Moises Auron, MD

This icon represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

An 81-year-old woman with a remote history of left proximal femoral fracture (status post–open reduction and internal fixation) acutely developed severe pain in her left lateral thigh while at her home. A few days prior to her left thigh pain, the patient had routine blood work done. Her lab results (prior to the onset of her symptoms) revealed that her hemoglobin decreased from 10 g/dL, noted 9 months earlier, to 6.6 g/dL. Her primary care physician, who was planning to see the patient for her next regularly scheduled follow-up, was made aware of the patient’s decline in hemoglobin prior to the planned visit. The primary care physician called the patient to inform her about her concerning lab findings and coincidentally became aware of the acute, new-onset left thigh pain. The primary care physician requested that the patient be taken by her daughter to the emergency department (ED) for further evaluation.

The acute decrease in hemoglobin carries a broad differential and may or may not be related to the subsequent development of thigh pain. The presentation of an acute onset of pain in the thigh within the context of this patient’s age and gender suggests a femur fracture; this can be osteoporosis-related or a pathologic fracture associated with malignancy. Several malignancies are plausible, including multiple myeloma (given the anemia) or breast cancer. The proximal part of long bones is the most common site of pathologic fractures, and the femur accounts for half of these cases. Plain radiographs would be appropriate initial imaging and may be followed by either a computed tomography (CT) scan or magnetic resonance imaging (MRI).

In the ED, she denied any recent trauma, hemoptysis, recent dark or bloody stools, vaginal bleeding, abdominal pain, or history of gastric ulcers. She had not experienced any similar episodes of thigh pain in the past. She had a history of atrial fibrillation, hypertension, diabetes mellitus type 2 with diabetic retinopathy and peripheral neuropathy, osteoporosis, nonalcoholic fatty liver disease (NAFLD), and internal hemorrhoids. Her medications included apixaban, metoprolol succinate, metformin, losartan, sitagliptin, calcium, vitamin D, alendronate, and fish oil. She had mild tenderness to palpation of her thigh, but her exam was otherwise normal. Radiography of the left hip and pelvis showed no acute fracture (Figure 1). An upper and lower endoscopy 3 years prior to her presentation revealed internal hemorrhoids.

The patient is taking apixaban, a direct factor Xa inhibitor. The absence of other obvious sources of bleeding suggests that the cause of anemia and pain is most likely bleeding into the anterior thigh compartment, exacerbated by the underlying anticoagulation. Since there was no trauma preceding this episode, the differential diagnosis must be expanded to include other, less common sources of bleeding, including a vascular anomaly such as a pseudoaneurysm or arteriovenous malformation. While the radiographs were normal, a CT scan or MRI may allow for identification of a fracture, other bone lesion, and/or hematoma.

A complete blood count revealed a hemoglobin of 6.6 g/dL (normal, 11.5-14.1 g/dL) with a mean corpuscular volume of 62 fL (normal, 79-96 fL). A CT scan of the abdomen and pelvis with intravenous contrast (Figure 2) was obtained to evaluate for intra-abdominal hemorrhage and retroperitoneal hematoma; it showed mild abdominal and pelvic ascites, a small right pleural effusion with compressive atelectasis, and generalized anasarca, but no evidence of bleeding. She was administered 2 units of packed red blood cells. Apixaban was held and 40 mg intravenous pantoprazole twice daily was started. Her iron level was 12 µg/dL (normal, 50-170 µg/dL); total iron-binding capacity (TIBC) was 431 µg/dL (normal, 179-378 µg/dL); and ferritin level was 19 ng/mL (normal, 10-204 ng/mL). Her basic metabolic panel, liver enzymes, international normalized ratio, partial thromboplastin time, and folate were normal. Serum vitamin B₁₂ level was 277 pg/mL (normal, 213-816 pg/mL), and the reticulocyte count was 1.7%.

Myopathies can be hereditary or acquired. Hereditary myopathies include congenital myopathies, muscular dystrophies, channelopathies, primary metabolic myopathies, and mitochondrial myopathies. Acquired myopathies include infectious myopathies, inflammatory myopathies, endocrine myopathies, secondary metabolic myopathies, and drug-induced and toxic myopathies. The findings of hemorrhagic myositis and skin edema are very intriguing, especially given their localized features. An overt femur fracture was previously ruled out, and an anterior thigh compartment syndrome was considered less likely after orthopedic surgery consultation. There is no description of the patient taking medications that could cause myopathy (such as statins), and there are also no clinical features suggestive of primary inflammatory myopathy, such as dermatomyositis. Increased suspicion of a focal inflammatory process such as localized scleroderma with regional inflammatory myopathy or another focal myopathy must be considered. The next diagnostic steps would include measuring the creatine kinase level, as well as obtaining an MRI of the leg to assess the nature and extent of the myopathy.

Multidisciplinary involvement, including hematology, rheumatology, and surgery, aided in narrowing the differential diagnosis. On hospital day 10, an MRI of the left thigh was performed for suspicion of diabetic myonecrosis (Figure 4). The MRI revealed a 10 cm × 3.6 cm × 22 cm intramuscular hematoma in the belly of the vastus lateralis muscle with associated soft tissue swelling, overlying subcutaneous edema, and skin thickening that was suggestive of hemorrhagic diabetic myonecrosis with some atypical features. A rheumatology consult was requested to evaluate for possible vasculitis in the left lower extremity, and vasculitis was not considered likely. The diagnosis of diabetic myonecrosis with associated intramuscular hemorrhage secondary to apixaban was made after careful reconsideration of the clinical presentation, imaging and laboratory data, and overall picture. Based on the clinical findings, imaging results, and exclusion of alternative causative pathologies of thigh swelling, no biopsy was performed, as it was not considered necessary to make the diagnosis of diabetic myonecrosis. The patient was discharged on hospital day 11 and was doing well. She followed up with her primary care doctor and has regained normal function of her leg.

Diabetic myonecrosis, or diabetic muscle infarction, is an uncommon nontraumatic myopathy that occurs in patients with diabetes who develop acute, focal muscle pain without recent trauma. In this case, the muscle infarction was further complicated by hemorrhagic transformation. Diabetic myonecrosis is relatively uncommon and a diagnosis made by combining history, examination, and laboratory findings and excluding other alternative conditions.

A clear schema for approaching the patient with acute, nontraumatic myopathies is important in avoiding diagnostic error. One effective schema is to divide myopathy into infectious and noninfectious categories. Causes of infectious myopathy include bacterial infections (eg, pyomyositis), inflammatory damage to muscles associated with viruses (eg, influenza), as well as rarer causes. Bacterial processes tend to be relatively focal and affect a specific muscle group or anatomic compartment, while viral causes are often more diffuse and occur in the context of a systemic viral syndrome. Bacterial causes range in severity, and life-threatening conditions, such as necrotizing soft tissue infection, must be considered. In this case, bacterial causes were less likely given the patient’s lack of fever, leukocytosis, and systemic signs of infection.^1,2 However, these findings are not uniformly sensitive, and clinicians should not exclude potentially life- or limb-threatening infections without thorough evaluation. For example, pyomyositis may present without fever in the subacute stage, without leukocytosis if the patient is immunocompromised, and without overt pus if the infection is not in the suppurative stage.³ Viral causes were made less likely in this patient given the lack of a current or recent systemic viral syndrome.

Once infectious etiologies are deemed unlikely, noninfectious etiologies for nontraumatic myopathies should be considered. Some causes of noninfectious myopathy present with the muscle symptoms as a predominant feature, while others present in the context of another illness such as cancer, metabolic disorders, or other systemic disorders. Many noninfectious causes of myopathy associated with systemic illnesses have diffuse or relatively diffuse symptoms, with pain and/or weakness in multiple muscle groups, often in a bilateral distribution. Such examples include dermatomyositis and polymyositis as well as myositis associated with other rheumatologic conditions. Nontraumatic rhabdomyolysis is diffuse and can occur in association with medications and/or genetic conditions.

Angervall and Stener⁴ first described diabetic myonecrosis in 1965 as tumoriform focal muscular degeneration due to diabetic microangiopathy. The most commonly affected muscle groups in diabetic myonecrosis are the anterior thigh, calf, and posterior thigh, followed by muscles in the upper extremities.⁵ Patients with diabetic myonecrosis have an overall mean age at presentation of 44.6 years; affected patients with type 1 diabetes mellitus present at a mean age nearly 20 years younger than those with type 2 diabetes mellitus (35.9 years vs 52.2 years, respectively).⁶ Patients tend to have a long (often >15 years) history of diabetes with microvascular complications such as retinopathy (reported in 71%), nephropathy (reported in 57%), and/or neuropathy (reported in 55%).⁷

The mainstay of the diagnosis of diabetic myonecrosis is a thorough history and physical examination and imaging. Routine laboratory evaluation is relatively unhelpful in diagnosing diabetic myonecrosis, but appropriate imaging can provide valuable supportive information. A CT scan and MRI are both helpful in excluding other etiologies as well as identifying features consistent with diabetic myonecrosis. A CT scan can help exclude a localized abscess, tumor, or bone destruction and, in affected patients, may show increased subcutaneous attenuation and increased muscle size with decreased attenuation secondary to edema.² However, a CT scan may not give optimal assessment of muscle tissue, and therefore MRI may need to be considered. MRI T2 images have a sensitivity nearing 90% for detecting myonecrosis.¹ The diagnostic value of MRI often obviates the need for muscle biopsy.

Spontaneous infarction with hemorrhagic features seen on imaging can be explained by a combination of damage from atherosclerotic or microvascular disease, an activated coagulation cascade, and an impaired fibrinolytic pathway.⁸ Hemorrhagic conversion in diabetic myonecrosis appears to be uncommon.⁹ In our case, we suspect that it developed because of the combination of bleeding risk from apixaban and the underlying mechanisms of diabetic myonecrosis.

The treatment of diabetic myonecrosis is mainly supportive, with an emphasis on rest, nonsteroidal anti-inflammatory agents, antiplatelet agents, and strict glycemic control.¹⁰ There is conflicting information about the value of limb immobilization versus active physical therapy as appropriate treatment modalities.¹¹ Patients who present with clinical concern for sepsis or compartment syndrome require consultation for consideration of acute surgical intervention.¹⁰ The short-term prognosis is promising with supportive therapy, but the condition may recur.¹² The recurrence rate may be as high as 40%, with a 2-year mortality of 10%.¹³ Ultimately, patients need to be followed closely in the outpatient setting to reduce the risk of recurrence.

In this patient, the simultaneous occurrence of focal pain and acute blood loss anemia led to a diagnosis of diabetic myonecrosis that was complicated by hemorrhagic conversion, a truly painful coincidence. The patient underwent a thorough evaluation for acute blood loss before the diagnosis was ultimately made. Clinicians should consider diabetic myonecrosis in patients with diabetes who present with acute muscle pain but no evidence of infection.

• Diabetic myonecrosis is an underrecognized entity and should be included in the differential diagnosis for patients with diabetes who present with acute muscle pain and no history of trauma.
• Imaging with CT and/or MRI of the affected region is the mainstay of diagnosis; treatment is predicated on severity and risk factors and can range from conservative therapy to operative intervention.
• Although the prognosis is good in these patients, careful outpatient follow-up is necessary to oversee their recovery to help reduce the risk of recurrence.

The authors thank Dr Vijay Singh for his radiology input on image selection for this manuscript.

This icon represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

An 81-year-old woman with a remote history of left proximal femoral fracture (status post–open reduction and internal fixation) acutely developed severe pain in her left lateral thigh while at her home. A few days prior to her left thigh pain, the patient had routine blood work done. Her lab results (prior to the onset of her symptoms) revealed that her hemoglobin decreased from 10 g/dL, noted 9 months earlier, to 6.6 g/dL. Her primary care physician, who was planning to see the patient for her next regularly scheduled follow-up, was made aware of the patient’s decline in hemoglobin prior to the planned visit. The primary care physician called the patient to inform her about her concerning lab findings and coincidentally became aware of the acute, new-onset left thigh pain. The primary care physician requested that the patient be taken by her daughter to the emergency department (ED) for further evaluation.

The acute decrease in hemoglobin carries a broad differential and may or may not be related to the subsequent development of thigh pain. The presentation of an acute onset of pain in the thigh within the context of this patient’s age and gender suggests a femur fracture; this can be osteoporosis-related or a pathologic fracture associated with malignancy. Several malignancies are plausible, including multiple myeloma (given the anemia) or breast cancer. The proximal part of long bones is the most common site of pathologic fractures, and the femur accounts for half of these cases. Plain radiographs would be appropriate initial imaging and may be followed by either a computed tomography (CT) scan or magnetic resonance imaging (MRI).

In the ED, she denied any recent trauma, hemoptysis, recent dark or bloody stools, vaginal bleeding, abdominal pain, or history of gastric ulcers. She had not experienced any similar episodes of thigh pain in the past. She had a history of atrial fibrillation, hypertension, diabetes mellitus type 2 with diabetic retinopathy and peripheral neuropathy, osteoporosis, nonalcoholic fatty liver disease (NAFLD), and internal hemorrhoids. Her medications included apixaban, metoprolol succinate, metformin, losartan, sitagliptin, calcium, vitamin D, alendronate, and fish oil. She had mild tenderness to palpation of her thigh, but her exam was otherwise normal. Radiography of the left hip and pelvis showed no acute fracture (Figure 1). An upper and lower endoscopy 3 years prior to her presentation revealed internal hemorrhoids.

The patient is taking apixaban, a direct factor Xa inhibitor. The absence of other obvious sources of bleeding suggests that the cause of anemia and pain is most likely bleeding into the anterior thigh compartment, exacerbated by the underlying anticoagulation. Since there was no trauma preceding this episode, the differential diagnosis must be expanded to include other, less common sources of bleeding, including a vascular anomaly such as a pseudoaneurysm or arteriovenous malformation. While the radiographs were normal, a CT scan or MRI may allow for identification of a fracture, other bone lesion, and/or hematoma.

A complete blood count revealed a hemoglobin of 6.6 g/dL (normal, 11.5-14.1 g/dL) with a mean corpuscular volume of 62 fL (normal, 79-96 fL). A CT scan of the abdomen and pelvis with intravenous contrast (Figure 2) was obtained to evaluate for intra-abdominal hemorrhage and retroperitoneal hematoma; it showed mild abdominal and pelvic ascites, a small right pleural effusion with compressive atelectasis, and generalized anasarca, but no evidence of bleeding. She was administered 2 units of packed red blood cells. Apixaban was held and 40 mg intravenous pantoprazole twice daily was started. Her iron level was 12 µg/dL (normal, 50-170 µg/dL); total iron-binding capacity (TIBC) was 431 µg/dL (normal, 179-378 µg/dL); and ferritin level was 19 ng/mL (normal, 10-204 ng/mL). Her basic metabolic panel, liver enzymes, international normalized ratio, partial thromboplastin time, and folate were normal. Serum vitamin B₁₂ level was 277 pg/mL (normal, 213-816 pg/mL), and the reticulocyte count was 1.7%.

Myopathies can be hereditary or acquired. Hereditary myopathies include congenital myopathies, muscular dystrophies, channelopathies, primary metabolic myopathies, and mitochondrial myopathies. Acquired myopathies include infectious myopathies, inflammatory myopathies, endocrine myopathies, secondary metabolic myopathies, and drug-induced and toxic myopathies. The findings of hemorrhagic myositis and skin edema are very intriguing, especially given their localized features. An overt femur fracture was previously ruled out, and an anterior thigh compartment syndrome was considered less likely after orthopedic surgery consultation. There is no description of the patient taking medications that could cause myopathy (such as statins), and there are also no clinical features suggestive of primary inflammatory myopathy, such as dermatomyositis. Increased suspicion of a focal inflammatory process such as localized scleroderma with regional inflammatory myopathy or another focal myopathy must be considered. The next diagnostic steps would include measuring the creatine kinase level, as well as obtaining an MRI of the leg to assess the nature and extent of the myopathy.

Multidisciplinary involvement, including hematology, rheumatology, and surgery, aided in narrowing the differential diagnosis. On hospital day 10, an MRI of the left thigh was performed for suspicion of diabetic myonecrosis (Figure 4). The MRI revealed a 10 cm × 3.6 cm × 22 cm intramuscular hematoma in the belly of the vastus lateralis muscle with associated soft tissue swelling, overlying subcutaneous edema, and skin thickening that was suggestive of hemorrhagic diabetic myonecrosis with some atypical features. A rheumatology consult was requested to evaluate for possible vasculitis in the left lower extremity, and vasculitis was not considered likely. The diagnosis of diabetic myonecrosis with associated intramuscular hemorrhage secondary to apixaban was made after careful reconsideration of the clinical presentation, imaging and laboratory data, and overall picture. Based on the clinical findings, imaging results, and exclusion of alternative causative pathologies of thigh swelling, no biopsy was performed, as it was not considered necessary to make the diagnosis of diabetic myonecrosis. The patient was discharged on hospital day 11 and was doing well. She followed up with her primary care doctor and has regained normal function of her leg.

Diabetic myonecrosis, or diabetic muscle infarction, is an uncommon nontraumatic myopathy that occurs in patients with diabetes who develop acute, focal muscle pain without recent trauma. In this case, the muscle infarction was further complicated by hemorrhagic transformation. Diabetic myonecrosis is relatively uncommon and a diagnosis made by combining history, examination, and laboratory findings and excluding other alternative conditions.

A clear schema for approaching the patient with acute, nontraumatic myopathies is important in avoiding diagnostic error. One effective schema is to divide myopathy into infectious and noninfectious categories. Causes of infectious myopathy include bacterial infections (eg, pyomyositis), inflammatory damage to muscles associated with viruses (eg, influenza), as well as rarer causes. Bacterial processes tend to be relatively focal and affect a specific muscle group or anatomic compartment, while viral causes are often more diffuse and occur in the context of a systemic viral syndrome. Bacterial causes range in severity, and life-threatening conditions, such as necrotizing soft tissue infection, must be considered. In this case, bacterial causes were less likely given the patient’s lack of fever, leukocytosis, and systemic signs of infection.^1,2 However, these findings are not uniformly sensitive, and clinicians should not exclude potentially life- or limb-threatening infections without thorough evaluation. For example, pyomyositis may present without fever in the subacute stage, without leukocytosis if the patient is immunocompromised, and without overt pus if the infection is not in the suppurative stage.³ Viral causes were made less likely in this patient given the lack of a current or recent systemic viral syndrome.

Once infectious etiologies are deemed unlikely, noninfectious etiologies for nontraumatic myopathies should be considered. Some causes of noninfectious myopathy present with the muscle symptoms as a predominant feature, while others present in the context of another illness such as cancer, metabolic disorders, or other systemic disorders. Many noninfectious causes of myopathy associated with systemic illnesses have diffuse or relatively diffuse symptoms, with pain and/or weakness in multiple muscle groups, often in a bilateral distribution. Such examples include dermatomyositis and polymyositis as well as myositis associated with other rheumatologic conditions. Nontraumatic rhabdomyolysis is diffuse and can occur in association with medications and/or genetic conditions.

Angervall and Stener⁴ first described diabetic myonecrosis in 1965 as tumoriform focal muscular degeneration due to diabetic microangiopathy. The most commonly affected muscle groups in diabetic myonecrosis are the anterior thigh, calf, and posterior thigh, followed by muscles in the upper extremities.⁵ Patients with diabetic myonecrosis have an overall mean age at presentation of 44.6 years; affected patients with type 1 diabetes mellitus present at a mean age nearly 20 years younger than those with type 2 diabetes mellitus (35.9 years vs 52.2 years, respectively).⁶ Patients tend to have a long (often >15 years) history of diabetes with microvascular complications such as retinopathy (reported in 71%), nephropathy (reported in 57%), and/or neuropathy (reported in 55%).⁷

The mainstay of the diagnosis of diabetic myonecrosis is a thorough history and physical examination and imaging. Routine laboratory evaluation is relatively unhelpful in diagnosing diabetic myonecrosis, but appropriate imaging can provide valuable supportive information. A CT scan and MRI are both helpful in excluding other etiologies as well as identifying features consistent with diabetic myonecrosis. A CT scan can help exclude a localized abscess, tumor, or bone destruction and, in affected patients, may show increased subcutaneous attenuation and increased muscle size with decreased attenuation secondary to edema.² However, a CT scan may not give optimal assessment of muscle tissue, and therefore MRI may need to be considered. MRI T2 images have a sensitivity nearing 90% for detecting myonecrosis.¹ The diagnostic value of MRI often obviates the need for muscle biopsy.

Spontaneous infarction with hemorrhagic features seen on imaging can be explained by a combination of damage from atherosclerotic or microvascular disease, an activated coagulation cascade, and an impaired fibrinolytic pathway.⁸ Hemorrhagic conversion in diabetic myonecrosis appears to be uncommon.⁹ In our case, we suspect that it developed because of the combination of bleeding risk from apixaban and the underlying mechanisms of diabetic myonecrosis.

The treatment of diabetic myonecrosis is mainly supportive, with an emphasis on rest, nonsteroidal anti-inflammatory agents, antiplatelet agents, and strict glycemic control.¹⁰ There is conflicting information about the value of limb immobilization versus active physical therapy as appropriate treatment modalities.¹¹ Patients who present with clinical concern for sepsis or compartment syndrome require consultation for consideration of acute surgical intervention.¹⁰ The short-term prognosis is promising with supportive therapy, but the condition may recur.¹² The recurrence rate may be as high as 40%, with a 2-year mortality of 10%.¹³ Ultimately, patients need to be followed closely in the outpatient setting to reduce the risk of recurrence.

In this patient, the simultaneous occurrence of focal pain and acute blood loss anemia led to a diagnosis of diabetic myonecrosis that was complicated by hemorrhagic conversion, a truly painful coincidence. The patient underwent a thorough evaluation for acute blood loss before the diagnosis was ultimately made. Clinicians should consider diabetic myonecrosis in patients with diabetes who present with acute muscle pain but no evidence of infection.

• Diabetic myonecrosis is an underrecognized entity and should be included in the differential diagnosis for patients with diabetes who present with acute muscle pain and no history of trauma.
• Imaging with CT and/or MRI of the affected region is the mainstay of diagnosis; treatment is predicated on severity and risk factors and can range from conservative therapy to operative intervention.
• Although the prognosis is good in these patients, careful outpatient follow-up is necessary to oversee their recovery to help reduce the risk of recurrence.

The authors thank Dr Vijay Singh for his radiology input on image selection for this manuscript.

This icon represents the patient’s case. Each paragraph that follows represents the discussant’s thoughts.

An 81-year-old woman with a remote history of left proximal femoral fracture (status post–open reduction and internal fixation) acutely developed severe pain in her left lateral thigh while at her home. A few days prior to her left thigh pain, the patient had routine blood work done. Her lab results (prior to the onset of her symptoms) revealed that her hemoglobin decreased from 10 g/dL, noted 9 months earlier, to 6.6 g/dL. Her primary care physician, who was planning to see the patient for her next regularly scheduled follow-up, was made aware of the patient’s decline in hemoglobin prior to the planned visit. The primary care physician called the patient to inform her about her concerning lab findings and coincidentally became aware of the acute, new-onset left thigh pain. The primary care physician requested that the patient be taken by her daughter to the emergency department (ED) for further evaluation.

The acute decrease in hemoglobin carries a broad differential and may or may not be related to the subsequent development of thigh pain. The presentation of an acute onset of pain in the thigh within the context of this patient’s age and gender suggests a femur fracture; this can be osteoporosis-related or a pathologic fracture associated with malignancy. Several malignancies are plausible, including multiple myeloma (given the anemia) or breast cancer. The proximal part of long bones is the most common site of pathologic fractures, and the femur accounts for half of these cases. Plain radiographs would be appropriate initial imaging and may be followed by either a computed tomography (CT) scan or magnetic resonance imaging (MRI).

In the ED, she denied any recent trauma, hemoptysis, recent dark or bloody stools, vaginal bleeding, abdominal pain, or history of gastric ulcers. She had not experienced any similar episodes of thigh pain in the past. She had a history of atrial fibrillation, hypertension, diabetes mellitus type 2 with diabetic retinopathy and peripheral neuropathy, osteoporosis, nonalcoholic fatty liver disease (NAFLD), and internal hemorrhoids. Her medications included apixaban, metoprolol succinate, metformin, losartan, sitagliptin, calcium, vitamin D, alendronate, and fish oil. She had mild tenderness to palpation of her thigh, but her exam was otherwise normal. Radiography of the left hip and pelvis showed no acute fracture (Figure 1). An upper and lower endoscopy 3 years prior to her presentation revealed internal hemorrhoids.

The patient is taking apixaban, a direct factor Xa inhibitor. The absence of other obvious sources of bleeding suggests that the cause of anemia and pain is most likely bleeding into the anterior thigh compartment, exacerbated by the underlying anticoagulation. Since there was no trauma preceding this episode, the differential diagnosis must be expanded to include other, less common sources of bleeding, including a vascular anomaly such as a pseudoaneurysm or arteriovenous malformation. While the radiographs were normal, a CT scan or MRI may allow for identification of a fracture, other bone lesion, and/or hematoma.

A complete blood count revealed a hemoglobin of 6.6 g/dL (normal, 11.5-14.1 g/dL) with a mean corpuscular volume of 62 fL (normal, 79-96 fL). A CT scan of the abdomen and pelvis with intravenous contrast (Figure 2) was obtained to evaluate for intra-abdominal hemorrhage and retroperitoneal hematoma; it showed mild abdominal and pelvic ascites, a small right pleural effusion with compressive atelectasis, and generalized anasarca, but no evidence of bleeding. She was administered 2 units of packed red blood cells. Apixaban was held and 40 mg intravenous pantoprazole twice daily was started. Her iron level was 12 µg/dL (normal, 50-170 µg/dL); total iron-binding capacity (TIBC) was 431 µg/dL (normal, 179-378 µg/dL); and ferritin level was 19 ng/mL (normal, 10-204 ng/mL). Her basic metabolic panel, liver enzymes, international normalized ratio, partial thromboplastin time, and folate were normal. Serum vitamin B₁₂ level was 277 pg/mL (normal, 213-816 pg/mL), and the reticulocyte count was 1.7%.

Myopathies can be hereditary or acquired. Hereditary myopathies include congenital myopathies, muscular dystrophies, channelopathies, primary metabolic myopathies, and mitochondrial myopathies. Acquired myopathies include infectious myopathies, inflammatory myopathies, endocrine myopathies, secondary metabolic myopathies, and drug-induced and toxic myopathies. The findings of hemorrhagic myositis and skin edema are very intriguing, especially given their localized features. An overt femur fracture was previously ruled out, and an anterior thigh compartment syndrome was considered less likely after orthopedic surgery consultation. There is no description of the patient taking medications that could cause myopathy (such as statins), and there are also no clinical features suggestive of primary inflammatory myopathy, such as dermatomyositis. Increased suspicion of a focal inflammatory process such as localized scleroderma with regional inflammatory myopathy or another focal myopathy must be considered. The next diagnostic steps would include measuring the creatine kinase level, as well as obtaining an MRI of the leg to assess the nature and extent of the myopathy.

Multidisciplinary involvement, including hematology, rheumatology, and surgery, aided in narrowing the differential diagnosis. On hospital day 10, an MRI of the left thigh was performed for suspicion of diabetic myonecrosis (Figure 4). The MRI revealed a 10 cm × 3.6 cm × 22 cm intramuscular hematoma in the belly of the vastus lateralis muscle with associated soft tissue swelling, overlying subcutaneous edema, and skin thickening that was suggestive of hemorrhagic diabetic myonecrosis with some atypical features. A rheumatology consult was requested to evaluate for possible vasculitis in the left lower extremity, and vasculitis was not considered likely. The diagnosis of diabetic myonecrosis with associated intramuscular hemorrhage secondary to apixaban was made after careful reconsideration of the clinical presentation, imaging and laboratory data, and overall picture. Based on the clinical findings, imaging results, and exclusion of alternative causative pathologies of thigh swelling, no biopsy was performed, as it was not considered necessary to make the diagnosis of diabetic myonecrosis. The patient was discharged on hospital day 11 and was doing well. She followed up with her primary care doctor and has regained normal function of her leg.

Diabetic myonecrosis, or diabetic muscle infarction, is an uncommon nontraumatic myopathy that occurs in patients with diabetes who develop acute, focal muscle pain without recent trauma. In this case, the muscle infarction was further complicated by hemorrhagic transformation. Diabetic myonecrosis is relatively uncommon and a diagnosis made by combining history, examination, and laboratory findings and excluding other alternative conditions.

A clear schema for approaching the patient with acute, nontraumatic myopathies is important in avoiding diagnostic error. One effective schema is to divide myopathy into infectious and noninfectious categories. Causes of infectious myopathy include bacterial infections (eg, pyomyositis), inflammatory damage to muscles associated with viruses (eg, influenza), as well as rarer causes. Bacterial processes tend to be relatively focal and affect a specific muscle group or anatomic compartment, while viral causes are often more diffuse and occur in the context of a systemic viral syndrome. Bacterial causes range in severity, and life-threatening conditions, such as necrotizing soft tissue infection, must be considered. In this case, bacterial causes were less likely given the patient’s lack of fever, leukocytosis, and systemic signs of infection.^1,2 However, these findings are not uniformly sensitive, and clinicians should not exclude potentially life- or limb-threatening infections without thorough evaluation. For example, pyomyositis may present without fever in the subacute stage, without leukocytosis if the patient is immunocompromised, and without overt pus if the infection is not in the suppurative stage.³ Viral causes were made less likely in this patient given the lack of a current or recent systemic viral syndrome.

Once infectious etiologies are deemed unlikely, noninfectious etiologies for nontraumatic myopathies should be considered. Some causes of noninfectious myopathy present with the muscle symptoms as a predominant feature, while others present in the context of another illness such as cancer, metabolic disorders, or other systemic disorders. Many noninfectious causes of myopathy associated with systemic illnesses have diffuse or relatively diffuse symptoms, with pain and/or weakness in multiple muscle groups, often in a bilateral distribution. Such examples include dermatomyositis and polymyositis as well as myositis associated with other rheumatologic conditions. Nontraumatic rhabdomyolysis is diffuse and can occur in association with medications and/or genetic conditions.

Angervall and Stener⁴ first described diabetic myonecrosis in 1965 as tumoriform focal muscular degeneration due to diabetic microangiopathy. The most commonly affected muscle groups in diabetic myonecrosis are the anterior thigh, calf, and posterior thigh, followed by muscles in the upper extremities.⁵ Patients with diabetic myonecrosis have an overall mean age at presentation of 44.6 years; affected patients with type 1 diabetes mellitus present at a mean age nearly 20 years younger than those with type 2 diabetes mellitus (35.9 years vs 52.2 years, respectively).⁶ Patients tend to have a long (often >15 years) history of diabetes with microvascular complications such as retinopathy (reported in 71%), nephropathy (reported in 57%), and/or neuropathy (reported in 55%).⁷

The mainstay of the diagnosis of diabetic myonecrosis is a thorough history and physical examination and imaging. Routine laboratory evaluation is relatively unhelpful in diagnosing diabetic myonecrosis, but appropriate imaging can provide valuable supportive information. A CT scan and MRI are both helpful in excluding other etiologies as well as identifying features consistent with diabetic myonecrosis. A CT scan can help exclude a localized abscess, tumor, or bone destruction and, in affected patients, may show increased subcutaneous attenuation and increased muscle size with decreased attenuation secondary to edema.² However, a CT scan may not give optimal assessment of muscle tissue, and therefore MRI may need to be considered. MRI T2 images have a sensitivity nearing 90% for detecting myonecrosis.¹ The diagnostic value of MRI often obviates the need for muscle biopsy.

Spontaneous infarction with hemorrhagic features seen on imaging can be explained by a combination of damage from atherosclerotic or microvascular disease, an activated coagulation cascade, and an impaired fibrinolytic pathway.⁸ Hemorrhagic conversion in diabetic myonecrosis appears to be uncommon.⁹ In our case, we suspect that it developed because of the combination of bleeding risk from apixaban and the underlying mechanisms of diabetic myonecrosis.

The treatment of diabetic myonecrosis is mainly supportive, with an emphasis on rest, nonsteroidal anti-inflammatory agents, antiplatelet agents, and strict glycemic control.¹⁰ There is conflicting information about the value of limb immobilization versus active physical therapy as appropriate treatment modalities.¹¹ Patients who present with clinical concern for sepsis or compartment syndrome require consultation for consideration of acute surgical intervention.¹⁰ The short-term prognosis is promising with supportive therapy, but the condition may recur.¹² The recurrence rate may be as high as 40%, with a 2-year mortality of 10%.¹³ Ultimately, patients need to be followed closely in the outpatient setting to reduce the risk of recurrence.

In this patient, the simultaneous occurrence of focal pain and acute blood loss anemia led to a diagnosis of diabetic myonecrosis that was complicated by hemorrhagic conversion, a truly painful coincidence. The patient underwent a thorough evaluation for acute blood loss before the diagnosis was ultimately made. Clinicians should consider diabetic myonecrosis in patients with diabetes who present with acute muscle pain but no evidence of infection.

• Diabetic myonecrosis is an underrecognized entity and should be included in the differential diagnosis for patients with diabetes who present with acute muscle pain and no history of trauma.
• Imaging with CT and/or MRI of the affected region is the mainstay of diagnosis; treatment is predicated on severity and risk factors and can range from conservative therapy to operative intervention.
• Although the prognosis is good in these patients, careful outpatient follow-up is necessary to oversee their recovery to help reduce the risk of recurrence.

The authors thank Dr Vijay Singh for his radiology input on image selection for this manuscript.

A 48-year-old woman presented to the emergency department after 2 days of nonproductive cough, chest discomfort, worsening shortness of breath, and subjective fever. She had a history of systemic sclerosis. She was currently taking prednisone 20 mg daily and aspirin 81 mg daily.

Physical examination revealed tachypnea (28 breaths per minute), and bronchial breath sounds in the left lower chest posteriorly.

The initial laboratory workup revealed:

• Hemoglobin 106 g/L (reference range 115–155)
• Mean corpuscular volume 84 fL (80–100)
• White blood cell count 29.4 × 10⁹/L (3.70–11.0), with 85% neutrophils
• Platelet count 180 × 10⁹/L (150–350)
• Lactate dehydrogenase 312 U/L (100–220).

Chest radiography showed opacification of the lower lobe of the left lung.

She was admitted to the hospital and started treatment with intravenous azithromycin and ceftriaxone for presumed community-acquired pneumonia, based on the clinical presentation and findings on chest radiography. Because of her immunosuppression (due to chronic prednisone therapy) and her high lactate dehydrogenase level, Pneumocystis jirovecii pneumonia was suspected, and because she had a history of allergy to trimethoprim-sulfamethoxazole and pentamidine, she was started on dapsone.

During the next 24 hours, she developed worsening dyspnea, hypoxia, and cyanosis. She was placed on an air-entrainment mask, with a fraction of inspired oxygen of 0.5. Pulse oximetry showed an oxygen saturation of 85%, but arterial blood gas analysis indicated an oxyhemoglobin concentration of 95%.

THE ‘SATURATION GAP’

1. Which is most likely to have caused the discrepancy between the oxyhemoglobin concentration and the oxygen saturation by pulse oximetry in this patient?

• Methemoglobinemia
• Carbon monoxide poisoning
• Inappropriate placement of the pulse oximeter probe
• Pulmonary embolism

Methemoglobinemia is the most likely cause of the discrepancy between the oxyhemoglobin levels and the oxygen saturation by pulse oximetry, a phenomenon also known as the “saturation gap.” Other common causes are cyanide poisoning and carbon monoxide poisoning.

P jirovecii pneumonia was suspected, and dapsone was started in light of her allergy to trimethoprim-sulfamethoxazole and pentamidine

Carbon monoxide poisoning, however, does not explain our patient’s cyanosis. On the contrary, carbon monoxide poisoning can actually cause the patient’s lips and mucous membranes to appear unnaturally bright pink. Also, carbon monoxide poisoning raises the blood concentration of carboxyhemoglobin (which has a high affinity for oxygen), and this usually causes pulse oximetry to read inappropriately high, whereas in our patient it read low.

Incorrect placement of the pulse oximeter probe can result in an inaccurate measurement of oxygen saturation. Visualization of the waveform on the plethysmograph or the signal quality index can be used to assess adequate placement of the pulse oximeter probe. However, inadequate probe placement does not explain our patient’s dyspnea and cyanosis.

Pulmonary embolism can lead to hypoxia as a result of ventilation-perfusion mismatch. However, pulmonary embolism leading to low oxygen saturation on pulse oximetry will also lead to concomitantly low oxyhemoglobin levels as measured by arterial blood gas analysis, and this was not seen in our patient.

BACK TO OUR PATIENT

Because there was a discrepancy between our patient’s pulse oximetry reading and oxyhemoglobin concentration by arterial blood gas measurement, her methemoglobin level was checked and was found to be 30%, thus confirming the diagnosis of methemoglobinemia.

WHAT IS METHEMOGLOBINEMIA, AND WHAT CAUSES IT?

Oxygen is normally bound to iron in its ferrous (Fe²⁺) form in hemoglobin to form oxyhemoglobin. Oxidative stress in the body can cause iron to change from the ferrous to the ferric (Fe³⁺) state, forming methemoglobin. Methemoglobin is normally present in the blood in low levels (< 1% of the total hemoglobin), and ferric iron is reduced and recycled back to the ferrous form by NADH-cytochrome b5 reductase, an enzyme present in red blood cells. This protective mechanism maintains methemoglobin levels within safe limits. But increased production can lead to accumulation of methemoglobin, resulting in dyspnea and hypoxia and the condition referred to as methemoglobinemia.¹

Increased levels of methemoglobin relative to normal hemoglobin cause tissue hypoxia by several mechanisms. Methemoglobin cannot efficiently carry oxygen; instead, it binds to water or to a hydroxide ion depending on the pH of the environment.² Therefore, the hemoglobin molecule does not carry its usual load of oxygen, and hypoxia results from the reduced delivery of oxygen to tissues. In addition, an increased concentration of methemoglobin causes a leftward shift in the oxygen-hemoglobin dissociation curve, representing an increased affinity to bound oxygen in the remaining heme groups. The tightly bound oxygen is not adequately released at the tissue level, thus causing cellular hypoxia.

Methemoglobinemia is most often caused by exposure to an oxidizing chemical or drug that increases production of methemoglobin. In rare cases, it is caused by a congenital deficiency of NADH-cytochrome b5 reductase.³

2. Which of the following drugs can cause methemoglobinemia?

• Acetaminophen
• Dapsone
• Benzocaine
• Primaquine

All four of these drugs are common culprits for causing acquired methemoglobinemia; others include chloroquine, nitroglycerin, and sulfonamides.^4–6

The increased production of methemoglobin caused by these drugs overwhelms the protective effect of reducing enzymes and can lead to an accumulation of methemoglobin. However, because of variability in cellular metabolism, not every person who takes these drugs develops dangerous levels of methemoglobin.

Dapsone and benzocaine are the most commonly encountered drugs known to cause methemoglobinemia (Table 1). Dapsone is an anti-inflammatory and antimicrobial agent most commonly used for treating lepromatous leprosy and dermatitis herpetiformis. It is also often prescribed for prophylaxis and treatment of P jirovecii pneumonia in immunosuppressed individuals.⁷ Benzocaine is a local anesthetic and was commonly used before procedures such as oral or dental surgery, transesophageal echocardiography, and endoscopy.^8–10 Even low doses of benzocaine can lead to high levels of methemoglobinemia. However, the availability of other, safer anesthetics now limits the use of benzocaine in major US centers. In addition, the topical anesthetic Emla (lidocaine plus prilocaine) has been recently reported as a cause of methemoglobinemia in infants and children.^11,12

Also, potentially fatal methemoglobinemia has been reported in patients with a deficiency of G-6-phosphate dehydrogenase (G6PD) who received rasburicase, a recombinant version of urate oxidase enzyme used to prevent and treat tumor lysis syndrome.^13,14

Lastly, methemoglobinemia has been reported in patients with inflammatory bowel disease treated with mesalamine.

Although this adverse reaction is rare, clinicians should be aware of it, since these agents are commonly used in everyday medical practice.¹⁵

RECOGNIZING THE DANGER SIGNS

The clinical manifestations of methemoglobinemia are directly proportional to the percentage of methemoglobin in red blood cells. Cyanosis generally becomes apparent at concentrations around 15%, at which point the patient may still have no symptoms. Anxiety, lightheadedness, tachycardia, and dizziness manifest at levels of 20% to 30%. Fatigue, confusion, dizziness, tachypnea, and worsening tachycardia occur at levels of 30% to 50%. Levels of 50% to 70% cause coma, seizures, arrhythmias, and acidosis, and levels over 70% are considered lethal.¹⁶

While these levels provide a general guideline of symptomatology in an otherwise healthy person, it is important to remember that patients with underlying conditions such as anemia, lung disease (both of which our patient had), sepsis, thalassemia, G6PD deficiency, and sickle cell disease can manifest symptoms at lower concentrations of methemoglobin.^1,17

Most patients who develop clinically significant levels of methemoglobin do so within the first few hours of starting one of the culprit drugs.

DIAGNOSIS: METHEMOGLOBINEMIA AND THE SATURATION GAP

In patients with methemoglobinemia, pulse oximetry gives lower values than arterial blood gas oxygen measurements. Regular pulse oximetry works by measuring light absorbance at two distinct wavelengths (660 and 940 nm) to calculate the ratio of oxyhemoglobin to deoxyhemoglobin. Methemoglobin absorbs light at both these wavelengths, thus lowering the pulse oximetry values.¹

In contrast, oxygen saturation of arterial blood gas (oxyhemoglobin) is calculated indirectly from the concentration of dissolved oxygen in the blood and does not include oxygen bound to hemoglobin. Therefore, the measured arterial oxygen saturation is often normal in patients with methemoglobinemia since it relies only on inspired oxygen content and is independent of the methemoglobin concentration.¹⁸

Patients with clinically significant methemoglobinemia usually have a saturation gap > 10%

Oxygen supplementation can raise the level of oxyhemoglobin, which is a measure of dissolved oxygen, but the oxygen saturation as measured by pulse oximetry remains largely unchanged—ie, the saturation gap. A difference of more than 5% between the oxygen saturation by pulse oximetry and blood gas analysis is abnormal. Patients with clinically significant methemoglobinemia usually have a saturation gap greater than 10%.

Several other unique features should raise suspicion of methemoglobinemia. It should be considered in a patient presenting with cyanosis out of proportion to the oxygen saturation and in a patient with low oxygen saturation and a normal chest radiograph. Other clues include blood that is chocolate-colored on gross examination, rather than the dark red of deoxygenated blood.

Co-oximetry measures oxygen saturation using different wavelengths of light to distinguish between fractions of oxyhemoglobin, deoxyhemoglobin, and methemoglobin, but it is not widely available.

THE NEXT STEP

3. What is the next step in the management of our patient?

• Discontinue the dapsone
• Start methylene blue
• Start hyperbaric oxygen
• Give sodium thiosulfate
• Discontinue dapsone and start methylene blue

The next step in her management should be to stop the dapsone and start an infusion of methylene blue. Hyperbaric oxygen is used in treating carbon monoxide poisoning, and sodium thiosulfate is used in treating cyanide toxicity. They would not be appropriate in this patient’s care.

MANAGEMENT OF ACQUIRED METHEMOGLOBINEMIA

The first, most critical step in managing acquired methemoglobinemia is to immediately discontinue the suspected offending agent. In most patients without a concomitant condition such as anemia or lung disease and with a methemoglobin level below 20%, discontinuing the offending agent may suffice. Patients with a level of 20% or greater and patients with cardiac and pulmonary disease, who develop symptoms at lower concentrations of methemoglobin, require infusion of methylene blue.

Methylene blue is converted to its reduced form, leukomethylene blue, by NADPH-methemoglobin reductase. As it is oxidized, leukomethylene blue reduces methemoglobin to hemoglobin. A dose of 1 mg/kg intravenously is given at first. The response is usually dramatic, with a reduction in methemoglobin levels and improvement in symptoms often within 30 to 60 minutes. If levels remain high, the dose can be repeated 1 hour later.¹⁹

A caveat: methylene blue should be avoided in patients with complete G6PD deficiency

A caveat: methylene blue therapy should be avoided in patients with complete G6PD deficiency. Methylene blue works through the enzyme NADPH-methemoglobin reductase, and since patients with G6PD deficiency lack this enzyme, methylene blue is ineffective. In fact, since it cannot be reduced, excessive methylene blue can oxidize hemoglobin to methemoglobin, further exacerbating the condition. In patients with partial G6PD deficiency, methylene blue is still recommended as a first-line treatment, but at a lower initial dose (0.3–0.5 mg/kg). However, in patients with significant hemolysis, an exchange transfusion is the only treatment option.

CASE CONCLUDED

Since dapsone was identified as the likely cause of methemoglobinemia in our patient, it was immediately discontinued. Because she was symptomatic, 70 mg of methylene blue was given intravenously. Over the next 60 minutes, her clinical condition improved significantly. A repeat methemoglobin measurement was 3%.

She was discharged home the next day on oral antibiotics to complete treatment for community-acquired pneumonia.

TAKE-HOME POINTS

• Consider methemoglobinemia in a patient with unexplained cyanosis.
• Pulse oximetry gives lower values than arterial blood gas oxygen measurements in patients with methemoglobinemia, and pulse oximetry readings do not improve with supplemental oxygen.
• A saturation gap greater than 5% strongly suggests methemoglobinemia.
• The diagnosis of methemoglobinemia is confirmed by measuring the methemoglobin concentration.
• Most healthy patients develop symptoms at methemoglobin levels of 20%, but patients with comorbidities can develop symptoms at lower levels.
• A number of drugs can cause methemoglobinemia, even at therapeutic dosages.
• Treatment is generally indicated in patients who have symptoms or in healthy patients who have a methemoglobin level of 20% or greater.
• Identifying and promptly discontinuing the causative agent and initiating methylene blue infusion (1 mg/kg over 5 minutes) is the preferred treatment.

A 48-year-old woman presented to the emergency department after 2 days of nonproductive cough, chest discomfort, worsening shortness of breath, and subjective fever. She had a history of systemic sclerosis. She was currently taking prednisone 20 mg daily and aspirin 81 mg daily.

Physical examination revealed tachypnea (28 breaths per minute), and bronchial breath sounds in the left lower chest posteriorly.

The initial laboratory workup revealed:

• Hemoglobin 106 g/L (reference range 115–155)
• Mean corpuscular volume 84 fL (80–100)
• White blood cell count 29.4 × 10⁹/L (3.70–11.0), with 85% neutrophils
• Platelet count 180 × 10⁹/L (150–350)
• Lactate dehydrogenase 312 U/L (100–220).

Chest radiography showed opacification of the lower lobe of the left lung.

She was admitted to the hospital and started treatment with intravenous azithromycin and ceftriaxone for presumed community-acquired pneumonia, based on the clinical presentation and findings on chest radiography. Because of her immunosuppression (due to chronic prednisone therapy) and her high lactate dehydrogenase level, Pneumocystis jirovecii pneumonia was suspected, and because she had a history of allergy to trimethoprim-sulfamethoxazole and pentamidine, she was started on dapsone.

During the next 24 hours, she developed worsening dyspnea, hypoxia, and cyanosis. She was placed on an air-entrainment mask, with a fraction of inspired oxygen of 0.5. Pulse oximetry showed an oxygen saturation of 85%, but arterial blood gas analysis indicated an oxyhemoglobin concentration of 95%.

THE ‘SATURATION GAP’

1. Which is most likely to have caused the discrepancy between the oxyhemoglobin concentration and the oxygen saturation by pulse oximetry in this patient?

• Methemoglobinemia
• Carbon monoxide poisoning
• Inappropriate placement of the pulse oximeter probe
• Pulmonary embolism

Methemoglobinemia is the most likely cause of the discrepancy between the oxyhemoglobin levels and the oxygen saturation by pulse oximetry, a phenomenon also known as the “saturation gap.” Other common causes are cyanide poisoning and carbon monoxide poisoning.

P jirovecii pneumonia was suspected, and dapsone was started in light of her allergy to trimethoprim-sulfamethoxazole and pentamidine

Carbon monoxide poisoning, however, does not explain our patient’s cyanosis. On the contrary, carbon monoxide poisoning can actually cause the patient’s lips and mucous membranes to appear unnaturally bright pink. Also, carbon monoxide poisoning raises the blood concentration of carboxyhemoglobin (which has a high affinity for oxygen), and this usually causes pulse oximetry to read inappropriately high, whereas in our patient it read low.

Incorrect placement of the pulse oximeter probe can result in an inaccurate measurement of oxygen saturation. Visualization of the waveform on the plethysmograph or the signal quality index can be used to assess adequate placement of the pulse oximeter probe. However, inadequate probe placement does not explain our patient’s dyspnea and cyanosis.

Pulmonary embolism can lead to hypoxia as a result of ventilation-perfusion mismatch. However, pulmonary embolism leading to low oxygen saturation on pulse oximetry will also lead to concomitantly low oxyhemoglobin levels as measured by arterial blood gas analysis, and this was not seen in our patient.

BACK TO OUR PATIENT

Because there was a discrepancy between our patient’s pulse oximetry reading and oxyhemoglobin concentration by arterial blood gas measurement, her methemoglobin level was checked and was found to be 30%, thus confirming the diagnosis of methemoglobinemia.

WHAT IS METHEMOGLOBINEMIA, AND WHAT CAUSES IT?

Oxygen is normally bound to iron in its ferrous (Fe²⁺) form in hemoglobin to form oxyhemoglobin. Oxidative stress in the body can cause iron to change from the ferrous to the ferric (Fe³⁺) state, forming methemoglobin. Methemoglobin is normally present in the blood in low levels (< 1% of the total hemoglobin), and ferric iron is reduced and recycled back to the ferrous form by NADH-cytochrome b5 reductase, an enzyme present in red blood cells. This protective mechanism maintains methemoglobin levels within safe limits. But increased production can lead to accumulation of methemoglobin, resulting in dyspnea and hypoxia and the condition referred to as methemoglobinemia.¹

Increased levels of methemoglobin relative to normal hemoglobin cause tissue hypoxia by several mechanisms. Methemoglobin cannot efficiently carry oxygen; instead, it binds to water or to a hydroxide ion depending on the pH of the environment.² Therefore, the hemoglobin molecule does not carry its usual load of oxygen, and hypoxia results from the reduced delivery of oxygen to tissues. In addition, an increased concentration of methemoglobin causes a leftward shift in the oxygen-hemoglobin dissociation curve, representing an increased affinity to bound oxygen in the remaining heme groups. The tightly bound oxygen is not adequately released at the tissue level, thus causing cellular hypoxia.

Methemoglobinemia is most often caused by exposure to an oxidizing chemical or drug that increases production of methemoglobin. In rare cases, it is caused by a congenital deficiency of NADH-cytochrome b5 reductase.³

2. Which of the following drugs can cause methemoglobinemia?

• Acetaminophen
• Dapsone
• Benzocaine
• Primaquine

All four of these drugs are common culprits for causing acquired methemoglobinemia; others include chloroquine, nitroglycerin, and sulfonamides.^4–6

The increased production of methemoglobin caused by these drugs overwhelms the protective effect of reducing enzymes and can lead to an accumulation of methemoglobin. However, because of variability in cellular metabolism, not every person who takes these drugs develops dangerous levels of methemoglobin.

Dapsone and benzocaine are the most commonly encountered drugs known to cause methemoglobinemia (Table 1). Dapsone is an anti-inflammatory and antimicrobial agent most commonly used for treating lepromatous leprosy and dermatitis herpetiformis. It is also often prescribed for prophylaxis and treatment of P jirovecii pneumonia in immunosuppressed individuals.⁷ Benzocaine is a local anesthetic and was commonly used before procedures such as oral or dental surgery, transesophageal echocardiography, and endoscopy.^8–10 Even low doses of benzocaine can lead to high levels of methemoglobinemia. However, the availability of other, safer anesthetics now limits the use of benzocaine in major US centers. In addition, the topical anesthetic Emla (lidocaine plus prilocaine) has been recently reported as a cause of methemoglobinemia in infants and children.^11,12

Also, potentially fatal methemoglobinemia has been reported in patients with a deficiency of G-6-phosphate dehydrogenase (G6PD) who received rasburicase, a recombinant version of urate oxidase enzyme used to prevent and treat tumor lysis syndrome.^13,14

Lastly, methemoglobinemia has been reported in patients with inflammatory bowel disease treated with mesalamine.

Although this adverse reaction is rare, clinicians should be aware of it, since these agents are commonly used in everyday medical practice.¹⁵

RECOGNIZING THE DANGER SIGNS

The clinical manifestations of methemoglobinemia are directly proportional to the percentage of methemoglobin in red blood cells. Cyanosis generally becomes apparent at concentrations around 15%, at which point the patient may still have no symptoms. Anxiety, lightheadedness, tachycardia, and dizziness manifest at levels of 20% to 30%. Fatigue, confusion, dizziness, tachypnea, and worsening tachycardia occur at levels of 30% to 50%. Levels of 50% to 70% cause coma, seizures, arrhythmias, and acidosis, and levels over 70% are considered lethal.¹⁶

While these levels provide a general guideline of symptomatology in an otherwise healthy person, it is important to remember that patients with underlying conditions such as anemia, lung disease (both of which our patient had), sepsis, thalassemia, G6PD deficiency, and sickle cell disease can manifest symptoms at lower concentrations of methemoglobin.^1,17

Most patients who develop clinically significant levels of methemoglobin do so within the first few hours of starting one of the culprit drugs.

DIAGNOSIS: METHEMOGLOBINEMIA AND THE SATURATION GAP

In patients with methemoglobinemia, pulse oximetry gives lower values than arterial blood gas oxygen measurements. Regular pulse oximetry works by measuring light absorbance at two distinct wavelengths (660 and 940 nm) to calculate the ratio of oxyhemoglobin to deoxyhemoglobin. Methemoglobin absorbs light at both these wavelengths, thus lowering the pulse oximetry values.¹

In contrast, oxygen saturation of arterial blood gas (oxyhemoglobin) is calculated indirectly from the concentration of dissolved oxygen in the blood and does not include oxygen bound to hemoglobin. Therefore, the measured arterial oxygen saturation is often normal in patients with methemoglobinemia since it relies only on inspired oxygen content and is independent of the methemoglobin concentration.¹⁸

Patients with clinically significant methemoglobinemia usually have a saturation gap > 10%

Oxygen supplementation can raise the level of oxyhemoglobin, which is a measure of dissolved oxygen, but the oxygen saturation as measured by pulse oximetry remains largely unchanged—ie, the saturation gap. A difference of more than 5% between the oxygen saturation by pulse oximetry and blood gas analysis is abnormal. Patients with clinically significant methemoglobinemia usually have a saturation gap greater than 10%.

Several other unique features should raise suspicion of methemoglobinemia. It should be considered in a patient presenting with cyanosis out of proportion to the oxygen saturation and in a patient with low oxygen saturation and a normal chest radiograph. Other clues include blood that is chocolate-colored on gross examination, rather than the dark red of deoxygenated blood.

Co-oximetry measures oxygen saturation using different wavelengths of light to distinguish between fractions of oxyhemoglobin, deoxyhemoglobin, and methemoglobin, but it is not widely available.

THE NEXT STEP

3. What is the next step in the management of our patient?

• Discontinue the dapsone
• Start methylene blue
• Start hyperbaric oxygen
• Give sodium thiosulfate
• Discontinue dapsone and start methylene blue

The next step in her management should be to stop the dapsone and start an infusion of methylene blue. Hyperbaric oxygen is used in treating carbon monoxide poisoning, and sodium thiosulfate is used in treating cyanide toxicity. They would not be appropriate in this patient’s care.

MANAGEMENT OF ACQUIRED METHEMOGLOBINEMIA

The first, most critical step in managing acquired methemoglobinemia is to immediately discontinue the suspected offending agent. In most patients without a concomitant condition such as anemia or lung disease and with a methemoglobin level below 20%, discontinuing the offending agent may suffice. Patients with a level of 20% or greater and patients with cardiac and pulmonary disease, who develop symptoms at lower concentrations of methemoglobin, require infusion of methylene blue.

Methylene blue is converted to its reduced form, leukomethylene blue, by NADPH-methemoglobin reductase. As it is oxidized, leukomethylene blue reduces methemoglobin to hemoglobin. A dose of 1 mg/kg intravenously is given at first. The response is usually dramatic, with a reduction in methemoglobin levels and improvement in symptoms often within 30 to 60 minutes. If levels remain high, the dose can be repeated 1 hour later.¹⁹

A caveat: methylene blue should be avoided in patients with complete G6PD deficiency

A caveat: methylene blue therapy should be avoided in patients with complete G6PD deficiency. Methylene blue works through the enzyme NADPH-methemoglobin reductase, and since patients with G6PD deficiency lack this enzyme, methylene blue is ineffective. In fact, since it cannot be reduced, excessive methylene blue can oxidize hemoglobin to methemoglobin, further exacerbating the condition. In patients with partial G6PD deficiency, methylene blue is still recommended as a first-line treatment, but at a lower initial dose (0.3–0.5 mg/kg). However, in patients with significant hemolysis, an exchange transfusion is the only treatment option.

CASE CONCLUDED

Since dapsone was identified as the likely cause of methemoglobinemia in our patient, it was immediately discontinued. Because she was symptomatic, 70 mg of methylene blue was given intravenously. Over the next 60 minutes, her clinical condition improved significantly. A repeat methemoglobin measurement was 3%.

She was discharged home the next day on oral antibiotics to complete treatment for community-acquired pneumonia.

TAKE-HOME POINTS

• Consider methemoglobinemia in a patient with unexplained cyanosis.
• Pulse oximetry gives lower values than arterial blood gas oxygen measurements in patients with methemoglobinemia, and pulse oximetry readings do not improve with supplemental oxygen.
• A saturation gap greater than 5% strongly suggests methemoglobinemia.
• The diagnosis of methemoglobinemia is confirmed by measuring the methemoglobin concentration.
• Most healthy patients develop symptoms at methemoglobin levels of 20%, but patients with comorbidities can develop symptoms at lower levels.
• A number of drugs can cause methemoglobinemia, even at therapeutic dosages.
• Treatment is generally indicated in patients who have symptoms or in healthy patients who have a methemoglobin level of 20% or greater.
• Identifying and promptly discontinuing the causative agent and initiating methylene blue infusion (1 mg/kg over 5 minutes) is the preferred treatment.

A 48-year-old woman presented to the emergency department after 2 days of nonproductive cough, chest discomfort, worsening shortness of breath, and subjective fever. She had a history of systemic sclerosis. She was currently taking prednisone 20 mg daily and aspirin 81 mg daily.

Physical examination revealed tachypnea (28 breaths per minute), and bronchial breath sounds in the left lower chest posteriorly.

The initial laboratory workup revealed:

• Hemoglobin 106 g/L (reference range 115–155)
• Mean corpuscular volume 84 fL (80–100)
• White blood cell count 29.4 × 10⁹/L (3.70–11.0), with 85% neutrophils
• Platelet count 180 × 10⁹/L (150–350)
• Lactate dehydrogenase 312 U/L (100–220).

Chest radiography showed opacification of the lower lobe of the left lung.

She was admitted to the hospital and started treatment with intravenous azithromycin and ceftriaxone for presumed community-acquired pneumonia, based on the clinical presentation and findings on chest radiography. Because of her immunosuppression (due to chronic prednisone therapy) and her high lactate dehydrogenase level, Pneumocystis jirovecii pneumonia was suspected, and because she had a history of allergy to trimethoprim-sulfamethoxazole and pentamidine, she was started on dapsone.

During the next 24 hours, she developed worsening dyspnea, hypoxia, and cyanosis. She was placed on an air-entrainment mask, with a fraction of inspired oxygen of 0.5. Pulse oximetry showed an oxygen saturation of 85%, but arterial blood gas analysis indicated an oxyhemoglobin concentration of 95%.

THE ‘SATURATION GAP’

1. Which is most likely to have caused the discrepancy between the oxyhemoglobin concentration and the oxygen saturation by pulse oximetry in this patient?

• Methemoglobinemia
• Carbon monoxide poisoning
• Inappropriate placement of the pulse oximeter probe
• Pulmonary embolism

Methemoglobinemia is the most likely cause of the discrepancy between the oxyhemoglobin levels and the oxygen saturation by pulse oximetry, a phenomenon also known as the “saturation gap.” Other common causes are cyanide poisoning and carbon monoxide poisoning.

P jirovecii pneumonia was suspected, and dapsone was started in light of her allergy to trimethoprim-sulfamethoxazole and pentamidine

Carbon monoxide poisoning, however, does not explain our patient’s cyanosis. On the contrary, carbon monoxide poisoning can actually cause the patient’s lips and mucous membranes to appear unnaturally bright pink. Also, carbon monoxide poisoning raises the blood concentration of carboxyhemoglobin (which has a high affinity for oxygen), and this usually causes pulse oximetry to read inappropriately high, whereas in our patient it read low.

Incorrect placement of the pulse oximeter probe can result in an inaccurate measurement of oxygen saturation. Visualization of the waveform on the plethysmograph or the signal quality index can be used to assess adequate placement of the pulse oximeter probe. However, inadequate probe placement does not explain our patient’s dyspnea and cyanosis.

Pulmonary embolism can lead to hypoxia as a result of ventilation-perfusion mismatch. However, pulmonary embolism leading to low oxygen saturation on pulse oximetry will also lead to concomitantly low oxyhemoglobin levels as measured by arterial blood gas analysis, and this was not seen in our patient.

BACK TO OUR PATIENT

Because there was a discrepancy between our patient’s pulse oximetry reading and oxyhemoglobin concentration by arterial blood gas measurement, her methemoglobin level was checked and was found to be 30%, thus confirming the diagnosis of methemoglobinemia.

WHAT IS METHEMOGLOBINEMIA, AND WHAT CAUSES IT?

Oxygen is normally bound to iron in its ferrous (Fe²⁺) form in hemoglobin to form oxyhemoglobin. Oxidative stress in the body can cause iron to change from the ferrous to the ferric (Fe³⁺) state, forming methemoglobin. Methemoglobin is normally present in the blood in low levels (< 1% of the total hemoglobin), and ferric iron is reduced and recycled back to the ferrous form by NADH-cytochrome b5 reductase, an enzyme present in red blood cells. This protective mechanism maintains methemoglobin levels within safe limits. But increased production can lead to accumulation of methemoglobin, resulting in dyspnea and hypoxia and the condition referred to as methemoglobinemia.¹

Increased levels of methemoglobin relative to normal hemoglobin cause tissue hypoxia by several mechanisms. Methemoglobin cannot efficiently carry oxygen; instead, it binds to water or to a hydroxide ion depending on the pH of the environment.² Therefore, the hemoglobin molecule does not carry its usual load of oxygen, and hypoxia results from the reduced delivery of oxygen to tissues. In addition, an increased concentration of methemoglobin causes a leftward shift in the oxygen-hemoglobin dissociation curve, representing an increased affinity to bound oxygen in the remaining heme groups. The tightly bound oxygen is not adequately released at the tissue level, thus causing cellular hypoxia.

Methemoglobinemia is most often caused by exposure to an oxidizing chemical or drug that increases production of methemoglobin. In rare cases, it is caused by a congenital deficiency of NADH-cytochrome b5 reductase.³

2. Which of the following drugs can cause methemoglobinemia?

• Acetaminophen
• Dapsone
• Benzocaine
• Primaquine

All four of these drugs are common culprits for causing acquired methemoglobinemia; others include chloroquine, nitroglycerin, and sulfonamides.^4–6

The increased production of methemoglobin caused by these drugs overwhelms the protective effect of reducing enzymes and can lead to an accumulation of methemoglobin. However, because of variability in cellular metabolism, not every person who takes these drugs develops dangerous levels of methemoglobin.

Dapsone and benzocaine are the most commonly encountered drugs known to cause methemoglobinemia (Table 1). Dapsone is an anti-inflammatory and antimicrobial agent most commonly used for treating lepromatous leprosy and dermatitis herpetiformis. It is also often prescribed for prophylaxis and treatment of P jirovecii pneumonia in immunosuppressed individuals.⁷ Benzocaine is a local anesthetic and was commonly used before procedures such as oral or dental surgery, transesophageal echocardiography, and endoscopy.^8–10 Even low doses of benzocaine can lead to high levels of methemoglobinemia. However, the availability of other, safer anesthetics now limits the use of benzocaine in major US centers. In addition, the topical anesthetic Emla (lidocaine plus prilocaine) has been recently reported as a cause of methemoglobinemia in infants and children.^11,12

Also, potentially fatal methemoglobinemia has been reported in patients with a deficiency of G-6-phosphate dehydrogenase (G6PD) who received rasburicase, a recombinant version of urate oxidase enzyme used to prevent and treat tumor lysis syndrome.^13,14

Lastly, methemoglobinemia has been reported in patients with inflammatory bowel disease treated with mesalamine.

Although this adverse reaction is rare, clinicians should be aware of it, since these agents are commonly used in everyday medical practice.¹⁵

RECOGNIZING THE DANGER SIGNS

The clinical manifestations of methemoglobinemia are directly proportional to the percentage of methemoglobin in red blood cells. Cyanosis generally becomes apparent at concentrations around 15%, at which point the patient may still have no symptoms. Anxiety, lightheadedness, tachycardia, and dizziness manifest at levels of 20% to 30%. Fatigue, confusion, dizziness, tachypnea, and worsening tachycardia occur at levels of 30% to 50%. Levels of 50% to 70% cause coma, seizures, arrhythmias, and acidosis, and levels over 70% are considered lethal.¹⁶

While these levels provide a general guideline of symptomatology in an otherwise healthy person, it is important to remember that patients with underlying conditions such as anemia, lung disease (both of which our patient had), sepsis, thalassemia, G6PD deficiency, and sickle cell disease can manifest symptoms at lower concentrations of methemoglobin.^1,17

Most patients who develop clinically significant levels of methemoglobin do so within the first few hours of starting one of the culprit drugs.

DIAGNOSIS: METHEMOGLOBINEMIA AND THE SATURATION GAP

In patients with methemoglobinemia, pulse oximetry gives lower values than arterial blood gas oxygen measurements. Regular pulse oximetry works by measuring light absorbance at two distinct wavelengths (660 and 940 nm) to calculate the ratio of oxyhemoglobin to deoxyhemoglobin. Methemoglobin absorbs light at both these wavelengths, thus lowering the pulse oximetry values.¹

In contrast, oxygen saturation of arterial blood gas (oxyhemoglobin) is calculated indirectly from the concentration of dissolved oxygen in the blood and does not include oxygen bound to hemoglobin. Therefore, the measured arterial oxygen saturation is often normal in patients with methemoglobinemia since it relies only on inspired oxygen content and is independent of the methemoglobin concentration.¹⁸

Patients with clinically significant methemoglobinemia usually have a saturation gap > 10%

Oxygen supplementation can raise the level of oxyhemoglobin, which is a measure of dissolved oxygen, but the oxygen saturation as measured by pulse oximetry remains largely unchanged—ie, the saturation gap. A difference of more than 5% between the oxygen saturation by pulse oximetry and blood gas analysis is abnormal. Patients with clinically significant methemoglobinemia usually have a saturation gap greater than 10%.

Several other unique features should raise suspicion of methemoglobinemia. It should be considered in a patient presenting with cyanosis out of proportion to the oxygen saturation and in a patient with low oxygen saturation and a normal chest radiograph. Other clues include blood that is chocolate-colored on gross examination, rather than the dark red of deoxygenated blood.

Co-oximetry measures oxygen saturation using different wavelengths of light to distinguish between fractions of oxyhemoglobin, deoxyhemoglobin, and methemoglobin, but it is not widely available.

THE NEXT STEP

3. What is the next step in the management of our patient?

• Discontinue the dapsone
• Start methylene blue
• Start hyperbaric oxygen
• Give sodium thiosulfate
• Discontinue dapsone and start methylene blue

The next step in her management should be to stop the dapsone and start an infusion of methylene blue. Hyperbaric oxygen is used in treating carbon monoxide poisoning, and sodium thiosulfate is used in treating cyanide toxicity. They would not be appropriate in this patient’s care.

MANAGEMENT OF ACQUIRED METHEMOGLOBINEMIA

The first, most critical step in managing acquired methemoglobinemia is to immediately discontinue the suspected offending agent. In most patients without a concomitant condition such as anemia or lung disease and with a methemoglobin level below 20%, discontinuing the offending agent may suffice. Patients with a level of 20% or greater and patients with cardiac and pulmonary disease, who develop symptoms at lower concentrations of methemoglobin, require infusion of methylene blue.

Methylene blue is converted to its reduced form, leukomethylene blue, by NADPH-methemoglobin reductase. As it is oxidized, leukomethylene blue reduces methemoglobin to hemoglobin. A dose of 1 mg/kg intravenously is given at first. The response is usually dramatic, with a reduction in methemoglobin levels and improvement in symptoms often within 30 to 60 minutes. If levels remain high, the dose can be repeated 1 hour later.¹⁹

A caveat: methylene blue should be avoided in patients with complete G6PD deficiency

A caveat: methylene blue therapy should be avoided in patients with complete G6PD deficiency. Methylene blue works through the enzyme NADPH-methemoglobin reductase, and since patients with G6PD deficiency lack this enzyme, methylene blue is ineffective. In fact, since it cannot be reduced, excessive methylene blue can oxidize hemoglobin to methemoglobin, further exacerbating the condition. In patients with partial G6PD deficiency, methylene blue is still recommended as a first-line treatment, but at a lower initial dose (0.3–0.5 mg/kg). However, in patients with significant hemolysis, an exchange transfusion is the only treatment option.

CASE CONCLUDED

Since dapsone was identified as the likely cause of methemoglobinemia in our patient, it was immediately discontinued. Because she was symptomatic, 70 mg of methylene blue was given intravenously. Over the next 60 minutes, her clinical condition improved significantly. A repeat methemoglobin measurement was 3%.

She was discharged home the next day on oral antibiotics to complete treatment for community-acquired pneumonia.

TAKE-HOME POINTS

• Consider methemoglobinemia in a patient with unexplained cyanosis.
• Pulse oximetry gives lower values than arterial blood gas oxygen measurements in patients with methemoglobinemia, and pulse oximetry readings do not improve with supplemental oxygen.
• A saturation gap greater than 5% strongly suggests methemoglobinemia.
• The diagnosis of methemoglobinemia is confirmed by measuring the methemoglobin concentration.
• Most healthy patients develop symptoms at methemoglobin levels of 20%, but patients with comorbidities can develop symptoms at lower levels.
• A number of drugs can cause methemoglobinemia, even at therapeutic dosages.
• Treatment is generally indicated in patients who have symptoms or in healthy patients who have a methemoglobin level of 20% or greater.
• Identifying and promptly discontinuing the causative agent and initiating methylene blue infusion (1 mg/kg over 5 minutes) is the preferred treatment.

Eating disorders are debilitating biopsychosocial illnesses associated with serious medical illness and a high risk of death.¹

Primary care physicians are often the first to see young women who have these problems, diagnose them, and start their evaluation and treatment.^2–4 Many patients require acute medical interventions as well as long-term care for chronic medical issues. Therefore, primary care physicians play essential front-line and long-term roles in the multidisciplinary treatment team.

DEFINITIONS OF EATING DISORDERS HAVE CHANGED

Several problems existed in the category of eating disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) and in the DSM-4 Text Revision (DSM-4-TR). These problems have been addressed in the fifth edition (DSM-5), released in 2013.⁵

One problem in the earlier editions was that many patients referred for treatment of eating disorders—more than 50% in one study⁶—did not meet the criteria for anorexia nervosa or bulimia nervosa and thus had to be categorized as having “eating disorder not otherwise specified.” Further, the earlier editions did not recognize that young children and adolescent males can be affected.⁷

Eating disorders are now recognized as an equal-opportunity disease, with all ethnic and socioeconomic groups affected. Children can run into medical trouble with even a small amount of weight loss or falling off the growth curve. Moreover, children and adolescents do not “experience” their bodies in the same way adults do; they may lack the vocabulary for eating-disorder thoughts.

For these reasons, the definitions of eating disorders have changed in the DSM-5.⁵

Anorexia nervosa. Older editions of the DSM listed amenorrhea as a criterion. This has been eliminated in DSM-5, since amenorrhea does not necessarily predict medical risk or treatment outcome; also, it is not applicable to males or premenorrheal girls and postmenopausal women.⁸ In addition, the requirement of low weight is now defined in the context of “age, sex, developmental trajectory, and physical health,” rather than the old threshold of 85% of expected weight.⁹

What remains unchanged is that anorexia nervosa is still characterized by self-starvation in order to maintain an abnormally low body weight, along with an intense fear of being fat and a disturbed self-image.

Bulimia nervosa. In both the old and the new editions of the DSM, bulimia nervosa is characterized by episodes of binge eating followed by inappropriate compensatory behaviors to avoid weight gain, such as vomiting, laxative abuse, diuretic abuse, and overexercise. In DSM-5, bulimia nervosa no longer has subtypes and requires only one binge per week with compensatory behavior, for at least 3 months. This change was based on the finding that there is no clear difference in psychopathology or treatment outcome between patients with one and two binge-purge episodes a week.¹⁰

“Eating disorder not otherwise specified” was a wastebasket category, lumping all those who did not meet the criteria for anorexia nervosa or bulimia nervosa or who did not neatly fit into a specific category.¹⁰ In DSM-5, subcategories were designed to help distinguish different treatment needs and outcomes between various subtypes.

Binge-eating disorder, one of the new subcategories, is characterized by binge eating without inappropriate compensatory behaviors.⁹ Patients with binge-eating disorder are often obese, have greater functional impairment, and are more likely to develop components of metabolic syndrome than obese patients without eating disorders.¹¹

Avoidant/restrictive food intake disorder is another new DSM-5 diagnosis, characterized by failure to meet nutritional needs for reasons other than weight control. Reasons include disinterest in eating, dislike of sensory characteristics of food, or avoidance of consequences of eating. This disorder replaces the category “feeding disorder of infancy or early childhood,” since the condition can also occur in adolescents and adults.¹²

Other new diagnoses are:

• Atypical anorexia nervosa (if the patient is not underweight)
• Purging disorder
• Subthreshold bulimia nervosa (if the patient has < 1 episode per week or has had them for < 3 months)
• Subthreshold binge eating disorder (< 1 time a week or < 3 months)
• Night eating syndrome
• Pica and rumination disorder.

Regardless of the diagnostic label, the medical evaluation and treatment of anyone with an eating disorder should be tailored to the specific behaviors of the eating disorder. Medical complications can be subdivided into those from starvation, from purging, and from refeeding.

MEDICAL COMPLICATIONS OF STARVATION

Cardiovascular effects of starvation

Malnutrition and starvation have multiple adverse effects on the heart.

Electrophysiologic effects. Sinus bradycardia (< 60 bpm) and hypotension are common cardiac manifestations of starvation.¹³ Bradycardia has been attributed to an adaptive increase in parasympathetic vagal tone.¹⁴ QTc prolongation is also seen in patients with malnutrition.¹⁵

Together, these electrocardiographic abnormalities predispose the patient to ventricular arrhythmia and sudden cardiac death.¹⁶ The risk of ventricular arrhythmia is particularly relevant when treating psychiatric symptoms, since antipsychotics and tricyclic antidepressants are among several drug classes that can cause further QTc prolongation (Table 1).^17,18

In patients with QTc prolongation, bradycardia, or both, the standard of care involves acute hospitalization for refeeding using continuous telemetric monitoring until normal rhythm is restored and the heart rate is above 40 at night and 50 by day.^4,19

Structural changes. Starvation also causes structural changes in the heart. Loss of lean body mass can reduce cardiac muscle mass, compromise cardiac output, and lead to mitral valve prolapse.²⁰ These changes are fully reversible with restored nutrition and regaining of heart mass.^21,22

Effects of starvation on the brain

Starvation can affect brain structure and cognitive function. Undernourished patients have reduced volumes of white and gray matter, a change that can occur within months. Cortical volumes may increase with weight gain, but a reduction in gray matter volume may not be completely reversible.²³

Furthermore, starvation impairs cognitive functions that are needed to stop eating-disorder behaviors; namely, decision-making, emotional control, regulation of appetite, and reward path-ways. Therefore, undernourished patients may not have sufficient insight into the disease to be able to make the best choices for recovery. This finding lends support for using the Maudsley method in adolescents, in which parents take control of their child’s eating until the child can maintain a healthy weight.²⁴

Gastrointestinal consequences of starvation

Patients with malnutrition have prolonged gastric emptying and colonic transit time with solid foods.²⁵ They often complain of early satiety, abdominal pain, bloating, and constipation, all symptoms that complicate the refeeding process. A prokinetic such as metoclopramide (Reglan), given 1 hour before meals and at bedtime, may provide some relief from gastrointestinal symptoms.²⁶

Patients may also experience transient lactose or fructose intolerance after prolonged starvation. Taking a lactase supplement (eg, Lactaid 1–10 tabs) before consuming dairy products and dextrose (contained in candies such as Smarties) before eating fruit or fructose-containing foods can sometimes partially relieve symptoms. In general, gastrointestinal function returns over time as nutritional status improves.

Patients with severe or prolonged starvation can develop steatosis accompanied by elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In reports of starvation-induced steatosis, liver enzyme levels rapidly normalize with nutritional rehabilitation.²⁷

Endocrine consequences of starvation

Amenorrhea. Dysregulation of the hypothalamic-pituitary-gonadal axis is a major endocrine complication of nutritional in-sufficiency. Weight loss disrupts the normal pulsatile secretion of gonadotropin-releasing hormone, reduces secretion of luteinizing hormone and follicle-stimulating hormone, and decreases estrogen levels.²⁸ Leptin deficiency likely plays a role in suppressing gonadotropin secretion with subsequent development of amenorrhea. With weight gain, levels of leptin and gonadotropins normalize and menstruation eventually returns.^29,30

Hypothyroidism. Starvation can also lead to dysregulation of the hypothalamic-pituitary-thyroid axis. Typically, the concentration of triiodothyronine (T3) is reduced, the ratio of thyroxine (T4) to T3 is elevated, and thyroid-stimulating hormone (TSH) is close to or within the normal range, creating a euthyroid sick syndrome. In eating disorders, this thyroid disturbance is a result of starvation and resolves with weight restoration. Therefore, thyroid hormone replacement therapy is not medically indicated.²⁸

Osteoporosis. Amenorrhea resulting from low estrogen levels in undernourished patients can raise the risk of osteoporosis and fractures, particularly in patients with a low body mass index. Osteopenia results from a negative balance between bone deposition and resorption.

Lack of bone deposition can be especially problematic when disordered eating occurs during peak bone mass development, ie, ages 11 to 14 for girls, and ages 15 to 17 for boys.^31,32 Even a 5% to 10% decrease in bone deposition can result in significant risk of osteopenia.³³ However, after age 30, bone resorption is a greater contributor.³⁴

Does hormone therapy correct bone loss? Given the association between estrogen deficiency and bone loss, estrogen supplementation was expected to be an effective treatment for bone loss in patients with eating disorders.³⁵ Also, the restoration of menses through hormone replacement may give underweight patients a false sense of achieving a “healthy” weight.³⁶

Golden et al³⁷ prospectively studied 50 adolescents and found no significant difference in bone mineral density at 1 year of follow-up between patients treated with estrogen and those who received only standard nutritional therapy. However, increased bone mineral density was achieved in adolescents with anorexia nervosa treated with transdermally administered estrogen dosed to mimic physiologic pubertal levels.³⁸

Klibanski et al³⁹ found that hormone therapy resulted in a 4% gain in bone density in an extremely low-weight subset of women with anorexia nervosa (< 70% of ideal body weight), whereas similar patients in the control group lost 20%. However, in all groups, only weight gain correlated with bone gain in women who were within 70% of their ideal body weight.

Divasta et al⁴⁰ evaluated 60 girls and women ages 13 to 27 with anorexia nervosa, randomized to receive either placebo or dehydroepiandrosterone combined with an estrogen-progestin oral contraceptive, and followed for 18 months. As in the study by Klibanski et al,³⁹ bone loss was prevented in the treatment group, but significant bone gain occurred only in the context of weight gain.

The bottom line is that only weight gain has resulted in significant increases in bone density in patients with anorexia nervosa, and hormone therapy without weight gain has not been shown to increase bone density effectively in this population. Although calcium and vitamin D in oral therapeutic doses through foods or through supplementation are required for bone gain, the combination is not enough to augment bone density in the absence of weight gain.³⁷ Although not curative, weight gain is currently the best option for treating bone loss, and no single pharmacologic treatment is effective.

COMPLICATIONS OF PURGING

Oral complications of purging

Patients who purge by vomiting are at risk of complications from exposure of the esophagus, pharynx, and mouth to acidic gastric contents.

Dental problems. Over time, contact with gastric acid wears down enamel on the lingual and occlusal surfaces of teeth, resulting in dental caries and periodontal disease. Until they can give up purging, patients should be instructed to rinse with mouthwash or water immediately after vomiting to reduce the acidity in the mouth.^41,42 We recommend that patients not brush their teeth after vomiting, because brushing can deliver acid to otherwise unreachable surfaces and thus worsen tooth erosion. For patients who are determined to brush after vomiting, a bicarbonate toothpaste might mitigate harm.⁴²

Sialadenosis (hypertrophy of the salivary glands) is another consequence of repeated vomiting, with elevated salivary amylase. Both the size of the glands and the salivary amylase level generally normalize on their own after vomiting is stopped, but parotitis can take up to a year to resolve. Similar to smoker’s cough, parotitis may acutely worsen when the patient abruptly stops vomiting and may worsen before it improves.

To reduce discomfort, patients can use hot compresses or sugarless hard candies.⁴⁴ However, the latter should not be substituted as a chronic habit in a patient with disordered eating. Patients need to be reassured that the swelling is not permanent, since they often interpret it as having fat cheeks (the “chipmunk sign”).

Hypokalemia, metabolic alkalosis, renal dysfunction

Chronic vomiting can cause electrolyte and acid-base imbalances, the most worrisome of which is hypokalemia. With repeated vomiting, loss of potassium and gastric acid causes metabolic alkalosis with hypokalemia, hypochloremia, and hypomagnesemia. Loss of water and the resultant volume contraction activates the renin-angiotensin-aldosterone system, and elevated aldosterone further decreases serum potassium.

In patients with eating disorders, who often have other factors contributing to electrolyte imbalance, vomiting-induced hypokalemia heightens the risk of cardiac arrhythmias.⁴³

Hypokalemia can also cause rhabdomyolysis and kidney damage.^41,43 Prolonged hypokalemia and reduced kidney perfusion in the setting of volume depletion causes acute kidney injury and impaired concentrating ability of the renal tubules. Hypovolemia can cause prerenal azotemia and increases the risk for nephrolithiasis and nephrocalcinosis.^44,45

When a patient stops vomiting, elevated aldosterone from prior hypovolemia results in water retention and can manifest in significant edema associated with hypochloremic alkalosis. This condition, known as pseudo-Bartter syndrome, usually resolves without treatment. In the meantime, salt restriction and leg elevation can help reduce edema.²⁶

Laxative abuse: A mode of purging

Many patients with eating disorders abuse laxatives to lose weight or to prevent weight gain. Believing that laxatives will prevent calorie absorption, patients commonly take them to compensate for caloric intake (eg, during a binge episode). The immediate weight loss, albeit artificial, is highly reinforcing for an eating-disorder patient. In some cases, patients with eating disorders also abuse laxatives to self-treat the constipation that results from chronic starvation.⁴⁶

Over time, tolerance to laxatives develops, and patients use increasingly larger doses. This can lead to activation of the renin-angiotensin-aldosterone system.⁴⁷ Patients interpret the resultant edema as true weight gain and again take laxatives to get rid of it. If laxatives are stopped abruptly, the patient may need inpatient and outpatient support for the resultant fluid shifts.

Gastrointestinal complications of laxative abuse include reflex hypofunction of the bowel, malabsorption, steatorrhea, and gastrointestinal bleeding.⁴⁷ Reflex hypofunction during laxative withdrawal is a consequence of the bowel becoming tolerant of laxatives.⁴⁸ Cathartic colon syndrome is a rare complication characterized by loss of the normal haustral markings and slowed or absent peristalsis in segments of the colon.⁴⁹

Systemically, the major risk of laxative abuse relates to electrolyte and acid-base imbalance. Loss of potassium and water in the stool can cause hypokalemia and metabolic alkalosis.⁴⁸ The disturbances caused by laxative abuse are similar to those caused by vomiting and diuretic use and have the same treatment.

The most important component of treating laxative abuse is giving patients realistic expectations to help them tolerate temporary discomfort and to help manage the edema and fluid shifts that can happen acutely with shifting of fluid into the intracellular space. In extreme cases, this may need to be managed in the hospital. To help relieve the initial anxiety, doctors should emphasize that any bloating the patient experiences is not true weight gain and will go away within a few days to weeks. In addition, explaining that laxatives reduce nutrient absorption only minimally may lessen the temptation to resume taking them.⁴⁸

Diuretic abuse: Another form of purging

Diuretic abuse is yet another mode of purging, with its own set of medical complications. Like laxatives, diuretics are not effective weight-loss agents, and the weight reduction they cause is only temporary.

As with vomiting, there is a compensatory activation of the renin-angiotensin-aldosterone system, and therefore subsequent fluid intake will lead to water retention, which encourages further diuretic use.⁴¹ Diuretics can also contribute to hypokalemia, hypomagnesemia, hypochloremia, and metabolic alkalosis.

Ipecac abuse can lead to heart failure

Ipecac syrup has long been used to induce vomiting, but this practice has become much less common since ipecac has become harder to obtain in the United States.⁵⁰ The emetine base contained in ipecac binds irreversibly to cardiac and skeletal muscle. With continued use, irreversible cardiomyopathy develops and can lead to heart failure. Treatment should include supportive care and immediate cessation of ipecac use.

Diabetic patients may skip insulin to lose weight

Patients with diabetes, especially those with type 1 that begins in childhood, are at greater risk of eating disorders over time.⁵¹ They may withhold insulin to lose weight, a practice referred to in the nonmedical literature as “diabulimia,” and they seem particularly more likely to develop bulimia nervosa than those without diabetes.⁵²

The medical prognosis is poor for patients with diabetes who develop eating disorders and do not receive intensive treatment.⁵¹ In addition, if a diabetic patient on an insulin pump becomes depressed in addition to having an eating disorder, careful monitoring for suicidal thoughts and a rapid follow-up with mental health services are in order.

REFEEDING SYNDROME

When refeeding is started, a high glucose load stimulates insulin secretion, resulting in cellular uptake of phosphorus along with potassium, magnesium, and glucose. In addition, total body phosphorus is depleted by the increased demand for adenosine triphosphate and 2,3-diphosphoglycerate for cellular metabolism.

When liver enzyme levels increase, the astute clinician will closely monitor the patient for evidence of refeeding syndrome. In a child, adolescent, or young adult, the standard of care is inpatient monitoring for acute stabilization.^4,19

Hypophosphatemia is the hallmark of refeeding syndrome, although hypomagnesemia, hypokalemia, and hypoglycemia can also occur.⁵³ In addition, sodium and water retention can lead to fluid overload, with shifting of fluid into the intracellular space, resulting in dependent edema.

Cardiovascular complications are the most worrisome manifestations of refeeding syndrome. Electrolyte shifts and increased fluid volume can cause arrhythmias and heart failure. Furthermore, severely undernourished patients may have reduced myocardial mass as well as electrocardiographic abnormalities associated with starvation, which further increase their vulnerability to electrolyte shifts and fluid retention during refeeding.¹⁵

Other manifestations of refeeding syndrome include delirium, seizures, rhabdomyolysis, and respiratory failure. In the most extreme cases, refeeding syndrome causes sudden death.⁵³

Fortunately, refeeding syndrome is easily preventable and treatable when recognized early. Electrolytes and cardiovascular and renal function must be carefully monitored, especially during the first week of nutritional restoration.⁵³ In patients with extremely low body mass (< 70% of ideal body weight) or with precipitous weight loss, close monitoring of the complete metabolic panel including electrolytes, AST, ALT, calcium, magnesium, and phosphorus may be required to detect changes that can affect cardiac status. Specific suggestions for refeeding are discussed below and in Table 2.⁴⁵

ACUTE CARE OF PATIENTS WITH EATING DISORDERS

Refeeding in the inpatient setting

The decision to hospitalize an eating-disorder patient is based on the current or potential risk of serious medical complications and the likelihood of success at home. Medical criteria for hospital admission are outlined in Table 3.^4,54

In refeeding undernourished patients, the challenge is to maximize weight gain while preventing refeeding syndrome. Undernourished patients are generally hypometabolic at baseline but become hypermetabolic once refeeding begins.

How many calories should refeeding start with? The traditional principle of “start low and go slow” has been recently challenged.⁵⁵ Starting at 1,200 kcal/day or less in the typical patient can result in failure to gain weight or even in weight loss in the first week of refeeding.⁵⁶ The goal is to achieve a weight gain of 0.2 kg/day while the patient is in the hospital. Thus, we start higher, and to date we have seen no cases of life-threatening refeeding syndrome. In all patients who need hospitalization or who are beginning the refeeding process as outpatients, caloric intake should be started at 1,500 to 2,000 kcal/day.^45,57 However, for exceptionally low-weight patients, intake may be started lower.

In Australia, patients are started at 1,900 kcal/day.⁵⁶ All patients in one program there receive nasogastric feeding initially in an intensive care unit and then are moved to a regular nursing floor where they graduate to full oral feeding as they improve cardiovascularly and behaviorally. In the United States, some programs use nasogastric feeding at night for caloric restoration; our program and others use nasogastric feeding as a behavioral modification strategy for patients who refuse food or supplements by mouth.

Phosphorus supplementation. Many centers give phosphorus supplements preventively. In our center, we give potassium phosphate (Neutra-Phos) 500 mg orally twice daily for 5 days, and we have seen no life-threatening cases of refeeding syndrome with that regimen. Other centers give phosphorus supplements in a dose of 250 mg orally twice a day for 5 days, while still others only supplement phosphorus reactively once a deficit has been identified. The latter method requires daily blood draws for monitoring and is reactive rather than proactive. Further studies can help clarify the optimal dosing and timing of phosphorus supplementation.

Managing fluid balance. Fluid-loading these patients may tip them over the edge into refeeding syndrome. Except in cases of shock, patients with eating disorders should not be given intravenous fluids, as it is safer to rehydrate and feed them orally. Electrolyte imbalances can be corrected orally with no need for intravenous supplementation. To avoid fluid overload, fluids can be started at 1,500 mL to 2,000 mL per day, with strict monitoring of intake and output. Fluids are liberalized if ALT and AST levels remain normal and to gradually correct orthostatic hypotension; caloric fluids are ideal to help address energy needs and improve bradycardia.

Laboratory monitoring. On admission, a urinalysis, complete blood cell count, complete metabolic panel, TSH, erythrocyte sedimentation rate, serum magnesium, and phosphorus should be obtained.²⁶ In addition, continuous electrocardiographic recording should begin on admission.⁴⁵ Inpatient use of a telemetry bed helps identify extreme tachycardia with arrhythmia, as well as profound bradycardia.^45,56

Some protocols call for daily laboratory monitoring, although that degree of testing is less cost-effective. If initial results are normal, clinical judgment can be used on when to repeat laboratory evaluation. For instance, patients with edema require repeat complete metabolic panels to assess for elevated ALT and AST, electrolyte imbalances, and other abnormalities.

Signs of refeeding syndrome include tachycardia, hepatosplenomegaly, peripheral edema, altered mental status, and electrolyte disturbances, specifically, acute or severe hypophosphatemia or hypokalemia.^26,45 If refeeding syndrome is suspected, the rate of caloric intake should be reduced or not advanced, fluid intake should be urgently reassessed for volume overload, and supportive care with close monitoring should be provided.

KNOWLEDGE SAVES LIVES

Eating disorders can lead to potentially life-threatening medical complications that require attentive care by the primary care clinician and subspecialist. Without thoughtful consideration, it is easy for even a caring medical team to unintentionally enable patients with these illnesses or to cause active harm in the case of underrecognized pathology.⁵⁸

Acute medical stabilization on an inpatient unit trained to recognize pathology and treat sequelae can be lifesaving. Arming patients and families with medical knowledge, as provided in the Academy for Eating Disorders’ brochure, “Critical Points for Early Recognition and Medical Risk Management in the Care of Individuals with Eating Disorders”⁵⁹ can help save patients’ lives.

Eating disorders are debilitating biopsychosocial illnesses associated with serious medical illness and a high risk of death.¹

Primary care physicians are often the first to see young women who have these problems, diagnose them, and start their evaluation and treatment.^2–4 Many patients require acute medical interventions as well as long-term care for chronic medical issues. Therefore, primary care physicians play essential front-line and long-term roles in the multidisciplinary treatment team.

DEFINITIONS OF EATING DISORDERS HAVE CHANGED

Several problems existed in the category of eating disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) and in the DSM-4 Text Revision (DSM-4-TR). These problems have been addressed in the fifth edition (DSM-5), released in 2013.⁵

One problem in the earlier editions was that many patients referred for treatment of eating disorders—more than 50% in one study⁶—did not meet the criteria for anorexia nervosa or bulimia nervosa and thus had to be categorized as having “eating disorder not otherwise specified.” Further, the earlier editions did not recognize that young children and adolescent males can be affected.⁷

Eating disorders are now recognized as an equal-opportunity disease, with all ethnic and socioeconomic groups affected. Children can run into medical trouble with even a small amount of weight loss or falling off the growth curve. Moreover, children and adolescents do not “experience” their bodies in the same way adults do; they may lack the vocabulary for eating-disorder thoughts.

For these reasons, the definitions of eating disorders have changed in the DSM-5.⁵

Anorexia nervosa. Older editions of the DSM listed amenorrhea as a criterion. This has been eliminated in DSM-5, since amenorrhea does not necessarily predict medical risk or treatment outcome; also, it is not applicable to males or premenorrheal girls and postmenopausal women.⁸ In addition, the requirement of low weight is now defined in the context of “age, sex, developmental trajectory, and physical health,” rather than the old threshold of 85% of expected weight.⁹

What remains unchanged is that anorexia nervosa is still characterized by self-starvation in order to maintain an abnormally low body weight, along with an intense fear of being fat and a disturbed self-image.

Bulimia nervosa. In both the old and the new editions of the DSM, bulimia nervosa is characterized by episodes of binge eating followed by inappropriate compensatory behaviors to avoid weight gain, such as vomiting, laxative abuse, diuretic abuse, and overexercise. In DSM-5, bulimia nervosa no longer has subtypes and requires only one binge per week with compensatory behavior, for at least 3 months. This change was based on the finding that there is no clear difference in psychopathology or treatment outcome between patients with one and two binge-purge episodes a week.¹⁰

“Eating disorder not otherwise specified” was a wastebasket category, lumping all those who did not meet the criteria for anorexia nervosa or bulimia nervosa or who did not neatly fit into a specific category.¹⁰ In DSM-5, subcategories were designed to help distinguish different treatment needs and outcomes between various subtypes.

Binge-eating disorder, one of the new subcategories, is characterized by binge eating without inappropriate compensatory behaviors.⁹ Patients with binge-eating disorder are often obese, have greater functional impairment, and are more likely to develop components of metabolic syndrome than obese patients without eating disorders.¹¹

Avoidant/restrictive food intake disorder is another new DSM-5 diagnosis, characterized by failure to meet nutritional needs for reasons other than weight control. Reasons include disinterest in eating, dislike of sensory characteristics of food, or avoidance of consequences of eating. This disorder replaces the category “feeding disorder of infancy or early childhood,” since the condition can also occur in adolescents and adults.¹²

Other new diagnoses are:

• Atypical anorexia nervosa (if the patient is not underweight)
• Purging disorder
• Subthreshold bulimia nervosa (if the patient has < 1 episode per week or has had them for < 3 months)
• Subthreshold binge eating disorder (< 1 time a week or < 3 months)
• Night eating syndrome
• Pica and rumination disorder.

Regardless of the diagnostic label, the medical evaluation and treatment of anyone with an eating disorder should be tailored to the specific behaviors of the eating disorder. Medical complications can be subdivided into those from starvation, from purging, and from refeeding.

MEDICAL COMPLICATIONS OF STARVATION

Cardiovascular effects of starvation

Malnutrition and starvation have multiple adverse effects on the heart.

Electrophysiologic effects. Sinus bradycardia (< 60 bpm) and hypotension are common cardiac manifestations of starvation.¹³ Bradycardia has been attributed to an adaptive increase in parasympathetic vagal tone.¹⁴ QTc prolongation is also seen in patients with malnutrition.¹⁵

Together, these electrocardiographic abnormalities predispose the patient to ventricular arrhythmia and sudden cardiac death.¹⁶ The risk of ventricular arrhythmia is particularly relevant when treating psychiatric symptoms, since antipsychotics and tricyclic antidepressants are among several drug classes that can cause further QTc prolongation (Table 1).^17,18

In patients with QTc prolongation, bradycardia, or both, the standard of care involves acute hospitalization for refeeding using continuous telemetric monitoring until normal rhythm is restored and the heart rate is above 40 at night and 50 by day.^4,19

Structural changes. Starvation also causes structural changes in the heart. Loss of lean body mass can reduce cardiac muscle mass, compromise cardiac output, and lead to mitral valve prolapse.²⁰ These changes are fully reversible with restored nutrition and regaining of heart mass.^21,22

Effects of starvation on the brain

Starvation can affect brain structure and cognitive function. Undernourished patients have reduced volumes of white and gray matter, a change that can occur within months. Cortical volumes may increase with weight gain, but a reduction in gray matter volume may not be completely reversible.²³

Furthermore, starvation impairs cognitive functions that are needed to stop eating-disorder behaviors; namely, decision-making, emotional control, regulation of appetite, and reward path-ways. Therefore, undernourished patients may not have sufficient insight into the disease to be able to make the best choices for recovery. This finding lends support for using the Maudsley method in adolescents, in which parents take control of their child’s eating until the child can maintain a healthy weight.²⁴

Gastrointestinal consequences of starvation

Patients with malnutrition have prolonged gastric emptying and colonic transit time with solid foods.²⁵ They often complain of early satiety, abdominal pain, bloating, and constipation, all symptoms that complicate the refeeding process. A prokinetic such as metoclopramide (Reglan), given 1 hour before meals and at bedtime, may provide some relief from gastrointestinal symptoms.²⁶

Patients may also experience transient lactose or fructose intolerance after prolonged starvation. Taking a lactase supplement (eg, Lactaid 1–10 tabs) before consuming dairy products and dextrose (contained in candies such as Smarties) before eating fruit or fructose-containing foods can sometimes partially relieve symptoms. In general, gastrointestinal function returns over time as nutritional status improves.

Patients with severe or prolonged starvation can develop steatosis accompanied by elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In reports of starvation-induced steatosis, liver enzyme levels rapidly normalize with nutritional rehabilitation.²⁷

Endocrine consequences of starvation

Amenorrhea. Dysregulation of the hypothalamic-pituitary-gonadal axis is a major endocrine complication of nutritional in-sufficiency. Weight loss disrupts the normal pulsatile secretion of gonadotropin-releasing hormone, reduces secretion of luteinizing hormone and follicle-stimulating hormone, and decreases estrogen levels.²⁸ Leptin deficiency likely plays a role in suppressing gonadotropin secretion with subsequent development of amenorrhea. With weight gain, levels of leptin and gonadotropins normalize and menstruation eventually returns.^29,30

Hypothyroidism. Starvation can also lead to dysregulation of the hypothalamic-pituitary-thyroid axis. Typically, the concentration of triiodothyronine (T3) is reduced, the ratio of thyroxine (T4) to T3 is elevated, and thyroid-stimulating hormone (TSH) is close to or within the normal range, creating a euthyroid sick syndrome. In eating disorders, this thyroid disturbance is a result of starvation and resolves with weight restoration. Therefore, thyroid hormone replacement therapy is not medically indicated.²⁸

Osteoporosis. Amenorrhea resulting from low estrogen levels in undernourished patients can raise the risk of osteoporosis and fractures, particularly in patients with a low body mass index. Osteopenia results from a negative balance between bone deposition and resorption.

Lack of bone deposition can be especially problematic when disordered eating occurs during peak bone mass development, ie, ages 11 to 14 for girls, and ages 15 to 17 for boys.^31,32 Even a 5% to 10% decrease in bone deposition can result in significant risk of osteopenia.³³ However, after age 30, bone resorption is a greater contributor.³⁴

Does hormone therapy correct bone loss? Given the association between estrogen deficiency and bone loss, estrogen supplementation was expected to be an effective treatment for bone loss in patients with eating disorders.³⁵ Also, the restoration of menses through hormone replacement may give underweight patients a false sense of achieving a “healthy” weight.³⁶

Golden et al³⁷ prospectively studied 50 adolescents and found no significant difference in bone mineral density at 1 year of follow-up between patients treated with estrogen and those who received only standard nutritional therapy. However, increased bone mineral density was achieved in adolescents with anorexia nervosa treated with transdermally administered estrogen dosed to mimic physiologic pubertal levels.³⁸

Klibanski et al³⁹ found that hormone therapy resulted in a 4% gain in bone density in an extremely low-weight subset of women with anorexia nervosa (< 70% of ideal body weight), whereas similar patients in the control group lost 20%. However, in all groups, only weight gain correlated with bone gain in women who were within 70% of their ideal body weight.

Divasta et al⁴⁰ evaluated 60 girls and women ages 13 to 27 with anorexia nervosa, randomized to receive either placebo or dehydroepiandrosterone combined with an estrogen-progestin oral contraceptive, and followed for 18 months. As in the study by Klibanski et al,³⁹ bone loss was prevented in the treatment group, but significant bone gain occurred only in the context of weight gain.

The bottom line is that only weight gain has resulted in significant increases in bone density in patients with anorexia nervosa, and hormone therapy without weight gain has not been shown to increase bone density effectively in this population. Although calcium and vitamin D in oral therapeutic doses through foods or through supplementation are required for bone gain, the combination is not enough to augment bone density in the absence of weight gain.³⁷ Although not curative, weight gain is currently the best option for treating bone loss, and no single pharmacologic treatment is effective.

COMPLICATIONS OF PURGING

Oral complications of purging

Patients who purge by vomiting are at risk of complications from exposure of the esophagus, pharynx, and mouth to acidic gastric contents.

Dental problems. Over time, contact with gastric acid wears down enamel on the lingual and occlusal surfaces of teeth, resulting in dental caries and periodontal disease. Until they can give up purging, patients should be instructed to rinse with mouthwash or water immediately after vomiting to reduce the acidity in the mouth.^41,42 We recommend that patients not brush their teeth after vomiting, because brushing can deliver acid to otherwise unreachable surfaces and thus worsen tooth erosion. For patients who are determined to brush after vomiting, a bicarbonate toothpaste might mitigate harm.⁴²

Sialadenosis (hypertrophy of the salivary glands) is another consequence of repeated vomiting, with elevated salivary amylase. Both the size of the glands and the salivary amylase level generally normalize on their own after vomiting is stopped, but parotitis can take up to a year to resolve. Similar to smoker’s cough, parotitis may acutely worsen when the patient abruptly stops vomiting and may worsen before it improves.

To reduce discomfort, patients can use hot compresses or sugarless hard candies.⁴⁴ However, the latter should not be substituted as a chronic habit in a patient with disordered eating. Patients need to be reassured that the swelling is not permanent, since they often interpret it as having fat cheeks (the “chipmunk sign”).

Hypokalemia, metabolic alkalosis, renal dysfunction

Chronic vomiting can cause electrolyte and acid-base imbalances, the most worrisome of which is hypokalemia. With repeated vomiting, loss of potassium and gastric acid causes metabolic alkalosis with hypokalemia, hypochloremia, and hypomagnesemia. Loss of water and the resultant volume contraction activates the renin-angiotensin-aldosterone system, and elevated aldosterone further decreases serum potassium.

In patients with eating disorders, who often have other factors contributing to electrolyte imbalance, vomiting-induced hypokalemia heightens the risk of cardiac arrhythmias.⁴³

Hypokalemia can also cause rhabdomyolysis and kidney damage.^41,43 Prolonged hypokalemia and reduced kidney perfusion in the setting of volume depletion causes acute kidney injury and impaired concentrating ability of the renal tubules. Hypovolemia can cause prerenal azotemia and increases the risk for nephrolithiasis and nephrocalcinosis.^44,45

When a patient stops vomiting, elevated aldosterone from prior hypovolemia results in water retention and can manifest in significant edema associated with hypochloremic alkalosis. This condition, known as pseudo-Bartter syndrome, usually resolves without treatment. In the meantime, salt restriction and leg elevation can help reduce edema.²⁶

Laxative abuse: A mode of purging

Many patients with eating disorders abuse laxatives to lose weight or to prevent weight gain. Believing that laxatives will prevent calorie absorption, patients commonly take them to compensate for caloric intake (eg, during a binge episode). The immediate weight loss, albeit artificial, is highly reinforcing for an eating-disorder patient. In some cases, patients with eating disorders also abuse laxatives to self-treat the constipation that results from chronic starvation.⁴⁶

Over time, tolerance to laxatives develops, and patients use increasingly larger doses. This can lead to activation of the renin-angiotensin-aldosterone system.⁴⁷ Patients interpret the resultant edema as true weight gain and again take laxatives to get rid of it. If laxatives are stopped abruptly, the patient may need inpatient and outpatient support for the resultant fluid shifts.

Gastrointestinal complications of laxative abuse include reflex hypofunction of the bowel, malabsorption, steatorrhea, and gastrointestinal bleeding.⁴⁷ Reflex hypofunction during laxative withdrawal is a consequence of the bowel becoming tolerant of laxatives.⁴⁸ Cathartic colon syndrome is a rare complication characterized by loss of the normal haustral markings and slowed or absent peristalsis in segments of the colon.⁴⁹

Systemically, the major risk of laxative abuse relates to electrolyte and acid-base imbalance. Loss of potassium and water in the stool can cause hypokalemia and metabolic alkalosis.⁴⁸ The disturbances caused by laxative abuse are similar to those caused by vomiting and diuretic use and have the same treatment.

The most important component of treating laxative abuse is giving patients realistic expectations to help them tolerate temporary discomfort and to help manage the edema and fluid shifts that can happen acutely with shifting of fluid into the intracellular space. In extreme cases, this may need to be managed in the hospital. To help relieve the initial anxiety, doctors should emphasize that any bloating the patient experiences is not true weight gain and will go away within a few days to weeks. In addition, explaining that laxatives reduce nutrient absorption only minimally may lessen the temptation to resume taking them.⁴⁸

Diuretic abuse: Another form of purging

Diuretic abuse is yet another mode of purging, with its own set of medical complications. Like laxatives, diuretics are not effective weight-loss agents, and the weight reduction they cause is only temporary.

As with vomiting, there is a compensatory activation of the renin-angiotensin-aldosterone system, and therefore subsequent fluid intake will lead to water retention, which encourages further diuretic use.⁴¹ Diuretics can also contribute to hypokalemia, hypomagnesemia, hypochloremia, and metabolic alkalosis.

Ipecac abuse can lead to heart failure

Ipecac syrup has long been used to induce vomiting, but this practice has become much less common since ipecac has become harder to obtain in the United States.⁵⁰ The emetine base contained in ipecac binds irreversibly to cardiac and skeletal muscle. With continued use, irreversible cardiomyopathy develops and can lead to heart failure. Treatment should include supportive care and immediate cessation of ipecac use.

Diabetic patients may skip insulin to lose weight

Patients with diabetes, especially those with type 1 that begins in childhood, are at greater risk of eating disorders over time.⁵¹ They may withhold insulin to lose weight, a practice referred to in the nonmedical literature as “diabulimia,” and they seem particularly more likely to develop bulimia nervosa than those without diabetes.⁵²

The medical prognosis is poor for patients with diabetes who develop eating disorders and do not receive intensive treatment.⁵¹ In addition, if a diabetic patient on an insulin pump becomes depressed in addition to having an eating disorder, careful monitoring for suicidal thoughts and a rapid follow-up with mental health services are in order.

REFEEDING SYNDROME

When refeeding is started, a high glucose load stimulates insulin secretion, resulting in cellular uptake of phosphorus along with potassium, magnesium, and glucose. In addition, total body phosphorus is depleted by the increased demand for adenosine triphosphate and 2,3-diphosphoglycerate for cellular metabolism.

When liver enzyme levels increase, the astute clinician will closely monitor the patient for evidence of refeeding syndrome. In a child, adolescent, or young adult, the standard of care is inpatient monitoring for acute stabilization.^4,19

Hypophosphatemia is the hallmark of refeeding syndrome, although hypomagnesemia, hypokalemia, and hypoglycemia can also occur.⁵³ In addition, sodium and water retention can lead to fluid overload, with shifting of fluid into the intracellular space, resulting in dependent edema.

Cardiovascular complications are the most worrisome manifestations of refeeding syndrome. Electrolyte shifts and increased fluid volume can cause arrhythmias and heart failure. Furthermore, severely undernourished patients may have reduced myocardial mass as well as electrocardiographic abnormalities associated with starvation, which further increase their vulnerability to electrolyte shifts and fluid retention during refeeding.¹⁵

Other manifestations of refeeding syndrome include delirium, seizures, rhabdomyolysis, and respiratory failure. In the most extreme cases, refeeding syndrome causes sudden death.⁵³

Fortunately, refeeding syndrome is easily preventable and treatable when recognized early. Electrolytes and cardiovascular and renal function must be carefully monitored, especially during the first week of nutritional restoration.⁵³ In patients with extremely low body mass (< 70% of ideal body weight) or with precipitous weight loss, close monitoring of the complete metabolic panel including electrolytes, AST, ALT, calcium, magnesium, and phosphorus may be required to detect changes that can affect cardiac status. Specific suggestions for refeeding are discussed below and in Table 2.⁴⁵

ACUTE CARE OF PATIENTS WITH EATING DISORDERS

Refeeding in the inpatient setting

The decision to hospitalize an eating-disorder patient is based on the current or potential risk of serious medical complications and the likelihood of success at home. Medical criteria for hospital admission are outlined in Table 3.^4,54

In refeeding undernourished patients, the challenge is to maximize weight gain while preventing refeeding syndrome. Undernourished patients are generally hypometabolic at baseline but become hypermetabolic once refeeding begins.

How many calories should refeeding start with? The traditional principle of “start low and go slow” has been recently challenged.⁵⁵ Starting at 1,200 kcal/day or less in the typical patient can result in failure to gain weight or even in weight loss in the first week of refeeding.⁵⁶ The goal is to achieve a weight gain of 0.2 kg/day while the patient is in the hospital. Thus, we start higher, and to date we have seen no cases of life-threatening refeeding syndrome. In all patients who need hospitalization or who are beginning the refeeding process as outpatients, caloric intake should be started at 1,500 to 2,000 kcal/day.^45,57 However, for exceptionally low-weight patients, intake may be started lower.

In Australia, patients are started at 1,900 kcal/day.⁵⁶ All patients in one program there receive nasogastric feeding initially in an intensive care unit and then are moved to a regular nursing floor where they graduate to full oral feeding as they improve cardiovascularly and behaviorally. In the United States, some programs use nasogastric feeding at night for caloric restoration; our program and others use nasogastric feeding as a behavioral modification strategy for patients who refuse food or supplements by mouth.

Phosphorus supplementation. Many centers give phosphorus supplements preventively. In our center, we give potassium phosphate (Neutra-Phos) 500 mg orally twice daily for 5 days, and we have seen no life-threatening cases of refeeding syndrome with that regimen. Other centers give phosphorus supplements in a dose of 250 mg orally twice a day for 5 days, while still others only supplement phosphorus reactively once a deficit has been identified. The latter method requires daily blood draws for monitoring and is reactive rather than proactive. Further studies can help clarify the optimal dosing and timing of phosphorus supplementation.

Managing fluid balance. Fluid-loading these patients may tip them over the edge into refeeding syndrome. Except in cases of shock, patients with eating disorders should not be given intravenous fluids, as it is safer to rehydrate and feed them orally. Electrolyte imbalances can be corrected orally with no need for intravenous supplementation. To avoid fluid overload, fluids can be started at 1,500 mL to 2,000 mL per day, with strict monitoring of intake and output. Fluids are liberalized if ALT and AST levels remain normal and to gradually correct orthostatic hypotension; caloric fluids are ideal to help address energy needs and improve bradycardia.

Laboratory monitoring. On admission, a urinalysis, complete blood cell count, complete metabolic panel, TSH, erythrocyte sedimentation rate, serum magnesium, and phosphorus should be obtained.²⁶ In addition, continuous electrocardiographic recording should begin on admission.⁴⁵ Inpatient use of a telemetry bed helps identify extreme tachycardia with arrhythmia, as well as profound bradycardia.^45,56

Some protocols call for daily laboratory monitoring, although that degree of testing is less cost-effective. If initial results are normal, clinical judgment can be used on when to repeat laboratory evaluation. For instance, patients with edema require repeat complete metabolic panels to assess for elevated ALT and AST, electrolyte imbalances, and other abnormalities.

Signs of refeeding syndrome include tachycardia, hepatosplenomegaly, peripheral edema, altered mental status, and electrolyte disturbances, specifically, acute or severe hypophosphatemia or hypokalemia.^26,45 If refeeding syndrome is suspected, the rate of caloric intake should be reduced or not advanced, fluid intake should be urgently reassessed for volume overload, and supportive care with close monitoring should be provided.

KNOWLEDGE SAVES LIVES

Eating disorders can lead to potentially life-threatening medical complications that require attentive care by the primary care clinician and subspecialist. Without thoughtful consideration, it is easy for even a caring medical team to unintentionally enable patients with these illnesses or to cause active harm in the case of underrecognized pathology.⁵⁸

Acute medical stabilization on an inpatient unit trained to recognize pathology and treat sequelae can be lifesaving. Arming patients and families with medical knowledge, as provided in the Academy for Eating Disorders’ brochure, “Critical Points for Early Recognition and Medical Risk Management in the Care of Individuals with Eating Disorders”⁵⁹ can help save patients’ lives.

Eating disorders are debilitating biopsychosocial illnesses associated with serious medical illness and a high risk of death.¹

Primary care physicians are often the first to see young women who have these problems, diagnose them, and start their evaluation and treatment.^2–4 Many patients require acute medical interventions as well as long-term care for chronic medical issues. Therefore, primary care physicians play essential front-line and long-term roles in the multidisciplinary treatment team.

DEFINITIONS OF EATING DISORDERS HAVE CHANGED

Several problems existed in the category of eating disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-4) and in the DSM-4 Text Revision (DSM-4-TR). These problems have been addressed in the fifth edition (DSM-5), released in 2013.⁵

One problem in the earlier editions was that many patients referred for treatment of eating disorders—more than 50% in one study⁶—did not meet the criteria for anorexia nervosa or bulimia nervosa and thus had to be categorized as having “eating disorder not otherwise specified.” Further, the earlier editions did not recognize that young children and adolescent males can be affected.⁷

Eating disorders are now recognized as an equal-opportunity disease, with all ethnic and socioeconomic groups affected. Children can run into medical trouble with even a small amount of weight loss or falling off the growth curve. Moreover, children and adolescents do not “experience” their bodies in the same way adults do; they may lack the vocabulary for eating-disorder thoughts.

For these reasons, the definitions of eating disorders have changed in the DSM-5.⁵

Anorexia nervosa. Older editions of the DSM listed amenorrhea as a criterion. This has been eliminated in DSM-5, since amenorrhea does not necessarily predict medical risk or treatment outcome; also, it is not applicable to males or premenorrheal girls and postmenopausal women.⁸ In addition, the requirement of low weight is now defined in the context of “age, sex, developmental trajectory, and physical health,” rather than the old threshold of 85% of expected weight.⁹

What remains unchanged is that anorexia nervosa is still characterized by self-starvation in order to maintain an abnormally low body weight, along with an intense fear of being fat and a disturbed self-image.

Bulimia nervosa. In both the old and the new editions of the DSM, bulimia nervosa is characterized by episodes of binge eating followed by inappropriate compensatory behaviors to avoid weight gain, such as vomiting, laxative abuse, diuretic abuse, and overexercise. In DSM-5, bulimia nervosa no longer has subtypes and requires only one binge per week with compensatory behavior, for at least 3 months. This change was based on the finding that there is no clear difference in psychopathology or treatment outcome between patients with one and two binge-purge episodes a week.¹⁰

“Eating disorder not otherwise specified” was a wastebasket category, lumping all those who did not meet the criteria for anorexia nervosa or bulimia nervosa or who did not neatly fit into a specific category.¹⁰ In DSM-5, subcategories were designed to help distinguish different treatment needs and outcomes between various subtypes.

Binge-eating disorder, one of the new subcategories, is characterized by binge eating without inappropriate compensatory behaviors.⁹ Patients with binge-eating disorder are often obese, have greater functional impairment, and are more likely to develop components of metabolic syndrome than obese patients without eating disorders.¹¹

Avoidant/restrictive food intake disorder is another new DSM-5 diagnosis, characterized by failure to meet nutritional needs for reasons other than weight control. Reasons include disinterest in eating, dislike of sensory characteristics of food, or avoidance of consequences of eating. This disorder replaces the category “feeding disorder of infancy or early childhood,” since the condition can also occur in adolescents and adults.¹²

Other new diagnoses are:

• Atypical anorexia nervosa (if the patient is not underweight)
• Purging disorder
• Subthreshold bulimia nervosa (if the patient has < 1 episode per week or has had them for < 3 months)
• Subthreshold binge eating disorder (< 1 time a week or < 3 months)
• Night eating syndrome
• Pica and rumination disorder.

Regardless of the diagnostic label, the medical evaluation and treatment of anyone with an eating disorder should be tailored to the specific behaviors of the eating disorder. Medical complications can be subdivided into those from starvation, from purging, and from refeeding.

MEDICAL COMPLICATIONS OF STARVATION

Cardiovascular effects of starvation

Malnutrition and starvation have multiple adverse effects on the heart.

Electrophysiologic effects. Sinus bradycardia (< 60 bpm) and hypotension are common cardiac manifestations of starvation.¹³ Bradycardia has been attributed to an adaptive increase in parasympathetic vagal tone.¹⁴ QTc prolongation is also seen in patients with malnutrition.¹⁵

Together, these electrocardiographic abnormalities predispose the patient to ventricular arrhythmia and sudden cardiac death.¹⁶ The risk of ventricular arrhythmia is particularly relevant when treating psychiatric symptoms, since antipsychotics and tricyclic antidepressants are among several drug classes that can cause further QTc prolongation (Table 1).^17,18

In patients with QTc prolongation, bradycardia, or both, the standard of care involves acute hospitalization for refeeding using continuous telemetric monitoring until normal rhythm is restored and the heart rate is above 40 at night and 50 by day.^4,19

Structural changes. Starvation also causes structural changes in the heart. Loss of lean body mass can reduce cardiac muscle mass, compromise cardiac output, and lead to mitral valve prolapse.²⁰ These changes are fully reversible with restored nutrition and regaining of heart mass.^21,22

Effects of starvation on the brain

Starvation can affect brain structure and cognitive function. Undernourished patients have reduced volumes of white and gray matter, a change that can occur within months. Cortical volumes may increase with weight gain, but a reduction in gray matter volume may not be completely reversible.²³

Furthermore, starvation impairs cognitive functions that are needed to stop eating-disorder behaviors; namely, decision-making, emotional control, regulation of appetite, and reward path-ways. Therefore, undernourished patients may not have sufficient insight into the disease to be able to make the best choices for recovery. This finding lends support for using the Maudsley method in adolescents, in which parents take control of their child’s eating until the child can maintain a healthy weight.²⁴

Gastrointestinal consequences of starvation

Patients with malnutrition have prolonged gastric emptying and colonic transit time with solid foods.²⁵ They often complain of early satiety, abdominal pain, bloating, and constipation, all symptoms that complicate the refeeding process. A prokinetic such as metoclopramide (Reglan), given 1 hour before meals and at bedtime, may provide some relief from gastrointestinal symptoms.²⁶

Patients may also experience transient lactose or fructose intolerance after prolonged starvation. Taking a lactase supplement (eg, Lactaid 1–10 tabs) before consuming dairy products and dextrose (contained in candies such as Smarties) before eating fruit or fructose-containing foods can sometimes partially relieve symptoms. In general, gastrointestinal function returns over time as nutritional status improves.

Patients with severe or prolonged starvation can develop steatosis accompanied by elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). In reports of starvation-induced steatosis, liver enzyme levels rapidly normalize with nutritional rehabilitation.²⁷

Endocrine consequences of starvation

Amenorrhea. Dysregulation of the hypothalamic-pituitary-gonadal axis is a major endocrine complication of nutritional in-sufficiency. Weight loss disrupts the normal pulsatile secretion of gonadotropin-releasing hormone, reduces secretion of luteinizing hormone and follicle-stimulating hormone, and decreases estrogen levels.²⁸ Leptin deficiency likely plays a role in suppressing gonadotropin secretion with subsequent development of amenorrhea. With weight gain, levels of leptin and gonadotropins normalize and menstruation eventually returns.^29,30

Hypothyroidism. Starvation can also lead to dysregulation of the hypothalamic-pituitary-thyroid axis. Typically, the concentration of triiodothyronine (T3) is reduced, the ratio of thyroxine (T4) to T3 is elevated, and thyroid-stimulating hormone (TSH) is close to or within the normal range, creating a euthyroid sick syndrome. In eating disorders, this thyroid disturbance is a result of starvation and resolves with weight restoration. Therefore, thyroid hormone replacement therapy is not medically indicated.²⁸

Osteoporosis. Amenorrhea resulting from low estrogen levels in undernourished patients can raise the risk of osteoporosis and fractures, particularly in patients with a low body mass index. Osteopenia results from a negative balance between bone deposition and resorption.

Lack of bone deposition can be especially problematic when disordered eating occurs during peak bone mass development, ie, ages 11 to 14 for girls, and ages 15 to 17 for boys.^31,32 Even a 5% to 10% decrease in bone deposition can result in significant risk of osteopenia.³³ However, after age 30, bone resorption is a greater contributor.³⁴

Does hormone therapy correct bone loss? Given the association between estrogen deficiency and bone loss, estrogen supplementation was expected to be an effective treatment for bone loss in patients with eating disorders.³⁵ Also, the restoration of menses through hormone replacement may give underweight patients a false sense of achieving a “healthy” weight.³⁶

Golden et al³⁷ prospectively studied 50 adolescents and found no significant difference in bone mineral density at 1 year of follow-up between patients treated with estrogen and those who received only standard nutritional therapy. However, increased bone mineral density was achieved in adolescents with anorexia nervosa treated with transdermally administered estrogen dosed to mimic physiologic pubertal levels.³⁸

Klibanski et al³⁹ found that hormone therapy resulted in a 4% gain in bone density in an extremely low-weight subset of women with anorexia nervosa (< 70% of ideal body weight), whereas similar patients in the control group lost 20%. However, in all groups, only weight gain correlated with bone gain in women who were within 70% of their ideal body weight.

Divasta et al⁴⁰ evaluated 60 girls and women ages 13 to 27 with anorexia nervosa, randomized to receive either placebo or dehydroepiandrosterone combined with an estrogen-progestin oral contraceptive, and followed for 18 months. As in the study by Klibanski et al,³⁹ bone loss was prevented in the treatment group, but significant bone gain occurred only in the context of weight gain.

The bottom line is that only weight gain has resulted in significant increases in bone density in patients with anorexia nervosa, and hormone therapy without weight gain has not been shown to increase bone density effectively in this population. Although calcium and vitamin D in oral therapeutic doses through foods or through supplementation are required for bone gain, the combination is not enough to augment bone density in the absence of weight gain.³⁷ Although not curative, weight gain is currently the best option for treating bone loss, and no single pharmacologic treatment is effective.

COMPLICATIONS OF PURGING

Oral complications of purging

Patients who purge by vomiting are at risk of complications from exposure of the esophagus, pharynx, and mouth to acidic gastric contents.

Dental problems. Over time, contact with gastric acid wears down enamel on the lingual and occlusal surfaces of teeth, resulting in dental caries and periodontal disease. Until they can give up purging, patients should be instructed to rinse with mouthwash or water immediately after vomiting to reduce the acidity in the mouth.^41,42 We recommend that patients not brush their teeth after vomiting, because brushing can deliver acid to otherwise unreachable surfaces and thus worsen tooth erosion. For patients who are determined to brush after vomiting, a bicarbonate toothpaste might mitigate harm.⁴²

Sialadenosis (hypertrophy of the salivary glands) is another consequence of repeated vomiting, with elevated salivary amylase. Both the size of the glands and the salivary amylase level generally normalize on their own after vomiting is stopped, but parotitis can take up to a year to resolve. Similar to smoker’s cough, parotitis may acutely worsen when the patient abruptly stops vomiting and may worsen before it improves.

To reduce discomfort, patients can use hot compresses or sugarless hard candies.⁴⁴ However, the latter should not be substituted as a chronic habit in a patient with disordered eating. Patients need to be reassured that the swelling is not permanent, since they often interpret it as having fat cheeks (the “chipmunk sign”).

Hypokalemia, metabolic alkalosis, renal dysfunction

Chronic vomiting can cause electrolyte and acid-base imbalances, the most worrisome of which is hypokalemia. With repeated vomiting, loss of potassium and gastric acid causes metabolic alkalosis with hypokalemia, hypochloremia, and hypomagnesemia. Loss of water and the resultant volume contraction activates the renin-angiotensin-aldosterone system, and elevated aldosterone further decreases serum potassium.

In patients with eating disorders, who often have other factors contributing to electrolyte imbalance, vomiting-induced hypokalemia heightens the risk of cardiac arrhythmias.⁴³

Hypokalemia can also cause rhabdomyolysis and kidney damage.^41,43 Prolonged hypokalemia and reduced kidney perfusion in the setting of volume depletion causes acute kidney injury and impaired concentrating ability of the renal tubules. Hypovolemia can cause prerenal azotemia and increases the risk for nephrolithiasis and nephrocalcinosis.^44,45

When a patient stops vomiting, elevated aldosterone from prior hypovolemia results in water retention and can manifest in significant edema associated with hypochloremic alkalosis. This condition, known as pseudo-Bartter syndrome, usually resolves without treatment. In the meantime, salt restriction and leg elevation can help reduce edema.²⁶

Laxative abuse: A mode of purging

Many patients with eating disorders abuse laxatives to lose weight or to prevent weight gain. Believing that laxatives will prevent calorie absorption, patients commonly take them to compensate for caloric intake (eg, during a binge episode). The immediate weight loss, albeit artificial, is highly reinforcing for an eating-disorder patient. In some cases, patients with eating disorders also abuse laxatives to self-treat the constipation that results from chronic starvation.⁴⁶

Over time, tolerance to laxatives develops, and patients use increasingly larger doses. This can lead to activation of the renin-angiotensin-aldosterone system.⁴⁷ Patients interpret the resultant edema as true weight gain and again take laxatives to get rid of it. If laxatives are stopped abruptly, the patient may need inpatient and outpatient support for the resultant fluid shifts.

Gastrointestinal complications of laxative abuse include reflex hypofunction of the bowel, malabsorption, steatorrhea, and gastrointestinal bleeding.⁴⁷ Reflex hypofunction during laxative withdrawal is a consequence of the bowel becoming tolerant of laxatives.⁴⁸ Cathartic colon syndrome is a rare complication characterized by loss of the normal haustral markings and slowed or absent peristalsis in segments of the colon.⁴⁹

Systemically, the major risk of laxative abuse relates to electrolyte and acid-base imbalance. Loss of potassium and water in the stool can cause hypokalemia and metabolic alkalosis.⁴⁸ The disturbances caused by laxative abuse are similar to those caused by vomiting and diuretic use and have the same treatment.

The most important component of treating laxative abuse is giving patients realistic expectations to help them tolerate temporary discomfort and to help manage the edema and fluid shifts that can happen acutely with shifting of fluid into the intracellular space. In extreme cases, this may need to be managed in the hospital. To help relieve the initial anxiety, doctors should emphasize that any bloating the patient experiences is not true weight gain and will go away within a few days to weeks. In addition, explaining that laxatives reduce nutrient absorption only minimally may lessen the temptation to resume taking them.⁴⁸

Diuretic abuse: Another form of purging

Diuretic abuse is yet another mode of purging, with its own set of medical complications. Like laxatives, diuretics are not effective weight-loss agents, and the weight reduction they cause is only temporary.

As with vomiting, there is a compensatory activation of the renin-angiotensin-aldosterone system, and therefore subsequent fluid intake will lead to water retention, which encourages further diuretic use.⁴¹ Diuretics can also contribute to hypokalemia, hypomagnesemia, hypochloremia, and metabolic alkalosis.

Ipecac abuse can lead to heart failure

Ipecac syrup has long been used to induce vomiting, but this practice has become much less common since ipecac has become harder to obtain in the United States.⁵⁰ The emetine base contained in ipecac binds irreversibly to cardiac and skeletal muscle. With continued use, irreversible cardiomyopathy develops and can lead to heart failure. Treatment should include supportive care and immediate cessation of ipecac use.

Diabetic patients may skip insulin to lose weight

Patients with diabetes, especially those with type 1 that begins in childhood, are at greater risk of eating disorders over time.⁵¹ They may withhold insulin to lose weight, a practice referred to in the nonmedical literature as “diabulimia,” and they seem particularly more likely to develop bulimia nervosa than those without diabetes.⁵²

The medical prognosis is poor for patients with diabetes who develop eating disorders and do not receive intensive treatment.⁵¹ In addition, if a diabetic patient on an insulin pump becomes depressed in addition to having an eating disorder, careful monitoring for suicidal thoughts and a rapid follow-up with mental health services are in order.

REFEEDING SYNDROME

When refeeding is started, a high glucose load stimulates insulin secretion, resulting in cellular uptake of phosphorus along with potassium, magnesium, and glucose. In addition, total body phosphorus is depleted by the increased demand for adenosine triphosphate and 2,3-diphosphoglycerate for cellular metabolism.

When liver enzyme levels increase, the astute clinician will closely monitor the patient for evidence of refeeding syndrome. In a child, adolescent, or young adult, the standard of care is inpatient monitoring for acute stabilization.^4,19

Hypophosphatemia is the hallmark of refeeding syndrome, although hypomagnesemia, hypokalemia, and hypoglycemia can also occur.⁵³ In addition, sodium and water retention can lead to fluid overload, with shifting of fluid into the intracellular space, resulting in dependent edema.

Cardiovascular complications are the most worrisome manifestations of refeeding syndrome. Electrolyte shifts and increased fluid volume can cause arrhythmias and heart failure. Furthermore, severely undernourished patients may have reduced myocardial mass as well as electrocardiographic abnormalities associated with starvation, which further increase their vulnerability to electrolyte shifts and fluid retention during refeeding.¹⁵

Other manifestations of refeeding syndrome include delirium, seizures, rhabdomyolysis, and respiratory failure. In the most extreme cases, refeeding syndrome causes sudden death.⁵³

Fortunately, refeeding syndrome is easily preventable and treatable when recognized early. Electrolytes and cardiovascular and renal function must be carefully monitored, especially during the first week of nutritional restoration.⁵³ In patients with extremely low body mass (< 70% of ideal body weight) or with precipitous weight loss, close monitoring of the complete metabolic panel including electrolytes, AST, ALT, calcium, magnesium, and phosphorus may be required to detect changes that can affect cardiac status. Specific suggestions for refeeding are discussed below and in Table 2.⁴⁵

ACUTE CARE OF PATIENTS WITH EATING DISORDERS

Refeeding in the inpatient setting

The decision to hospitalize an eating-disorder patient is based on the current or potential risk of serious medical complications and the likelihood of success at home. Medical criteria for hospital admission are outlined in Table 3.^4,54

In refeeding undernourished patients, the challenge is to maximize weight gain while preventing refeeding syndrome. Undernourished patients are generally hypometabolic at baseline but become hypermetabolic once refeeding begins.

How many calories should refeeding start with? The traditional principle of “start low and go slow” has been recently challenged.⁵⁵ Starting at 1,200 kcal/day or less in the typical patient can result in failure to gain weight or even in weight loss in the first week of refeeding.⁵⁶ The goal is to achieve a weight gain of 0.2 kg/day while the patient is in the hospital. Thus, we start higher, and to date we have seen no cases of life-threatening refeeding syndrome. In all patients who need hospitalization or who are beginning the refeeding process as outpatients, caloric intake should be started at 1,500 to 2,000 kcal/day.^45,57 However, for exceptionally low-weight patients, intake may be started lower.

In Australia, patients are started at 1,900 kcal/day.⁵⁶ All patients in one program there receive nasogastric feeding initially in an intensive care unit and then are moved to a regular nursing floor where they graduate to full oral feeding as they improve cardiovascularly and behaviorally. In the United States, some programs use nasogastric feeding at night for caloric restoration; our program and others use nasogastric feeding as a behavioral modification strategy for patients who refuse food or supplements by mouth.

Phosphorus supplementation. Many centers give phosphorus supplements preventively. In our center, we give potassium phosphate (Neutra-Phos) 500 mg orally twice daily for 5 days, and we have seen no life-threatening cases of refeeding syndrome with that regimen. Other centers give phosphorus supplements in a dose of 250 mg orally twice a day for 5 days, while still others only supplement phosphorus reactively once a deficit has been identified. The latter method requires daily blood draws for monitoring and is reactive rather than proactive. Further studies can help clarify the optimal dosing and timing of phosphorus supplementation.

Managing fluid balance. Fluid-loading these patients may tip them over the edge into refeeding syndrome. Except in cases of shock, patients with eating disorders should not be given intravenous fluids, as it is safer to rehydrate and feed them orally. Electrolyte imbalances can be corrected orally with no need for intravenous supplementation. To avoid fluid overload, fluids can be started at 1,500 mL to 2,000 mL per day, with strict monitoring of intake and output. Fluids are liberalized if ALT and AST levels remain normal and to gradually correct orthostatic hypotension; caloric fluids are ideal to help address energy needs and improve bradycardia.

Laboratory monitoring. On admission, a urinalysis, complete blood cell count, complete metabolic panel, TSH, erythrocyte sedimentation rate, serum magnesium, and phosphorus should be obtained.²⁶ In addition, continuous electrocardiographic recording should begin on admission.⁴⁵ Inpatient use of a telemetry bed helps identify extreme tachycardia with arrhythmia, as well as profound bradycardia.^45,56

Some protocols call for daily laboratory monitoring, although that degree of testing is less cost-effective. If initial results are normal, clinical judgment can be used on when to repeat laboratory evaluation. For instance, patients with edema require repeat complete metabolic panels to assess for elevated ALT and AST, electrolyte imbalances, and other abnormalities.

Signs of refeeding syndrome include tachycardia, hepatosplenomegaly, peripheral edema, altered mental status, and electrolyte disturbances, specifically, acute or severe hypophosphatemia or hypokalemia.^26,45 If refeeding syndrome is suspected, the rate of caloric intake should be reduced or not advanced, fluid intake should be urgently reassessed for volume overload, and supportive care with close monitoring should be provided.

KNOWLEDGE SAVES LIVES

Eating disorders can lead to potentially life-threatening medical complications that require attentive care by the primary care clinician and subspecialist. Without thoughtful consideration, it is easy for even a caring medical team to unintentionally enable patients with these illnesses or to cause active harm in the case of underrecognized pathology.⁵⁸

Acute medical stabilization on an inpatient unit trained to recognize pathology and treat sequelae can be lifesaving. Arming patients and families with medical knowledge, as provided in the Academy for Eating Disorders’ brochure, “Critical Points for Early Recognition and Medical Risk Management in the Care of Individuals with Eating Disorders”⁵⁹ can help save patients’ lives.