopenia (eg, anemia and thrombocytopenia), abdominal ultrasonography should be done to evaluate for splenomegaly.

Blood tests to evaluate for immune-mediated cytopenias, including idiopathic thrombocytopenic purpura and hemolytic anemia, include the direct and indirect Coombs antiglobulin tests, the lactate dehydrogenase level, the reticulocyte count, and the haptoglobin level. Other immune-mediated causes of cytopenia include connective tissue disorders and vasculitides, and an antinuclear antibody titer and rheumatoid factor level can also be considered.

Referral if tests are negative

If all these tests are negative, the next step is referral to a hematologist-oncologist for further workup, which may include a review of the peripheral blood smear; bone marrow aspiration and biopsy for evaluation of iron stores and bone marrow cellularity; and specialized tests such as assessment of antiplatelet antibodies, protein electrophoresis, or fluorescence in situ hybridization to evaluate for specific clonal disorders. The purpose of bone marrow aspiration and biopsy in MDS is to evaluate the morphology of the bone marrow and the patient’s cytogenetic profile. Each has its prognostic and therapeutic implications.

SCORING SYSTEMS FOR MDS, RATHER THAN STAGING SYSTEMS

The purpose of classification systems for any medical condition is to uniformly evaluate and group patients with a disease subtype to compare patient populations similarly throughout the world, to predict prognosis, and to dictate therapeutic directions.

MDS have two main classification systems, the FAB (French-American-British) and the WHO (World Health Organization). Revised in 2008,¹⁶ the WHO classification (Table 2, not available online)¹⁷ is widely accepted because it incorporates morphologic and cytogenetic factors and correlates with prognosis.¹⁸ The categories are distinguished by specific characteristics of peripheral blood and bone marrow.

Unlike many other cancers, MDS are not “staged.” Rather, prognostic systems have been devised to predict the risk of transformation to AML and to predict overall survival. These systems are based on:

• The number of myeloblasts in the bone marrow (the higher the count, the worse the prognosis)
• The number or degree of cytopenias
• Cytogenetic abnormalities (acquired genetic abnormalities in the neoplastic clone), found in about half of patients with MDS.¹⁹

The most widely used prognostic systems are the International Prognostic Scoring System (Table 3, not available online)² and the WPSS (WHO Classification-based Prognostic Scoring System¹). The latter system encorporates transfusion burden.

Supportive care includes transfusion of blood products to minimize complications of cytopenias and to improve quality of life, as well as antibiotics to treat active infections.

Transfusions

Almost all patients with MDS need red cell transfusions at some point, while fewer need platelets. The frequency of transfusion depends on the extent of the disease and on comorbidities.

Red blood cells typically are given when the hemoglobin level falls below 8.5 g/dL, and platelets are given when the platelet count is below 100 × 10⁹/L, in the absence of symptoms. Patients with symptomatic anemia should receive transfusion to relieve their symptoms. Some patients need transfusions occasionally, while others are transfusion-dependent.

Iron chelation

Blood product transfusions can lead to iron overload, particularly with a lifetime administration of more than 20 units, or with a year of continuous transfusions, and this is associated with diminished survival.²⁰

However, considering the short survival of patients with MDS, the benefit of iron chelation is debatable. This intervention should be reserved for patients with lower-risk disease who are expected to survive more than 1 year and who have received more than 25 units of packed red blood cells.²¹

Antibiotics

Neutropenia is defined as an absolute neutrophil count less than 1.5 × 10⁹/L. The risk of infection, particularly bacterial infection, is significantly increased when the neutrophil count is below 0.5 × 10⁹/L. Fever (temperature > 100.4°F or 38.0°C) in neutropenic patients is an emergency, requiring hospitalization and immediate initiation of broad-spectrum antibiotics along with a workup for the cause of the fever.²² Prophylactic antibiotics have no proven role in MDS patients with neutropenia.

TREATMENT OF LOWER-RISK DISEASE

Erythropoiesis-stimulating agents

Once a patient starts to require red blood cell transfusions, an erythropoiesis-stimulating agent (EPA) can be considered.^23,24 These include recombinant agents such as erythropoietin (Procrit) and darbepoetin alfa (Aranesp).

Response is measured as an improvement in hemoglobin or as independence from transfusions in those previously dependent on them. Patients most likely to respond are those whose pretransfusion erythropoietin level is below 100 IU/L and who have minimal transfusion needs.^25,26 Addition of a colony-stimulating factor can be considered for patients with neutropenia. On average, about 40% of patients ultimately respond to an EPA, but those who respond eventually develop resistance to the agent. Retrospective data indicate that use of EPAs may improve survival in MDS.^23,24

The recommended threshold hemoglobin level for starting an EPA is less than 10 g/dL. Patients need to be monitored with a CBC every time they receive treatment. The agent should be stopped once the hemoglobin level reaches 12 g/dL. A number of studies have shown lower survival rates when ESAs are used in nonhematologic malignancies, particularly if the malignancy is advanced and when the ESA is used to achieve a goal hemoglobin above 12 g/dL. There are no data to suggest a higher death rate in patients with hematologic malignancies who take ESAs. The use of ESAs in MDS patients should be judicious, however, and titrated to a goal hemoglobin level no higher than 12 g/dL.²⁷

Other treatments

If ESA treatment is ineffective, other treatments may be considered, usually initiated by a hematologist or medical oncologist.

Immunosuppressive therapy with antithymocyte globulin (Thymoglobulin)²⁸ is an option for patients with hypocellular or immune-mediated MDS. This treatment may decrease the need for transfusion and may improve the blood count.

Lenalidomide (Revlimid) for MDS with isolated chromosome 5q deletion²⁹ can decrease the need for blood transfusion in approximately two-thirds of these patients.

Azacitidine (Vidaza) or decitabine (Dacogen), in patients with more advanced subtypes of MDS (eg, those with excess blasts) or with pancytopenia unresponsive to other therapies, can induce hematologic improvement and decrease transfusion dependence, as well as prolong survival.

Stem cell transplantation, for patients with more advanced subtypes of MDS and who have an appropriately matched donor, has the potential of being curative.

Experimental treatments are available in clinical trials.

TREATMENT OF HIGHER-RISK DISEASE

About 25% of patients with newly diagnosed MDS and 15% to 20% of patients with established MDS have higher-risk disease.³⁰ These patients should almost always be followed by a hematologist or medical oncologist, with therapy initiated immediately, regardless of blood counts, given the high likelihood of transformation to AML or death within 1.5 years.

The treatment options for higher-risk disease include:

• Methyltransferase inhibitors such as azacitidine and decitabine^31–34
• Cytotoxic chemotherapy (similar to treatment of acute myeloid leukemia)
• Bone marrow-hematopoeitic stem cell transplantation^35,36
• Experimental treatments in clinical trials.

As mentioned earlier, outside of transplantation, only azacitidine has been shown to improve overall survival (with a doubling of survival at 2 years, to 50%), and no drug therapy is curative. Managing patient expectations for treatment outcome is thus crucial in higher-risk disease, and ongoing assessments of quality of life, both on or off therapy, should be considered obligatory.

Stem cell transplantation cures MDS

MDS are complex and heterogeneous, so treatment options range from supportive care to chemotherapy and allogeneic stem cell transplantation.⁶ The choice depends on the severity of disease, ie, lower-risk or higherrisk (Table 3, not available online), as well as on the prognosis, the availability of therapeutic options, and the patient’s expectations.

Hematopoietic stem cell transplantation is the only curative treatment for MDS. However, it is performed in fewer than 5% of patients,³⁰ usually younger patients with few comorbidities, because the rate of transplantrelated death is high. Therefore, most treatments are palliative, aimed at improving the quality of life and prolonging survival.

The balance between risks and benefits of these treatments must be justifiable.³⁰ Further, patients who have no symptoms or who have lower-risk disease need no treatment and may not for years. However, they do need close follow-up, because their symptoms will worsen and will eventually require treatment.

TAKE-HOME POINTS

• Myelodysplastic syndromes are more prevalent than previously realized. Mainly a disease of older adults, they should be suspected in any patient with unexplained cytopenia.
• Life expectancy at the time of diagnosis depends on the types of cells affected.
• Supportive and disease-altering options are available.
• Prompt referral to a hematologist or oncologist is important for confirmation of the diagnosis and initiation of an appropriate treatment plan. Patients with lower-risk disease can continue follow-up with their primary care provider once treatment goals and plans are established.

ACKNOWLEDGMENT

We thank Dr. Karl Theil of the Cleveland Clinic Department of Clinical Pathology for the photomicrographs used on the cover.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders of blood cell production in the bone marrow that can transform into acute myeloid leukemia (AML).^1,2 They are diagnosed most often in the elderly.

Primary care physicians and geriatricians tend to be the first to identify the problem, as they recognize that cytopenias are not simply a normal consequence of aging.

MDS are considered to be cancers, akin to chronic leukemia or acute leukemia, with epidemiologic data tracked by national cancer registries and the US Centers for Disease Control and Prevention, under the auspices of the Surveillance, Epidemiology, and End Results (SEER) program.³

In this article, we briefly review the classification of MDS, current epidemiologic data, key diagnostic features, and current management options.

WHEN TO SUSPECT MDS

In many patients, MDS are asymptomatic and appear as an abnormality on a routine complete blood cell count (CBC) or as part of a workup for anemia. Symptoms develop as the bone marrow’s ability to produce normal-functioning blood cells is more and more compromised. The range of symptoms depends on the bone marrow cell type affected.

Patients with MDS typically have some degree of anemia, often detected incidentally on a routine CBC, or they have symptoms stemming from anemia or thrombocytopenia, or have recurrent infections.

Subtypes of MDS have different pathologic and clinical presentations and different prognoses. They are often categorized as lower-risk or higher-risk, depending on the likelihood of transforming to AML. Patients with lower-risk MDS survive a median of 3 to 7 years. Higher-risk types are pathobiologically similar to AML in older adults, and patients either develop AML or die of complications of MDS, on average within 1.5 years.

Several classification schemes and prognostic models guide the selection of the most appropriate therapy.

Older age and comorbidities such as coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease make MDS more difficult to manage and worsen the prognosis.⁴

MOST PATIENTS ARE OLDER

Only since 2001, when MDS became reportable to SEER,^3,5 has the epidemiology of MDS been reported in the United States.

MDS are currently diagnosed in an estimated 3.4 per 100,000 US citizens yearly.

The incidence rate increased from 3.28 per 100,000 per year in 2001 to 3.56 per 100,000 in 2004.⁵ The increase has been attributed to enhanced awareness of the disease and to the aging of the population, with the number of people age 65 or older in the United States expected to double from the year 2000 to 2030. Another factor is that effective therapies are now available, possibly making hematologists and oncologists more likely to pursue the diagnosis.

These numbers translate to 10,000 to 15,000 new cases annually, and given the life expectancy of patients affected by this disease (and the life-extending treatments for it), an estimated 30,000 to 60,000 Americans living with MDS.^6,7

Even though MDS can occur at any age, most patients are older. The median age at diagnosis is 71 years,^3,5,8 and 72% of patients are age 70 or older.³ The prevalence increases with age, to a rate of 36 per 100,000 in those age 80 and older.⁹ However, in areas of East Asia, it occurs at ages almost 2 decades younger than in the rest of the world.⁵

MDS are more common in men than in women and in whites than in blacks. Smoking appears to increase the risk, but alcohol consumption does not.¹⁰

About 10% of cases of MDS are secondary, most often due to radiation treatment or chemotherapy (particularly with alkylating agents and topoisomerase inhibitors) for cancer. The time from treatment of a primary malignancy (most often prostate, breast, bladder, lung, or non-Hodgkin lymphoma) to the development of MDS is about 5 years.⁵ A small number of cases are due to occupational exposure to radiation or benzene or other organic solvents, as might occur in the rubber industry (see below). Secondary MDS have a worse prognosis than primary (de novo) MDS.

GENETIC AND ENVIRONMENTAL FACTORS

The cause of de novo MDS is not known. Genetic and environmental factors probably both play a role. The lower median age at diagnosis in Eastern countries such as Japan than in the United States suggests that environmental factors¹¹ such as smoking, ionizing radiation, and benzene exposure play a role.^12,13 Some epidemiologic evidence suggests a higher incidence of MDS after exposure to solvents, hair dyes, and pesticides.¹³

Congenital conditions such as Down syndrome, Fanconi anemia, and Bloom syndrome are associated with MDS. Those affected usually present at an earlier age,¹³ suggesting a “multiple-hit” mechanism of cancer development with genetic and environmental factors. MDS rarely run in families.

SYMPTOMS ARE OFTEN NONSPECIFIC

Symptoms of MDS are often vague and nonspecific, and the diagnosis is often made during a workup for anemia, thrombocytopenia, or neutropenia discovered on a CBC. If present, signs and symptoms depend on the blood and bone marrow cell types that are affected.

When erythrocytes are affected (the most common situation), patients present with signs of anemia, including pallor, pale conjunctiva, tachycardia, hypotension, fatigue, headache, and exercise intolerance, or with signs and symptoms of a worsening underlying condition such as angina pectoris, heart failure, or emphysema.

When platelets or neutrophils are affected. Fewer than 20% of patients present with symptoms of isolated thrombocytopenia such as minor bleeding (eg, mucosal bleeding, petechiae, easy bruising, epistaxis) or major bleeding (eg, gastrointestinal bleeding, intracranial hemorrhage) or of isolated neutropenia (eg, fatigue, frequent bacterial infections of different organs systems).

Splenomegaly and lymphadenopathy are uncommon in MDS and, if detected, should raise suspicion of a myeloproliferative or lymphoproliferative neoplasm.

LABORATORY TESTS NEEDED

Complete blood cell count

Once the common causes of patient’s symptoms are evaluated, a CBC is needed to look for a hematologic cause. If a patient is ultimately determined to have MDS, anemia is the most common finding on the CBC: about 80% of patients with MDS are anemic at presentation. ⁶

Anemia associated with MDS can be microcytic, normocytic, or, most commonly, macrocytic. ¹⁴ Thrombocytopenia and neutropenia can be solitary or associated with anemia, and they are seen in about 40% of patients at the time of diagnosis.⁶ As the disease progresses, the degree of cytopenia worsens and, in most cases, preserved cell lineages are eventually affected.

Once cytopenia is discovered, a workup for the cause is needed. We emphasize a workup first for anemia, as it is the most common form of cytopenia in MDS. A workup for isolated thrombocytopenia or neutropenia usually requires a bone marrow examination earlier in the course, and we will discuss it only briefly here. Multilineage cytopenia almost always suggests abnormal bone marrow function and can be the basis for referral to a hematologist or oncologist.

Evaluation of anemia

If anemia is detected, it is reasonable to look for nonhematologic causes such as gastrointestinal bleeding, a cardiac cause, or a nutritional deficiency.

Anemia has a variety of possible hematologic causes, as shown in a study in the United States.¹⁵ When blood samples were collected from more than 2,000 people age 65 and older, 10.6% were found to have anemia, categorized as follows:

• Nutrient-deficiency anemia, related to low levels of vitamin B₁₂, folate, or more commonly iron
• Anemia of chronic inflammation (formerly anemia of chronic disease, associated with a major medical disorder)
• Unexplained anemia (of those with unexplained anemia, 17.4% had blood findings compatible with MDS).¹⁵

• Tests for nutrient deficiencies such as iron, vitamin B₁₂, and folate levels. Subsequent tests can include assessment for copper deficiencies. Vitamin B₁₂ and copper deficiency can mimic MDS.
• Fecal occult blood testing, and, if positive, further evaluation for a source of gastrointestinal bleeding.
• Liver function tests, renal function tests, and tests for endocrine disorders, such as thyroid function tests.
• Review of drugs that can cause megaloblastoid erythropoiesis, such as methotrexate (Trexall), valproic acid (Depakote), phenytoin (Dilantin), phenobarbital (Luminal), sulfasalazine (Sulfazine), and zidovudine (Retrovir).
• Assesment of the responsiveness of the bone marrow to anemia, via a reticulocyte count or an erythropoietin level, or both, prior to any blood transfusion.
• Screening for relevant infections, including human immunodeficiency virus (HIV), hepatitis, or, in rare cases, parvovirus.
• Screening for lifestyle factors that may result in bone marrow suppression, such as excessive alcohol intake.

Evaluation of other cytopenias

In cases of isolated thrombocytopenia or combined bicytopenia (eg, anemia and thrombocytopenia), abdominal ultrasonography should be done to evaluate for splenomegaly.

Blood tests to evaluate for immune-mediated cytopenias, including idiopathic thrombocytopenic purpura and hemolytic anemia, include the direct and indirect Coombs antiglobulin tests, the lactate dehydrogenase level, the reticulocyte count, and the haptoglobin level. Other immune-mediated causes of cytopenia include connective tissue disorders and vasculitides, and an antinuclear antibody titer and rheumatoid factor level can also be considered.

Referral if tests are negative

If all these tests are negative, the next step is referral to a hematologist-oncologist for further workup, which may include a review of the peripheral blood smear; bone marrow aspiration and biopsy for evaluation of iron stores and bone marrow cellularity; and specialized tests such as assessment of antiplatelet antibodies, protein electrophoresis, or fluorescence in situ hybridization to evaluate for specific clonal disorders. The purpose of bone marrow aspiration and biopsy in MDS is to evaluate the morphology of the bone marrow and the patient’s cytogenetic profile. Each has its prognostic and therapeutic implications.

SCORING SYSTEMS FOR MDS, RATHER THAN STAGING SYSTEMS

The purpose of classification systems for any medical condition is to uniformly evaluate and group patients with a disease subtype to compare patient populations similarly throughout the world, to predict prognosis, and to dictate therapeutic directions.

MDS have two main classification systems, the FAB (French-American-British) and the WHO (World Health Organization). Revised in 2008,¹⁶ the WHO classification (Table 2, not available online)¹⁷ is widely accepted because it incorporates morphologic and cytogenetic factors and correlates with prognosis.¹⁸ The categories are distinguished by specific characteristics of peripheral blood and bone marrow.

Unlike many other cancers, MDS are not “staged.” Rather, prognostic systems have been devised to predict the risk of transformation to AML and to predict overall survival. These systems are based on:

• The number of myeloblasts in the bone marrow (the higher the count, the worse the prognosis)
• The number or degree of cytopenias
• Cytogenetic abnormalities (acquired genetic abnormalities in the neoplastic clone), found in about half of patients with MDS.¹⁹

The most widely used prognostic systems are the International Prognostic Scoring System (Table 3, not available online)² and the WPSS (WHO Classification-based Prognostic Scoring System¹). The latter system encorporates transfusion burden.

Supportive care includes transfusion of blood products to minimize complications of cytopenias and to improve quality of life, as well as antibiotics to treat active infections.

Transfusions

Almost all patients with MDS need red cell transfusions at some point, while fewer need platelets. The frequency of transfusion depends on the extent of the disease and on comorbidities.

Red blood cells typically are given when the hemoglobin level falls below 8.5 g/dL, and platelets are given when the platelet count is below 100 × 10⁹/L, in the absence of symptoms. Patients with symptomatic anemia should receive transfusion to relieve their symptoms. Some patients need transfusions occasionally, while others are transfusion-dependent.

Iron chelation

Blood product transfusions can lead to iron overload, particularly with a lifetime administration of more than 20 units, or with a year of continuous transfusions, and this is associated with diminished survival.²⁰

However, considering the short survival of patients with MDS, the benefit of iron chelation is debatable. This intervention should be reserved for patients with lower-risk disease who are expected to survive more than 1 year and who have received more than 25 units of packed red blood cells.²¹

Antibiotics

Neutropenia is defined as an absolute neutrophil count less than 1.5 × 10⁹/L. The risk of infection, particularly bacterial infection, is significantly increased when the neutrophil count is below 0.5 × 10⁹/L. Fever (temperature > 100.4°F or 38.0°C) in neutropenic patients is an emergency, requiring hospitalization and immediate initiation of broad-spectrum antibiotics along with a workup for the cause of the fever.²² Prophylactic antibiotics have no proven role in MDS patients with neutropenia.

TREATMENT OF LOWER-RISK DISEASE

Erythropoiesis-stimulating agents

Once a patient starts to require red blood cell transfusions, an erythropoiesis-stimulating agent (EPA) can be considered.^23,24 These include recombinant agents such as erythropoietin (Procrit) and darbepoetin alfa (Aranesp).

Response is measured as an improvement in hemoglobin or as independence from transfusions in those previously dependent on them. Patients most likely to respond are those whose pretransfusion erythropoietin level is below 100 IU/L and who have minimal transfusion needs.^25,26 Addition of a colony-stimulating factor can be considered for patients with neutropenia. On average, about 40% of patients ultimately respond to an EPA, but those who respond eventually develop resistance to the agent. Retrospective data indicate that use of EPAs may improve survival in MDS.^23,24

The recommended threshold hemoglobin level for starting an EPA is less than 10 g/dL. Patients need to be monitored with a CBC every time they receive treatment. The agent should be stopped once the hemoglobin level reaches 12 g/dL. A number of studies have shown lower survival rates when ESAs are used in nonhematologic malignancies, particularly if the malignancy is advanced and when the ESA is used to achieve a goal hemoglobin above 12 g/dL. There are no data to suggest a higher death rate in patients with hematologic malignancies who take ESAs. The use of ESAs in MDS patients should be judicious, however, and titrated to a goal hemoglobin level no higher than 12 g/dL.²⁷

Other treatments

If ESA treatment is ineffective, other treatments may be considered, usually initiated by a hematologist or medical oncologist.

Immunosuppressive therapy with antithymocyte globulin (Thymoglobulin)²⁸ is an option for patients with hypocellular or immune-mediated MDS. This treatment may decrease the need for transfusion and may improve the blood count.

Lenalidomide (Revlimid) for MDS with isolated chromosome 5q deletion²⁹ can decrease the need for blood transfusion in approximately two-thirds of these patients.

Azacitidine (Vidaza) or decitabine (Dacogen), in patients with more advanced subtypes of MDS (eg, those with excess blasts) or with pancytopenia unresponsive to other therapies, can induce hematologic improvement and decrease transfusion dependence, as well as prolong survival.

Stem cell transplantation, for patients with more advanced subtypes of MDS and who have an appropriately matched donor, has the potential of being curative.

Experimental treatments are available in clinical trials.

TREATMENT OF HIGHER-RISK DISEASE

About 25% of patients with newly diagnosed MDS and 15% to 20% of patients with established MDS have higher-risk disease.³⁰ These patients should almost always be followed by a hematologist or medical oncologist, with therapy initiated immediately, regardless of blood counts, given the high likelihood of transformation to AML or death within 1.5 years.

The treatment options for higher-risk disease include:

• Methyltransferase inhibitors such as azacitidine and decitabine^31–34
• Cytotoxic chemotherapy (similar to treatment of acute myeloid leukemia)
• Bone marrow-hematopoeitic stem cell transplantation^35,36
• Experimental treatments in clinical trials.

As mentioned earlier, outside of transplantation, only azacitidine has been shown to improve overall survival (with a doubling of survival at 2 years, to 50%), and no drug therapy is curative. Managing patient expectations for treatment outcome is thus crucial in higher-risk disease, and ongoing assessments of quality of life, both on or off therapy, should be considered obligatory.

Stem cell transplantation cures MDS

MDS are complex and heterogeneous, so treatment options range from supportive care to chemotherapy and allogeneic stem cell transplantation.⁶ The choice depends on the severity of disease, ie, lower-risk or higherrisk (Table 3, not available online), as well as on the prognosis, the availability of therapeutic options, and the patient’s expectations.

Hematopoietic stem cell transplantation is the only curative treatment for MDS. However, it is performed in fewer than 5% of patients,³⁰ usually younger patients with few comorbidities, because the rate of transplantrelated death is high. Therefore, most treatments are palliative, aimed at improving the quality of life and prolonging survival.

The balance between risks and benefits of these treatments must be justifiable.³⁰ Further, patients who have no symptoms or who have lower-risk disease need no treatment and may not for years. However, they do need close follow-up, because their symptoms will worsen and will eventually require treatment.

TAKE-HOME POINTS

• Myelodysplastic syndromes are more prevalent than previously realized. Mainly a disease of older adults, they should be suspected in any patient with unexplained cytopenia.
• Life expectancy at the time of diagnosis depends on the types of cells affected.
• Supportive and disease-altering options are available.
• Prompt referral to a hematologist or oncologist is important for confirmation of the diagnosis and initiation of an appropriate treatment plan. Patients with lower-risk disease can continue follow-up with their primary care provider once treatment goals and plans are established.

ACKNOWLEDGMENT

We thank Dr. Karl Theil of the Cleveland Clinic Department of Clinical Pathology for the photomicrographs used on the cover.

Q: Which is the most likely diagnosis?

• Addison disease
• Lupus erythematosus
• Polymorphous light eruption
• Porphyria cutanea tarda
• Bullous pemphigoid

A: Urine testing, including examination under ultraviolet light with a Wood lamp, indicates porphyria cutanea tarda. This is the most common porphyria, occurring mainly in men. Its true prevalence is not known but is estimated to be from 1:5,000 to 1:25,000.¹

There are three types of porphyria cutanea tarda. About 80% of cases are type I, also referred to as “sporadic.” In type I, levels of uroporphyrinogen decarboxylase (UROD) in red blood cells are normal, but are low in the liver during episodes of the disease. In type II, UROD levels are about 50% below normal in all tissues. Type III is similar to type I, except that it occurs in more than one family member.

The genetic mutation that produces a deficiency of UROD leads to an excess of uroporphyrins and porphyrins that are partially decarboxylated and that irreversibly oxidize. When they are deposited in the skin and the skin is exposed to the sun, they cause the classic cutaneous manifestations.¹

Risk factors² for porphyria cutanea tarda can be extrinsic (eg, high iron blood levels,^2,3 excessive ethanol intake, hepatitis C,^2,4 human immunodeficiency virus, estrogen use,⁵ dialysis for end-stage renal disease) or intrinsic (altered iron metabolism or cytochrome P450 function²).

CLINICAL PRESENTATION

The cardinal symptom of porphyria cutanea tarda is photosensitivity, with the development of chronic blistering lesions on sun-exposed areas such as the hands, face, and forearms. Fluid-filled vesicles develop and rupture easily, and the denuded areas become crusted and heal slowly.⁵ Secondary infections can occur. Previous areas of blisters may appear atrophic, brownish, or violaceous. Small white plaques (milia) are also common and may precede or follow vesicle formation. These cutaneous lesions, however, are not specific to porphyria cutanea tarda and can appear in variegated porphyria and coproporphyria. Hypertrichosis⁵ and hyperpigmentation are usually present, mainly over the cheekbones and around the eyes. Patches of alopecia and hypopigmented sclerodermiform lesions may also be observed.

Porphyria cutanea tarda is usually accompanied by alterations in liver metabolism, affecting mainly aminotransferases and gammaglutamyltransferase. The absence of hepatitis C infection does not rule out porphyria cutanea tarda. About 50% of patients have pathologic structural changes in the liver such as lobular necrosis or fibrotic tracts, and 15% of patients have cirrhosis at presentation.⁶ The risk of hepatocellular carcinoma is clearly increased.⁶ Hepatitis C virus infection, iron overload, and excessive ethanol intake lead to a more severe liver disease.

DIAGNOSIS

The diagnosis of porphyria cutanea tarda is strongly suggested by the characteristic skin lesions in sun-exposed areas, but confirmation requires demonstration of high levels of uroporphyrins or coproporphyrins, or both.

Porphyrins accumulate in the liver, plasma, urine, and feces. Plasma porphyrin levels in porphyria cutanea tarda are usually above 10 μg/dL (normal < 1.4 μg/dL), and plasma fluorescence scanning usually shows a maximum fluorescence emission at an excitation wavelength of 619 nm. In this patient, however, the definitive diagnosis was made by chromatographic separation and the quantification of porphyrins in the urine and feces, which showed a predominance of uroporphyrins and heptacarboxyporphyrins in the urine and an excess of isocoproporphyrins in the feces.¹

Analysis of UROD activity in erythrocytes can help determine the type of porphyria cutanea tarda. Type I and type III and porphyria cutanea tarda secondary to hepatotoxin exposure have normal levels, whereas type II and the hepatoerythropoietic form have abnormally low levels. Examination of the urine with a Wood lamp reveals coral pink fluorescence due to elimination of porphyrins, and this is another diagnostic clue.

Conditions that need to be ruled out include viral infection with hepatitis B or C or human immunodeficiency virus, iron overload, and hereditary hemochromatosis. Serum alpha fetoprotein level assessment, liver ultrasonography, or even biopsy may be indicated to exclude hepatocellular carcinoma.

TREATMENT

Once secondary causes of porphyria are excluded or treated (eg, advising the patient to avoid alcohol, discontinuing estrogens or iron intake), the next step in management is to reduce the patient’s porphyrin and iron loads. Phlebotomy is the standard way to reduce stores of iron throughout the body and particularly in the liver. It works by interrupting iron-mediated oxidative inhibition of hepatic UROD and the oxidation of hepatic porphyrinogens to porphyrinogens.

This adjustment must be gradual, with about 450 mL of blood removed at intervals of 1 to 2 weeks.⁷ This improves the cutaneous symptoms progressively, with resolution of vesicles in 2 to 3 months, improvement of skin fragility in 6 to 9 months, and normalization of porphyrin levels in 13 months. The scleroderma, atrophy, hyperpigmentation, and hypertrichosis respond more slowly and may take years to resolve.

Porphyria cutanea tarda can recur, usually with new exposure to risk factors. Treatment by phlebotomy may be stopped when the serum ferritin level has reached low-normal levels; the porphyrin levels may not yet be normal at that point but may continue to decline without additional phlebotomy sessions.

If phlebotomy is contraindicated, alternatives include iron chelation with deferoxamine (Desferal),⁷ or a low dose of chloroquine (Aralen) (125–250 mg orally twice a week) or hydroxychloroquine (Plaquenil) (100 mg orally twice a week) to avoid acute hepatic damage that may be caused by the release of large amounts of porphyrins that accompany standard dosing levels.