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case records of the massachusetts general hospital

Founded by Richard C. Cabot

Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 21-2012: A 27-Year-Old Man

with Fatigue, Weakness, Weight Loss,
and Decreased Libido
Daniel P. Hunt, M.D., Anne E. Becker, M.D., Ph.D.,
Alexander R. Guimaraes, M.D., Ph.D., Anat Stemmer-Rachamimov, M.D.,
and Joseph Misdraji, M.D.

Pr e sen tat ion of C a se

Dr. Fernando M. Contreras (Medicine): A 27-year-old man with a history of obesity was From the Departments of Medicine
seen in the endocrinology clinic at this hospital because of fatigue, myalgias, weak- (D.P.H.), Psychiatry (A.E.B.), Radiology
(A.R.G.), and Pathology (A.S.-R., J.M.),
ness, weight loss, and loss of libido. Massachusetts General Hospital; and
Thirteen months before presentation, the patient reported weighing 108.9 kg the Departments of Medicine (D.P.H.),
(body-mass index [BMI, the weight in kilograms divided by the square of the height Psychiatry (A.E.B.), Radiology (A.R.G.),
and Pathology (A.S.-R., J.M.), Harvard
in meters], 35.4) and began aerobic exercises, 2 hours daily, and a calorie-restricted Medical School both in Boston.
diet (2400 kcal daily), resulting in a loss of 36.3 kg in 10 months. Two months
before evaluation, arm weakness, numbness and aching in his legs, decreased li- This article was updated on August 7, 2012,
at NEJM.org.
bido with loss of morning erections, and a faint lacy rash on his legs developed.
He reportedly stopped aerobics, began lifting weights, and increased his caloric N Engl J Med 2012;367:157-69.
DOI: 10.1056/NEJMcpc1110053
intake, without improvement in his symptoms. On evaluation by his physician at Copyright 2012 Massachusetts Medical Society.
another hospital, the white-cell and differential counts and blood levels of calcium,
lipids, prolactin, thyrotropin, and vitamin D were normal; testing for IgA auto-
antibodies to transglutaminase and screening tests for antinuclear antibodies, the
human immunodeficiency virus (HIV), viral hepatitis (types A, B, and C), and
Lyme disease were negative; and testing for parvovirus suggested past infection.
Other test results are shown in Table 1. Topical testosterone gel was prescribed.
During the next 3 weeks, additional consultations and testing were obtained.
Serum levels of alpha-fetoprotein and complement (C3 and C4) were normal; testing
for autoantibodies to double-stranded DNA, rheumatoid factor, Ro (SSA), and La
(SSB) were negative; other test results are shown in Table 1. Computed tomography
(CT) of the chest, abdomen, and pelvis reportedly revealed multiple small gas bub-
bles in the mediastinum (a finding consistent with pneumomediastinum), decreased
intraabdominal and intrapelvic fat, and opacities suggestive of stool throughout the
colon. A magnetic resonance imaging (MRI) scan of the pituitary gland was normal.
An MRI scan of the abdomen and liver, obtained after the administration of gado-
linium, reportedly showed higher signal intensity in the liver than in the spleen,
with no evidence of masses, iron overload, ascites, or lymphadenopathy.

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 158
Table 1. Laboratory Data.*

Reference Physicians This

Variable Range, Adults Office Other Hospital This Hospital Other Hospital Hospital

7 Wk before 5 Wk before 10 Days before On Presentation, 2 Wk Later, 6 Wk after

8 Wk before Presentation, Presentation, Presentation, Endocrinology 1st 3.5 Wk after 6 Wk after Presentation,
Presentation Outpatient on Admission Outpatient Clinic Admission Presentation Presentation 2nd Admission
Hematocrit (%) 41.053.0 (men) 42.5 30.3 31.2 29.6 34.3 33.7
Hemoglobin (g/dl) 13.517.5 (men) 15.3 10.6 10.5 10.1 11.9 11.6
The

White-cell count (per 450011,000 4400 (ref 6000 11,300 5400 6900 5000
mm3) 480010,800)
Mean corpuscular volume 80100 88.3 91 91 92 92.8 92
(m3)
Platelet count (per mm3) 150,000400,000 187,000 149,000 344,000 322,000 103,000 103,000,
large forms
Erythrocyte sedimentation 011 (men) 7 (ref 015) 84 6
rate (mm/hr)
Prothrombin time (sec) 10.813.4 20.1 20.6
International normalized 1.87 1.9
ratio for prothrom-
n e w e ng l a n d j o u r na l

bin time

The New England Journal of Medicine

of

Sodium (mmol/liter) 135145 138 136 136 137 137 133 137 134
Potassium (mmol/liter) 3.44.8 5.3 4.5 4.1 5.6 4.1 4.0 4.0 3.9

n engl j med 367;2 nejm.org july 12, 2012

(ref 3.65.0)
Chloride (mmol/liter) 100108 99 97 99 97 95 93 98 96

Copyright 2012 Massachusetts Medical Society. All rights reserved.

m e dic i n e

(ref 98107)
Carbon dioxide (mmol/ 23.031.9 36 35 35 37 29.4 35.0 36 33.5
liter) (ref 2230)
Urea nitrogen (mg/dl) 825 37 34 (ref 920) 25 29 13 26 45 31

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Creatinine (mg/dl) 0.601.50 1.22 0.92 0.56 0.69 0.70 0.79 0.83 0.67
Glucose (mg/dl) 70110 71 75 (ref 75110) 55 67 73 74 30 72
 Protein (g/dl)
Total 6.08.3 7.1 (ref 6.3 7.0 5.1 6.0 7.0 5.9 5.9 5.7
8.2)
Albumin 3.35.0 4.4 (ref 3.5 4.4 2.8 3.1 3.8 3.5 3.2 3.5
5.0)
Total bilirubin (mg/dl) 0.01.0 0.8 (ref 0.2 0.8 0.6 0.8 0.8 0.4 2.1 2.8
1.3)
Direct bilirubin (mg/dl) 0.00.4 0 0 (ref 0.21.3) 0 0 0.2 0.1 1.4 2.1
Alkaline phosphatase 45115 80 (ref 38126) 79 138 289 196 109 352 406
(U/liter)
Aspartate aminotransfer- 1040 97 (ref 1759) 234 229 103 23 16 3996 3969
ase (U/liter)
Alanine aminotransferase 1055 248 (ref 1166) 382 474 335 57 17 2427 2576
(U/liter)
Lactate dehydrogenase 110210 855 179
(U/liter)
Creatine kinase (U/liter) 60400 (men) 210 (ref 55 39 29 752 847
170)
Creatine kinase isoen- 0.06.9 27.7
zymes (ng/ml)
IgE (IU/ml) 324.0 (ref
<114.0)
25-hydroxyvitamin D >32 40.11 (ref 30 27

n engl j med 367;2 nejm.org july 12, 2012

(ng/ml) 100)

The New England Journal of Medicine

Follicle-stimulating hor- 0.85 <0.3
mone (mIU/ml) (ref 1.418.1,
men)
Luteinizing hormone 0.29 <0.07
case records of the massachusetts gener al hospital

(mIU/ml) (ref 1.59.3,

Copyright 2012 Massachusetts Medical Society. All rights reserved.

men ages 20
70 yr)

Total testosterone (ng/dl) 2701070 58.04 394 (ref 240 707 5020
(ref 241827) 950) (ref 2741194)

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159
 160
Free testosterone (ng/dl) 14.6 (ref 930)
Aldolase (U/liter) <7.7 11 (ref <8) 2.2
Ferritin (ng/ml) 30300 1520.9 (ref 20 11,063
350)
Iron (g/dl) 45160 223 (ref 49 181
181)
Total iron-binding capaci- 230404 218 (ref 250 Unable to
ty (g/dl) 450) perform
test
Transferrin (mg/dl) 170340 129
Corticotropin (pg/ml) 26 (ref 643)
Cortisol, morning (g/dl) 35.43 (ref 4.2 35.27
The

22.4)
Free triiodothyronine 1.56 (ref 2.34.2)
(pg/ml)
Free thyroxine (ng/dl) 0.91.8 0.81 (ref 0.89 0.8 1.0
1.76)
Total triiodothyronine 60181 38 42
(ng/dl)
Insulin (U/ml) 2.625 2.4
C-reactive protein <8.0 for 8.0 (ref 010) 50.1 8.0
(mg/liter) inflammation
n e w e ng l a n d j o u r na l

Total complement (U/ml) 63145 225

The New England Journal of Medicine

of

Lipase (U/liter) 1360 1239 (ref 132

23300)
Amylase (U/liter) 3100 130 (ref 118

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30110)

Copyright 2012 Massachusetts Medical Society. All rights reserved.

Myoglobin (ng/ml) >1000 (ref
m e dic i n e

0110)

* Ref denotes reference range at the other facility. To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per
liter, multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for bilirubin to micromoles per liter, multiply by 17.1. To convert
the values for 25-hydroxyvitamin D to nanomoles per liter, multiply by 2.496. To convert the values for testosterone to nanomoles per liter, multiply by 0.03467. To convert the values for

Downloaded from nejm.org on January 3, 2016. For personal use only. No other uses without permission.
iron and iron-binding capacity to micromoles per liter, multiply by 0.1791. To convert the values for corticotropin to picomoles per liter, multiply by 0.2202. To convert the values for corti-
sol to nanomoles per liter, multiply by 27.59. To convert the values for free thyroxine to picomoles per liter, multiply by 12.87. To convert the values for free triiodothyronine to picomoles
per liter, multiply by 1.536. To convert the values for total triiodothyronine to nanomoles per liter, multiply by 0.01536. To convert the values for insulin to picomoles per liter, multiply by
6.945.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults who
are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.
 case records of the massachusetts gener al hospital

Approximately 5 weeks before this presenta-

tion, the patient was admitted to the other hos-
pital because of a submandibular abscess in the
neck, associated with dental caries. The abscess
was incised and drained, and antibiotics were
administered, with improvement. Pathological ex-
amination of a biopsy specimen of a lymph node
showed areas of infarction, necrosis, and acute
inflammation, without evidence of cancer. Culture
of the tissue grew alpha-hemolytic streptococci.
He was discharged on the third hospital day.
The patient reportedly stopped exercising but
continued to lose weight. Echocardiography re-
vealed normal left ventricular size and function,
and a small pericardial effusion, without tam-
ponade. Two weeks after discharge, a biopsy of
the liver was performed; pathological examination
of a specimen showed moderate hepatic sidero-
sis, mostly involving macrophages but with a
minor hepatocellular component. He was referred
to the endocrinology clinic at this hospital.
The patient reported fatigue, intermittent ab-
dominal pain, constipation (one bowel movement
weekly for months), swelling in his feet, and Figure 1. Clinical Photographs.
decreased testicular size. Pubertal development Posterior views of the patient show the profound loss
of weight and muscle mass, as evidenced by the prom-
and previous sexual function had been normal.
inent spine, ribs, and scapulae.
He had asthma. Medications included transder-
mal testosterone gel, gabapentin, morphine sul-
fate as needed for pain, and albuterol by inhala-
tion as needed for asthma. He had no allergies. tologist, the patient reported diffuse pain (espe-
He had stopped smoking and drinking 1 year cially in the feet), which he rated at 8 on a scale
earlier. He did not use illicit drugs, including of 1 to 10, with 10 indicating the most severe
anabolic steroids. He lived with his girlfriend and pain. On examination, the blood pressure was
was receiving disability payments because of his 103/55 mm Hg, the pulse 56 beats per minute,
illness; he owned rabbits. His father had type 2 the temperature 36.6C, and the weight 51.3 kg
diabetes mellitus, cirrhosis, and hepatitis C virus (BMI, 16.7). There was poor dentition, severe
infection; his mother had anemia; and his son diffuse muscle tenderness, edematous ankles,
and half-siblings were well. There was no family decreased strength (4 out of 5) in the ankles and
history of autoimmune disease. lower legs, nonblanching macular erythematous
On examination, the patient was cachectic rash on the thighs, and decreased sensation of
(Fig. 1), with bitemporal wasting. The abdomen light touch over the legs. Testing for antinuclear
was flat and nontender, with striae without pig- antibodies was positive at a 1:40 dilution, in a
mentation; the feet were slightly edematous, with speckled pattern; blood levels of C3, C4, vita-
a blanching erythematous macular rash on the min C, cryoglobulins, and immunoglobulins
dorsal surface. Proximal muscles were weak, with were normal, as were serum protein electropho-
severe wasting in the thighs. The pubic-hair dis- resis and urinalysis; and screening for other
tribution was classified as Tanner stage 5; phal- autoantibodies, antibodies to HIV, and urinary
lus length was 4 cm, and testicular volume was Bence Jones proteins was negative. The patient
15 ml (estimated) bilaterally. Urinalysis and blood declined admission for further evaluation.
levels of globulin, phosphorus, vitamin B12, thy- On follow-up 6 days later, the weight had
roxine, and leptin were normal; other test results decreased to 50.2 kg (BMI, 16.3); the patient
are shown in Table 1. was admitted to this hospital. Examination re-
Twelve days later, on evaluation by a rheuma- vealed painful pitting (1+) edema to the mid-

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 The n e w e ng l a n d j o u r na l
shins; tenderness of the Achilles tendons; xero-
sis of the legs with nearly platelike scaling,
blanchable eczematous erythema on the feet and
legs, sparse petechiae and reticulate violaceous
discoloration, vertical striae on the abdomen,
mild hyperkeratosis with fissuring of both soles,
and diminished hair growth on the lower legs.
Strength was diminished in the legs more than
in the arms; the proximal and distal muscles
were affected. Sensation and reflexes were nor-
mal. Blood levels of carcinoembryonic antigen
and tissue transglutaminase IgA antibodies
were normal, as were protein electrophoresis
and immunofixation; testing for cryoglobulins
and urine porphobilinogens was negative; addi-
tional test results are shown in Table 1. Patho-
logical examination of a skin-biopsy specimen
was thought to be consistent with morphea.
Neuromuscular electromyography revealed bi-
lateral peroneal mononeuropathies, a finding
consistent with a focal demyelinating process.
The patient was discharged on the second hos-
pital day. Additional testing was performed (Table
1). One month after discharge, examination of
biopsy specimens of the sural nerve and skele-
tal muscle revealed a mild demyelinating neu-
ropathy and myopathic and neurogenic changes
in the muscle.
Five days later, the patient felt weak while
showering; after lying down, he was unable to
arise. Emergency medical services personnel were
called. On examination, the capillary blood glu-
cose was reportedly 26 mg per deciliter; glucose
was administered intravenously, with a follow-
up level of 88 mg per deciliter. He was taken to
the other hospital. Respirations were normal. The
blood pressure was 108/80 mm Hg, the pulse 53
beats per minute, and the temperature 32.1C.
The weight was 40.8 kg (BMI, 13.3). He was alert
and cachectic, with a decubitus ulcer on the sa-
crum. An electrocardiogram revealed a sinus rate
of 43 beats per minute, with T-wave abnormali-
ties in the inferior and anterolateral leads. A chest
radiograph showed subcutaneous emphysema of
the visualized lower portion of the neck, soft-
tissue air deep to the right clavicle, and a small
amount of pneumomediastinum parallel to the
trachea. The activated partial-thromboplastin
time and the troponin I level were normal; other
test results are shown in Table 1. A warming
blanket was applied, and dexamethasone, vanco-
mycin, imipenem, warmed normal saline, glu-
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of m e dic i n e
cose, and narcotic analgesics were adminis-
tered. The temperature rose to 34.6C. He was
transferred to this hospital.
On arrival, the patient reported diffuse weak-
ness and persistent constipation, with no anorexia;
he was on a low-carbohydrate, 2000-kcal diet.
His girlfriend had noted jaundiced skin the day
before. Respirations were normal. The blood
pressure was 114/76 mm Hg, the pulse 42 beats
per minute, the temperature 34.6C, and the weight
42.9 kg (BMI, 14.0). He was cachectic and had a
depressed affect. The oral mucosa was dry. The
abdomen was scaphoid (i.e., it had a concave
anterior wall) and soft, with a palpable liver edge
3 cm below the costal margin; a lymph node was
palpated in the right inguinal region. The skin
was slightly jaundiced, with a bleeding laceration
on the head, a healed laceration on the arm,
petechiae and edema (1+) of the legs, and a stage
II sacral decubitus ulcer. The extremities were
cool to palpation. Levels of fibrinogen, calcium,
magnesium, lactic acid, ammonia, vitamin B12,
folate, thyrotropin, thyroxine, troponin T, ceru-
loplasmin, and alpha1-antitrypsin were normal;
other laboratory-test results are shown in Table 1.
An electrocardiogram showed sinus rhythm at
43 beats per minute and T-wave abnormalities in
the inferior and anterolateral leads. A barium-
swallow examination was normal. CT of the
chest revealed extensive pneumomediastinum
and associated subcutaneous emphysema. Lung
windows revealed bilateral patchy ground-glass
opacities, without air bronchograms, and dif-
fuse, bilateral bronchial-wall thickening, with a
thin-walled cyst or bulla in the right lower lobe.
Soft-tissue windows were notable for marked
cachexia and a loss of subcutaneous fat.
After review of the patients history, findings
on examination, and test results, a diagnosis
was made.
Differ en t i a l Di agnosis
Dr. Daniel P. Hunt: May we review the radiology
studies?
Dr. Alexander R. Guimaraes: Coronal and sagittal
reformatted images of the thorax from a con-
trast-enhanced CT examination of the chest at
the level of the carinal bifurcation show exten-
sive gas throughout the middle and posterior
mediastinum, dissecting into the fascial planes
of the neck (Fig. 2A and 2B). No evidence of
 case records of the massachusetts gener al hospital

A B

C D

Figure 2. Imaging Studies.

Coronal (Panel A) and sagittal (Panel B) reformatted CT images of the thorax, obtained in lung windows, show ex-
tensive pneumomediastinum (arrows) surrounding the esophagus and trachea and extending to the fascial planes
of the neck. Coronal (Panel C) and axial (Panel D) T2 -weighted half-Fourier single-shot turbo spinecho and forced
recovery images of the upper abdomen show abnormally low T2 -weighted signal in the liver and spleen (white ar-
rows), without a clinically significant loss of signal in the pancreas (black arrows).

pneumoperitoneum or pneumothorax is identi- and postinfectious causes, as well as hypereme-

fied. From the same CT examination, axial im-
ages at the level of the lung bases show a pneu-
matocele at the right lung base and patchy,
reticulonodular opacities at the left lung base, in
addition to the previously mentioned pneumo-
mediastinum. Differential considerations for pneu-
momediastinum include post-traumatic causes
sis (in patients with Boerhaaves syndrome).
Ultrasonography performed for the evalua-
tion of abdominal pain revealed a cystic mass
adjacent to the gallbladder, which was incom-
pletely characterized on this examination. As a
result, MRI was performed for further charac-
terization. Coronal and axial T2-weighted half-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Medical differential diagnosis

Table 2. Problem List.
Dr. Hunt: This young man has a progressive, se-
Profound weight loss vere, subacute illness affecting multiple systems.
Weakness of the extremities It is essential to construct a problem list (Table
Numbness and aching of the legs and abnormal biopsy specimens of the 2) of all the issues we need to address to arrive at
nerves and muscles a unifying diagnosis.
Decreased libido, loss of morning erections, and low levels of follicle-stimulat- I would like to approach the differential diag-
ing hormone, luteinizing hormone, and testosterone nosis for this patients underlying illness by us-
Pneumomediastinum ing two different constructs. Assuming that each
Hypotension on evaluation 6 wk before this admission approach yields a similar diagnosis, we will then
Hypothermia
return to the problem list and make sure that
the proposed diagnosis accounts for each prob-
Hypoglycemia
lem. It is critical that we maintain an open mind
Normocytic anemia about the diagnosis and not ignore or discard
Hypoalbuminemia inconsistencies that might point us in a different
Elevated liver-enzyme levels, with severe elevations at this admission direction.
Elevated lactate dehydrogenase level
Mildly elevated lipase and amylase levels Pneumomediastinum
It is highly unusual for air in the mediastinum to
Episode of submandibular abscess requiring drainage, before this admission
be incidentally detected in a young man during
Poor dentition
evaluation for weakness, myalgias, weight loss,
Constipation and loss of libido. This finding is inconsistent
Painful pitting edema of the lower extremities with simple, intended weight loss. There are well-
History of asthma described causes of pneumomediastinum, includ-
Skin findings, including xerosis, hyperkeratosis of soles, and a sacral ulcer ing exercise or retching1-6; however, spontaneous
Bradycardia
pneumomediastinum has been associated with
interstitial lung disease, asthma, bronchiolitis
Thrombocytopenia (late development)
obliterans, chronic obstructive pulmonary dis-
Elevated prothrombin time
ease, cystic lung lesions, or malignant condi-
Abnormal thyroid-function test results tions. This patient does not appear to have severe
Abnormal cortisol level symptomatic asthma or any of the other condi-
tions. There are multiple case reports of sponta-
neous pneumomediastinum occurring in associ-
Fourier single-shot turbo spinecho images (Fig. ation with anorexia nervosa.1,3,5,7-9 Does this
2C and 2D) show a T2-weighted, hyperintense patient have anorexia nervosa?
mass in the liver, adjacent to and inseparable
from the gallbladder. The mass shows mild het- Weight Loss
erogeneity on T2-weighted imaging, with no en- This patients illness extended over a period of at
hancement on T1-weighted axial images obtained least 13 months, and he reported that his weight
at the level of the mass after the administration fell by 33% during a period of 10 months. This is
of gadolinium. Differential considerations of this well outside normal weight change for a healthy
mass include a duplicated gallbladder, a complex adult.10,11 Perhaps it is a consequence of a rigor-
cyst, or possibly an old hematoma, all benign ous exercise program and moderate caloric re-
causes. Incidental note is also made of low sig- striction. However, weight loss continued at a
nal intensity in the liver and spleen in a pattern rapid pace even after the patient reported reduced
that is consistent with hemosiderosis and iron, exercise, and it was not recognized as an illness
or heavy metal, in the reticuloendothelial system. until it impaired his normal function. His physi-
The absence of low signal in the pancreas, con- cians were appropriately concerned about many
comitant with the low signal in the spleen, systemic or malignant illnesses. The patient was
makes this finding not compatible with primary described as being cachectic, but did he in fact
hemochromatosis. have symptoms of cachexia or, rather, of starva-

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 case records of the massachusetts gener al hospital
tion? Processes that lead to malnutrition may be
classified into one of three distinct syndromes:
starvation-related malnutrition (e.g., anorexia ner-
vosa), chronic diseaserelated malnutrition asso-
ciated with mild-to-moderate inflammation, and
acute disease or injuries with a marked inflam-
matory response.12
Cachexia versus Starvation
Cachexia is unintended weight loss due to under-
lying chronic illness and is typically associated
with an inflammatory state or a disorder of me-
tabolism. This patient does not have objective
evidence for either of these conditions. On at
least two occasions, the patients C-reactive pro-
tein level, a marker of inflammation, was nor-
mal. His insulin level was low on one measure-
ment, a feature consistent with starvation, not
cachexia. The overall description includes brady-
cardia, hypothermia, profound asthenia, marked-
ly reduced activity that resulted in a decubitus
ulcer, and hypoglycemia and is, simplistically
thinking, that of a body attempting to adapt in
the face of markedly restricted access to calories.
This is the picture of starvation, not cachexia.
This again puts anorexia nervosa at the top of
our diagnostic considerations. Now we need to
be sure that the list of problems (Table 2) is ex-
plained by this diagnosis.
The problem list
Peripheral neuropathy occurs in patients with
anorexia nervosa and may include isolated pero-
neal neuropathy.13 Reduced libido and loss of
morning erections are common in men with an-
orexia nervosa.14 Cardiovascular complications
associated with anorexia nervosa include brady-
cardia, hypotension, diminished cardiac output,
conduction delays, and ventricular arrhythmias.15
Hypothermia is well described in patients with
anorexia nervosa, and a temperature below
36.1C is an indication for hospitalization.16 Ane-
mia is common in anorexia nervosa, and it is
notable that about one third of patients have an
elevated ferritin level that improves with refeed-
ing.17 Mild thrombocytopenia occurs in 5 to 11%
of patients with anorexia nervosa.17 Dermato-
logic signs of anorexia nervosa include xerosis,
telogen effluvium, lanugo-like body hair, purpura,
acne, and carotenoderma.18 Oral manifestations
of eating disorders include mucosal atrophy, den-
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tal erosions, caries, gingivitis, periodontitis, sial-
adenosis, and necrotizing sialometaplasia.19 Endo-
crine abnormalities in anorexia nervosa include
hypogonadotropic hypogonadism, hypercorti-
solism, and transient depression of the hypotha-
lamicpituitarythyroid axis in nonthyroidal ill-
ness (formerly called euthyroid sick syndrome),
all of which are present in this patient.20
The final remaining problems on our list in-
clude abnormal liver-enzyme levels and elevated
levels of amylase and lipase. Among patients
with anorexia nervosa, there may be an inverse
relationship between BMI and the degree of eleva-
tion of aminotransferase levels. Several case se-
ries have described marked abnormalities in
liver- and pancreatic-enzyme levels in patients
with anorexia nervosa.21,22 Encouragingly, refeed-
ing in these case series resulted in prompt im-
provement.
In summary, I believe this young man has
anorexia nervosa. The condition is clearly ad-
vanced, and there is great urgency to begin re
feeding, with careful monitoring.
Psychiatric Differential Diagnosis
Dr. Anne E. Becker: I am aware of the diagnosis in
this case. This patients medically unexplained,
continued rapid weight loss after presentation
raised concern about an eating disorder. In par-
ticular, his self-reported dietary restriction in the
context of his extremely low weight suggested a
diagnosis of anorexia nervosa, although men do
not usually present with this disorder.23
Many of the patients physical findings on
presentation are consistent with severe nutritional
compromise associated with anorexia nervosa
but are diagnostically nonspecific. Although the
patient reported that he had no history of purg-
ing, the finding of dental caries in the context of
these other findings also raises clinical suspi-
cion for undisclosed chronic induced vomiting.
Pneumomediastinum associated with induced
vomiting in patients with anorexia nervosa has
been reported.24 This patients reportedly good
appetite was inconsistent with the anorexia of
major depression, and both major depressive
disorder and factitious disorder were ruled out
as the primary diagnosis.
Although a diagnosis of an eating disorder
was suspected, the intense fear of weight gain
that is the sine qua non of anorexia nervosa and
165
 The n e w e ng l a n d j o u r na l
is intrinsic to the core psychopathology of the
condition could not be established with cer-
tainty for this patient. He reported that he had
no history of an eating disorder, rationalized his
previous diet and exercise regimen as being mo-
tivated by a goal of a healthier lifestyle, re-
canted his initial report of calorie restriction
before this admission, and asserted his intention
to gain weight. He even articulated a weight goal
of 170 lb (77 kg), which at his height of 175 cm,
would have resulted in a BMI of 25.1, a value
slightly higher than the ideal range. He described
increasing his caloric intake before this admis-
sion and adjusting his exercise regimen in order
to regain weight. Taken together, his history ap-
peared inconsistent with that of a patient with
an intense fear of weight gain.
During the hospital course, however, several
behaviors were observed that contradicted and
undermined the patients stated desire to gain
weight. His nurse reported that he was eating
only 50% of his meals and that nutritional sup-
plements ordered for him were found, uncon-
sumed, in a drawer in his room. On one occa-
sion, vomitus was discovered in the patients
bathroom, although he denied emesis then and
a history of purging. He repeatedly requested to
be discharged, despite having been informed of
his serious risk of refeeding complications re-
quiring inpatient care. This patients poor coop-
eration and limited insight were consistent with
his lack of recognition of the serious medical con-
sequences of his extremely low weight, a mani-
festation of a body-image disturbance charac-
teristic of anorexia nervosa.
This patients clinical presentation met the
definition of eating disorder not otherwise speci-
fied (EDNOS), according to the criteria of the
Diagnostic and Statistical Manual of Mental Disorders,
fourth edition, text revision (DSM-IV-TR).25 EDNOS
is a heterogeneous residual category comprising,
among other presentations, subthreshold an-
orexia nervosa, and it is the most prevalent
clinical diagnosis made for an eating disorder.26
However, under proposed criteria for DSM-5, evi-
dence of this patients persistent behaviors that
interfere with weight gain would most likely
support a diagnosis of anorexia nervosa, even with-
out his acknowledgment of any concern about
weight.27
166 n engl j med 367;2 nejm.org july 12, 2012
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of m e dic i n e
DR . DA NIEL P. HUN T S DI AGNOSE S
Anorexia nervosa.
Severe malnutrition.
Acute liver dysfunction due to anorexia nervosa.
DR . A NNE E . BECK ERS DI AGNOSIS
Eating disorder not otherwise specified (EDNOS).
Pathol o gic a l Discussion
Dr. Joseph Misdraji: A liver-biopsy specimen shows
mildly increased lipofuscin pigment in hepato-
cytes (Fig. 3A). Prussian blue staining reveals an
increased deposition of iron in Kupffer cells and
periportal hepatocytes (Fig. 3B). Increased lipo-
fuscin has been reported in cases of anorexia
nervosa,22 but it is a common finding in liver bi-
opsies and offers little or no diagnostic informa-
tion. Increased deposition of iron has also been
reported in anorexia nervosa,22,28 although the
cause is uncertain. In other forms of starvation,
increased iron in the liver has been described,
presumably because protein deficiency leads to
decreased substrate for hemoglobin synthesis
and a reduced demand for iron in the body. Since
iron excretion is limited, the unused iron accu-
mulates in the liver.
Dr. Anat Stemmer-Rachamimov: Sections of the
peripheral-nerve (sural-nerve) biopsy specimen
show rare degenerating axons and regenerating
clusters, features consistent with active axonal
neuropathy (Fig. 3C). In addition, there are occa-
sional lipid-laden macrophages and thinly myelin-
ated large axons, features suggestive of a second-
ary ongoing demyelinating process. The histologic
changes in the peripheral nerve in cases of star-
vation or malnutrition are not specific; axonal,
demyelinating, and mixed neuropathies may oc-
cur, since deficiencies of multiple nutrients (min-
erals and vitamins) may be involved.29-32
Sections of the gastrocnemius-biopsy specimen
show marked variation in fiber size with many
scattered atrophic type II fibers. In addition,
NADH staining shows a targetoid pattern (cen-
tral clearing) that is consistent with neurogenic
changes. However, periodic acidSchiff staining
highlights the most striking finding marked
depletion of glycogen in all muscle fibers (Fig.
 case records of the massachusetts gener al hospital

A B

C D
*

Figure 3. Biopsy Specimens.

A liver-biopsy specimen (Panel A, hematoxylin and eosin) shows increased pigment in centrilobular hepatocytes,
a feature consistent with lipofuscin. In Panel B, Prussian blue staining shows mildly increased hemosiderin in some
hepatocytes (arrows) and in Kupffer cells (arrowheads). An Epon-embedded section from a peripheral-nervebiopsy
specimen (Panel C, toluidine blue) shows a degenerating axon (asterisk). Frozen sections of muscle-biopsy speci-
mens from the patient (Panel D, periodic acidSchiff) and from a control patient (inset) show marked depletion of
glycogen in all this patients muscle fibers. A skin-biopsy specimen (Panel E, hematoxylin and eosin) shows serous
atrophy of subcutaneous fat.

3D). This finding was confirmed on electron more pronounced when coupled with magne-
microscopical examination. Glycogen depletion sium deficiency. Atrophy of type II fibers may
can be seen after intense exercise and may be be seen in anorexia nervosa,33 and the neuro-

n engl j med 367;2 nejm.org july 12, 2012 167

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Copyright 2012 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

genic changes are consistent with the axonal
neuropathy.
Finally, the skin-biopsy specimen shows clini-
cally significant serous atrophy of the subcuta-
neous fat, with marked deposition of extracellular
mucopolysaccharides (Fig. 3E). These findings
are similar to the serous atrophy described in
the bone marrow in cases of starvation. In sum-
mary, examination of this patients skin, muscle,
and nerve shows changes that have been reported
in starvation. In addition, the muscle-biopsy
specimen shows the effects of intense exercise.
Taken together, these findings are consistent
with severe malnutrition and starvation.
discussion of M A NAGEMEN T
Dr. Becker: Acute management priorities in this
case of severe nutritional compromise are medi-
cal stabilization, treatment of associated compli-
cations, and nutritional rehabilitation, preferably
by oral refeeding in conjunction with behavioral
management.34 The last intervention requires
formulation and implementation of a dietary and
behavioral plan to meet energy requirements that
result in adequate and controlled weight gain
and to correct deficiencies in micronutrients.
Hospital-level care is required for medically safe
and effective nutritional rehabilitation, since the
refeeding syndrome, a potentially lethal compli- Eating disorder not otherwise specified (EDNOS).
cation of anorexia nervosa, can occur in the early
stages of refeeding.
Psychosocial intervention in the acute care
the full text of this article at NEJM.org.
setting should focus on supporting the immedi-
ate medical and nutritional goals, evaluating and the patient.
treating coexisting mental illness, and engaging
the patient in the transition to postdischarge
treatment for the eating disorder. Expectations
for his participation in weight regain should be
made clear to the patient. These expectations
would include adherence to a prescribed meal
plan, caloric supplements, and restrictions on
physical activity or unsupervised bathroom use.
This patient may have subverted therapeutic in-
terventions by discarding food and vomiting;
clinicians should maintain vigilance for surrep-
titious behaviors and be prepared to respond
therapeutically with psychosocial support and
appropriate behavioral interventions.34
Dr. Rosenberg: Dr. Contreras, would you tell us
how you treated this patient and how he is now?
Dr. Contreras: Once we started feeding him, the
levels of liver aminotransferases rapidly improved.
He remained in the hospital for 25 days and
insisted on being discharged. At the time of
discharge, his weight was 51 kg. He refused to
pursue additional inpatient psychiatric treatment
for his eating disorder. He was referred to out-
patient treatment with a multidisciplinary team
from the psychiatry and nutrition departments,
as well as his primary care physician.
fina l Di agnosis
Presented at the Medicine Case Conference.
Disclosure forms provided by the authors are available with
We thank Dr. John H. Stone for the clinical photographs of

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