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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 20-2008: A 57-Year-Old Woman

with Abdominal Pain and Weakness
after Gastric Bypass Surgery
Herbert L. Bonkovsky, M.D., Peter Siao, M.D., Zulmarie Roig, M.D.,
E. Tessa Hedley-Whyte, M.D., and Thomas J. Flotte, M.D.

Pr e sen tat ion of C a se

Dr. Allyson K. Bloom (Medicine): A 57-year-old woman was admitted to this hospital From the Departments of Medicine and
because of abdominal pain and weakness. One month earlier, a laparoscopic Roux-en-Y Molecular, Microbial, and Structural Bi-
ology, University of Connecticut Health
gastric bypass and cholecystectomy were performed for treatment of obesity and Center, Farmington; the Department of
gallstones. Pathological examination of a liver-biopsy specimen revealed nonalcoholic Medicine, Carolinas Medical Center,
fatty liver disease. The immediate postoperative course was uncomplicated, and she Charlotte, NC, and University of North
Carolina, Chapel Hill; and the Depart-
was discharged 2 days after surgery. At follow-up visits, she reported poor oral intake, ment of Biology, University of North
episodes of tachycardia (which had occurred intermittently in the past), intermittent Carolina, Charlotte (H.L.B.); and the De-
passage of watery stool and dark urine, and suprapubic and epigastric pain; on two partments of Neurology (P.S.), Radiology
(Z.R.), and Pathology (E.T.H-W., T.J.F.),
occasions, fluids were administered intravenously in the emergency department or Massachusetts General Hospital; and
clinic. Eighteen days before this admission, she returned to the emergency department the Departments of Neurology (P.S.), Ra-
with diffuse, crampy abdominal pain and was admitted to the surgical service. diology (Z.R.), and Pathology (E.T.H-W.,
T.J.F.), Harvard Medical School — both
The patient’s vital signs and the results of a physical examination were normal in Boston.
except for a pulse of 56 beats per minute. Electrocardiography showed sinus brady-
cardia, with a rate of 41 beats per minute. Computed tomographic (CT) scanning of N Engl J Med 2008;358:2813-25.
Copyright © 2008 Massachusetts Medical Society.
the abdomen showed two adrenal nodules: one, 3.2 cm in diameter, on the right
side, and the other, 1.7 cm in diameter, on the left. Neither nodule could be further
characterized. There was no evidence of bowel obstruction or intra-abdominal fluid
collection. Intravenous fluids, acetaminophen, tramadol, and gabapentin were given,
and the pain diminished. She was discharged on the 4th hospital day.
Eight days before this admission, abdominal pain recurred. The patient was re-
admitted to the surgical service. A specimen of urine grew Klebsiella pneumoniae. Labo-
ratory test results are shown in Table 1. Levofloxacin and phenazopyridine were
administered. After one dose, a tonic–clonic seizure occurred. Treatment with phe-
nytoin was begun. CT scanning of the brain showed areas of decreased attenuation
in the occipital, posterior temporal, and parietal lobes. Magnetic resonance imaging
(MRI) of the brain showed bilateral cortical and subcortical areas of hyperintensity
in the occipital, posterior temporal, and parietal lobes on T2-weighted images. These
areas were also hyperintense on diffusion-weighted images, with elevated diffusion
on apparent diffusion-coefficient maps, suggesting posterior reversible encephalopa-
thy. Changes related to a seizure or encephalitis could not be ruled out. Treatment

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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

Table 1. Laboratory Test Results.*

Reference 18 Days 10 Days 8 Days 2 Days 10th

Range, before before before before On Hospital
Variable Adults† Admission Admission Admission Admission Admission Day
Serum
Glucose (mg/dl) 70–110 124 125 129 174 191 161
Sodium (mmol/liter) 135–145 137 137 134 129 120 133
Potassium (mmol/liter) 3.4–4.8 4.1 4.3 5.4 (hemo- 4.0 4.4 3.4
lyzed sample)
Chloride (mmol/liter) 100–108 98 95 95 90 84 97
Carbon dioxide (mmol/liter) 23.0–31.9 26.0 27.0 25.2 26.4 27.6 26.9
Magnesium (mmol/liter) 0.7–1.0 0.8
Aspartate aminotransferase (U/liter) 9–32 27 43 53 83
Alanine aminotransferase (U/liter) 7–30 25 35 47 59
Urine
Color Yellow Yellow Yellow Amber Brown
Appearance Clear Clear Cloudy Clear Turbid
pH 5.0–9.0 5.5 6.5 6.5 5.0 6.5
Specific gravity 1.001– 1.009 1.006 1.017 1.030 1.020
1.035
Screening dipstick
Glucose Negative Negative Negative Negative Negative 1+
Bilirubin Negative 2+ 1+ 3+ Negative
Ketones Negative 2+ 2+ 3+ 1+ 1+
Blood Negative Negative 1+ Trace Negative Trace-
lysed
Albumin Negative Negative Negative Negative 1+ 2+
Urobilinogen Negative Trace Trace Trace 2+
Nitrite Negative Negative Positive Negative Positive Positive
White cells Negative 1+ 3+ 2+ 1+ 3+
Sediment
Bacteria None Few Many Few Few Moderate
Bladder cells None Few
Granular casts (no./low-power field) None 3–5
Hyaline casts (no./low-power field) 0–5 0–5 0–2 0–2 None 3–5
Red cells (no./high-power field) 0–2 0–2 0–2 0–2 None 3–5
Squamous cells (no./high-power field) None Few Few Few Moderate Negative
White cells (no./high-power field) 0–2 5–10 20–50 >100 3–5 0–2
Uric acid crystals None Many
Sodium (mmol/liter) 146
Osmolality (mOsm/kg) 543
Creatinine (mg/dl) 0.6–1.5 0.41

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for magnesium to milliequivalents per li-
ter, multiply by 2.0. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
† Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at the
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.

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 case records of the massachuset ts gener al hospital
with trimethoprim–sulfamethoxazole was begun.
Electroencephalographic findings were normal.
CT scanning of the abdomen after the adminis-
tration of oral and intravenous contrast material
showed no new abnormalities. Phenytoin was dis-
continued, and the patient was discharged home
on the 6th hospital day. Three days later, she re-
turned to the emergency department because of
persistent lower abdominal and pelvic pain and red
urine. She was readmitted to the surgical service.
The patient reported that for the previous 2 days
she had had poor appetite, lightheadedness, gen-
eralized weakness, nausea, cold sweats, mild con-
stipation, and red-tinged urine that was at times
“raspberry” in color. She did not have dysuria,
headache, localized weakness, or double vision.
She had a history of obesity since childhood, with
a body-mass index (the weight in kilograms di-
vided by the square of the height in meters) of 45
before bariatric surgery. She had diabetes melli-
tus, which was controlled by diet; intermittent
tachycardia; hypertension; hyperlipidemia; gas-
troesophageal reflux disease; anxiety; dermatogra-
phism with pruritus; facial hyperpigmentation
after sun exposure; and facial hirsutism. A total
abdominal hysterectomy and oophorectomy had
been performed because of leiomyomas and dys-
functional uterine bleeding. Preoperative stress
testing had revealed an ejection fraction of 72%
with normal perfusion and was nondiagnostic
for ischemia because of failure to reach 85% of
maximum heart rate. Medications included eso­
mep­razole, tramadol, lisinopril, nadolol, and tri­
meth­o­prim–sulfamethoxazole. The patient was
divorced, lived with one of her daughters, worked
in an office, and was of Italian ancestry. She had
stopped smoking 20 years earlier and did not drink
alcohol or use illicit drugs. There was a family
history of coronary artery disease, cerebrovascu-
lar disease, diabetes mellitus, and cholelithiasis.
On examination, the patient appeared to be
comfortable. Her height was 157.5 cm, weight
110 kg (body-mass index, 44), blood pressure
193/103 mm Hg, pulse 72 beats per minute, and
temperature 35.8°C. Respirations were 18 breaths
per minute, and the oxygen saturation was 98%
while she breathed ambient air. There was hyper-
pigmentation of the face and palmar creases. The
abdomen was obese, without striae. Motor strength
in the arms and legs was 4+ out of 5, with nor-
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mal reflexes. The remainder of the examination
was normal.
A culture of the urine grew enterococcus spe-
cies. A complete blood count and serum levels of
glucose, calcium, phosphorus, magnesium, total
protein, albumin, globulin, bilirubin, creatine ki-
nase, creatine kinase MB, troponin T, alkaline
phosphatase, amylase, and lipase were normal.
The fasting level of plasma cortisol was 37.1 μg per
deciliter (1023.6 nmol per liter) (reference range,
5 to 25 μg per deciliter [138.0–689.8 nmol per li-
ter]), the 24-hour urinary free cortisol level 456 μg
(reference range, 20 to 70), and the plasma epi-
nephrine level 122 pg per milliliter (665.9 pmol
per liter) (normal value, ≤110 pg per milliliter
[≤600.4 pmol per liter]). Other tests of adrenal
function, including corticotropin-releasing hor-
mone and cosyntropin stimulation testing, were
normal. Results of other laboratory tests are
shown in Table 1. CT scanning of the abdomen
showed no evidence of bowel obstruction, fluid
collection, or renal calculi; the adrenal lesions were
unchanged. Oxycodone and acetaminophen were
given orally, and normal saline and vancomycin
were administered intravenously. Oral intake of
water was restricted, and sodium chloride tablets
and hypertonic saline were administered.
On the 2nd hospital day, weakness, numbness,
and tingling developed in the patient’s legs; she
fell while walking and had an episode of confu-
sion and urinary incontinence. On the 3rd day, for
further evaluation of the adrenal glands, CT scan-
ning of the abdomen was performed after the
oral and intravenous administration of contrast
material. Two small nodules were seen in the left
adrenal gland and a single nodule was seen in the
right adrenal gland, all probably representing ad-
renal adenomas. During the next 3 days, the pa-
tient became unable to stand or sit independently,
became incontinent of stool, and reported numb-
ness and tingling over the lower half of her body;
she was transferred to the medical service on the
5th day. A peripherally inserted central catheter
was placed.
On examination by a neurologist on the 6th
day, the cranial nerves were normal; motor strength
was 4+ out of 5 in the arms, with rapid fatigue,
and 4 out of 5 in the legs. Deep-tendon reflexes
were absent in both legs. Sensation was normal
with respect to temperature, vibration, propriocep-
www.nejm.org june 26, 2008 2815
 The n e w e ng l a n d j o u r na l
tion, and light touch, but sensation to pinprick
was decreased in the trunk and pelvic girdle. MRI
of the spine showed multiple disk extrusions from
T5–T6 to T7–T8, with narrowing of the left neu-
ral foramen at T5–T6 and slight indentation of the
ventral cord at T6–T8 and T7–T8, without com-
pression. There was mild volume loss and hyper-
intensity in the cord at T7–T8 on T2-weighted im-
ages, findings that were suggestive of chronic
myelomalacia.
A lumbar puncture on the 7th day showed a
glucose level of 98 mg per deciliter (5.4 mmol per
liter) (reference range, 50 to 75 mg per deciliter
[2.8 to 4.2 mmol per liter]) and a protein level of
40 mg per deciliter (reference range, 5 to 55), with
1 white cell per high-power field; no cells or or-
ganisms were seen on Gram’s staining. Electro-
myography and nerve-conduction studies showed
changes suggestive of an acute generalized, pre-
dominantly motor neuropathy. The patient was
transferred to the neurology service.
On the 8th day, strength was 1 to 3 out of 5
in the upper portion of the arms, 0 to 4 out of 5
in the fingers, 0 out of 5 in the upper legs, and
2 out of 5 in the lower legs. Levels of folate and
vitamin B12 were normal. A 5-day course of im-
mune globulin was begun intravenously. MRI of
the brain disclosed no abnormalities of the pitu-
itary and showed resolution of the abnormalities
noted on the previous examination. The patient
had difficulty breathing, and the respiratory rate
increased; the trachea was intubated electively, and
mechanical ventilation was begun. She was trans-
ferred to the neurologic intensive care unit. Treat-
ment with metyrapone was begun.
During the next 4 weeks, fevers, urinary tract
infections, line infections, and ventilator-associ-
ated pneumonia developed, all of which were
treated with antibiotics. Dexamethasone was add-
ed on the 14th day. Tracheostomy and gastrosto-
my were performed. Repeated lumbar puncture
showed a glucose level of 117 mg per deciliter
(6.5 mmol per liter) and a protein level of 53 mg
per deciliter; neither varicella–zoster virus nor
Epstein–Barr virus was detected by polymerase-
chain-reaction assay. Tests for Lyme disease and
heterophile antibodies and cytomegalovirus anti-
gen were negative; a test for IgG antibodies
against cytomegalovirus was positive. Tests for
autoantibodies and paraneoplastic antibodies were
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of m e dic i n e
negative. The urinary cadmium level was 6.0 μg
per liter (reference range, 0 to 5.0); screening for
other heavy metals was negative.
Another electromyographic study performed on
the 11th day disclosed worsening sensorimotor
polyneuropathy, with no definite evidence of a
primary demyelinating polyneuropathy; on the
32nd day, the ulnar and tibial motor responses
were no longer recordable, and needle electromyo-
graphic examination showed fibrillation potentials
with no voluntary motor-unit potentials, findings
that were consistent with severe sensorimotor neu-
ropathy. A specimen from a sural-nerve biopsy
showed severe axonal neuropathy; a specimen
from a gastrocnemius-muscle biopsy showed mild
neurogenic changes.
Hypotension developed, which responded to
phenylephrine and stress doses of corticosteroids.
Episodes of bradycardia and asystole occurred,
which responded to atropine; electrocardiography
and measurements of cardiac biomarkers showed
no evidence of ischemia. Transcutaneous pacing
and treatment with theophylline were begun.
A diagnostic test result was reported.
Differ en t i a l Di agnosis
Dr. Herbert L. Bonkovsky: May we review the imag-
ing studies?
Dr. Zulmarie Roig: CT of the head obtained 8 days
before admission reveals areas of decreased atten-
uation in the occipital lobes (Fig. 1A). MRI of the
brain obtained on the same day shows multiple
regions of signal hyperintensity in the cortex and
subcortical white matter of the posterior temporal,
occipital, and parietal lobes on T2-weighted images
(Fig. 1B), with corresponding hyperintensity on
diffusion-weighted images (Fig. 1C) and elevated
water diffusion on apparent diffusion coefficient
maps. The distribution and radiographic charac-
teristics of these findings are suggestive of pos-
terior reversible encephalopathy. CT of the abdo-
men that was obtained for further evaluation of
bilateral adrenal lesions shows characteristics that
are consistent with the presence of adenomas.
Dr. Bonkovsky: Approximately 1 month after gas-
tric bypass surgery, this woman had recurrent
lower abdominal and pelvic pain and red urine,
followed by generalized weakness, which pro-
gressed to flaccid quadriparesis. She also had hy-
www.nejm.org june 26, 2008
 case records of the massachuset ts gener al hospital

A B C

Figure 1. MRI Images of the Brain.

An MRI scan of the brain was obtained without contrast material. An axial fluid-attenuated inversion recovery image
(Panel A) shows hyperintense lesions within the occipital cortex and subcortical white matter (arrow). On a diffu-
sion-weighted image (Panel B), there AUTHOR Bonkovsky
ICMis corresponding RETAKE
hyperintensity (arrow); 1st
likewise, a region with elevated water
diffusion (arrow) is hyperintense onREG F FIGURE
a map of apparent1a-cdiffusion coefficient (Panel 2nd
C). These changes are consistent
CASE 3rd
with posterior reversible encephalopathy, TITLE
but the differential diagnosis includes
Revisedchanges that can be seen after a
EMail 4-C
Lineto movement
seizure, as well as other causes. Blurring of the images is due by the patient.
Enon ARTIST: mst SIZE
H/T H/T
FILL Combo 33p9
AUTHOR, PLEASE NOTE:
been redrawnRapidly Progressive Weakness
pertension, a low serum sodiumFigure level,hasand epi-checkand
Please
type has
carefully.
been reset.

sodes of bradycardia and asystole. Neurologic disease with severe sensorimotor dys-
JOB: 35826 function ISSUE:of the legs, confusion and delirium, and
6-26-08
Abdominal Pain urinary and fecal incontinence came to dominate
The differential diagnosis of diffuse, colicky ab- the clinical picture in this case. Weakness of re-
dominal pain after bariatric surgery includes com- spiratory muscles required intubation, followed by
plications of the surgery (Table 2). In this case, tracheostomy and gastrostomy. Imaging studies
appropriate studies, including abdominal imaging showed abnormalities of intervertebral disks, but
studies and laboratory tests, ruled out many of nothing that could explain this patient’s weakness.
these possibilities. More detailed neurologic evaluations included elec-
tromyographic and nerve-conduction studies. May
Red Urine we review these studies?
The most common cause of red urine is hematu- Dr. Peter Siao: The electromyogram of the left
ria. This patient had positive urine cultures, mak- arm and leg on the 7th hospital day showed that
ing hematuria associated with cystitis a likely the amplitude of the median-nerve motor response
cause; she also had suprapubic pain, which may was mildly reduced and the distal latency was pro-
occur with cystitis. However, she did not have dys- longed. The F responses of the left median and
uria. Other causes of red urine include other sourc- peroneal nerves were absent, and the latencies of
es of heme, especially myoglobin. Reddish pig- the F responses of the ulnar and tibial nerves were
ments can enter the urine from ingested drugs or mildly prolonged. The median-nerve sensory po-
foods. The patient had taken phenazopyridine for tential was small. Radial and ulnar sensory poten-
a urinary tract infection, but this drug results in tials were normal. Needle electromyographic ex-
an orange rather than a red color. The most com- amination showed no fibrillation potentials. The
mon cause of red urine due to food intake is beets, motor-unit action potentials appeared to be nor-
but we can assume that this was not the cause. mal, but a neurogenic recruitment pattern was
Porphyrins may cause a pink or red urine, and the noted. These findings are consistent with an acute,
presence of red urine without dysuria, accompa- predominantly motor polyneuropathy.
nied by abdominal and pelvic pain, raises the sus- Four days later, the median and peroneal mo-
picion of porphyria in this case. tor responses could no longer be recorded. The

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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

graphic examination showed no fibrillation poten-

Table 2. Differential Diagnosis of Abdominal Pain
after Gastric Bypass Surgery for Morbid Obesity tials, but motor-unit action potentials could no
with Cholecystectomy. longer be recruited. Three weeks later, the ulnar
and tibial motor responses were absent, and needle
Complications of surgery
electromyographic examination showed fibrilla-
Anastomotic leak — gut or biliary tion potentials with no recruitable motor-unit ac-
Intraabdominal infection tion potentials in the muscles of the arm and leg.
Severe electrolyte derangements These results favor a primarily axonal polyneu-
Small-bowel obstruction ropathy; however, because motor nerves may be
Postoperative pancreatitis
inexcitable in primary demyelinating neuropathy,
that diagnosis cannot be ruled out entirely.
Ligation of or damage to common hepatic or com-
mon bile duct, hepatic artery, or portal vein Dr. Bonkovsky: The differential diagnosis of rap-
Infections outside the abdomen
idly progressive weakness is broad (Table 3). The
most common cause is the Guillain–Barré syn-
Adverse effect of drugs or complementary or alternative
medications drome. The presence of seizures and sensory
changes makes myasthenia gravis unlikely, and
Other causes of abdominal pain
the history and laboratory studies rule out most
Acute porphyria
of the other possible causes. Those caring for the
Arsenic or lead poisoning patient administered immune globulin intrave-
Ischemic or thrombotic disease of the gut nously, which, with plasmapheresis and plasma
exchange, is the current treatment of choice for
the Guillain–Barré syndrome. However, her neu-
Table 3. Differential Diagnosis of Rapidly Progressive rologic status did not improve. The combination
Weakness. of abdominal pain, red urine, and progressive mo-
Myelopathy tor weakness, associated with severe axonal neu-
Myasthenia gravis ropathy, are all consistent with a diagnosis of an
Guillain–Barré syndrome
acute porphyria.
Vasculitic polyneuropathy
Other Features of This Case
Neoplastic polyradiculoneuropathy (Eaton–Lambert On admission, the serum sodium level was 120
syndrome)
mmol per liter at a time when the urinary sodium
Acute porphyria
level was 146 mmol per liter and urinary osmolal-
Toxic polyneuropathy (poisoning) ity was 543 mOsm per kilogram. These results sug-
Arsenic gest the presence of the syndrome of inappropri-
Lead ate antidiuretic hormone excretion (SIADH), as do
Shellfish the facts that restriction of free water and supple-
Thallium
mental sodium led to gradual improvement in the
serum sodium concentration. Abdominal imaging
Acute polyneuropathy related to gastric bypass surgery
studies indicated the presence of adrenal adeno-
Hypokalemia
mas; an extensive evaluation for endocrinologic
Hypomagnesemia disorders was performed, and the only notable
Hypophosphatemia finding was increased catecholamine levels, as one
might see in a systemic stress response. SIADH can
be seen in acute porphyria and thus supports this
amplitude of the ulnar motor response dropped diagnosis.
from 11,400 to 1000 μV (see Fig. 1 in the Supple- This patient had a history of intermittent tachy-
mentary Appendix, available with the full text of cardia, and during the course of this illness, she
this article at www.nejm.org). The amplitude of had episodes of both bradycardia and asystole. In
the tibial motor response dropped from 6600 to addition, her blood pressure was elevated on ad-
1500 μV. The ulnar and tibial F responses were mission, despite the use of two antihypertensive
absent. The previously normal sensory potentials agents. Tachycardia, bradycardia, and asystole may
became unrecordable. The needle electromyo- occur in association with attacks of acute por-

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 case records of the massachuset ts gener al hospital

phyria, and systolic arterial hypertension is also
characteristic.
Features consistent with reversible posterior
leukoencephalopathy were seen on an MRI scan
of the brain that was obtained on the second ad-
mission. Although these findings are not specific
and could have been due to the recent seizure,
such findings may be seen in acute porphyria
attacks.
than the upper abdomen. Both hereditary cop-
roporphyria and variegate porphyria may pre­
sent with either neurovisceral features such as
abdominal pain or with cutaneous features (a var-
iegated presentation). Lead poisoning and heredi-
tary tyrosinemia type 1, both of which are char-
acterized by inhibition of ALA dehydratase with
overproduction of ALA, may have similar presen-
tations.

Acute Porphyria Causes of Attacks of Acute Porphyria

I believe that this patient had an acute porphyria, What caused this patient’s acute porphyric attack?
which was first manifested clinically after gastric A number of factors precipitate or exacerbate at-
bypass surgery. tacks, including starvation, poor intake of carbo-
hydrates and energy, drugs, alcohol, smoking, in-
Diagnosis of Porphyria fections, and other forms of stress. Although the
The possibility of acute porphyria should be con- pathogenesis is not completely understood, it ap-
sidered in patients with recurrent, severe abdom- pears likely that many aspects of such an attack
inal pain when clinical evaluation has not revealed are due to adverse effects of excess ALA, which is
a cause. Features that should raise the level of sus- structurally similar to γ-aminobutyric acid, the ma-
picion include dark or reddish urine, systemic ar- jor inhibitory neurotransmitter of the vertebrate
terial hypertension, tachycardia, and constipation. central nervous system; ALA has partial agonist
Unfortunately, all of these findings occur in other, and stronger antagonist effects on γ-aminobutyric
more common conditions, and the diagnosis of acid receptors. Porphobilinogen and its products
porphyria is therefore easily overlooked. The di- seem less likely culprits, in part because patients
agnostic study of choice is the measurement of with ALA dehydratase–deficiency porphyria, lead
5-aminolevulinic acid (ALA) and porphobilinogen poisoning, and hereditary tyrosinemia type 1, in
in urine or serum. A rapid, qualitative test for por- whom ALA but not porphobilinogen is overpro-
phobilinogen in urine (the Hoesch or Watson– duced, may have acute porphyric attacks.1 Heme
Schwartz test) is available in some laboratories. deficiency in nerves, muscles, or both2 seems less
An early diagnosis of an acute porphyria is more likely, since orthotropic liver transplantation, which
important than deciding which of the four types corrects the hepatic overproduction of ALA but not
the patient has, since the immediate management neuromuscular heme deficiency, led to the resolu-
is the same regardless of the type. tion of porphyric symptoms3 in a patient with acute
intermittent porphyria.
Classification of Porphyrias This patient’s acute attack was probably pre-
What type of porphyria does this patient have? cipitated by the negative energy balance that is the
The porphyrias are due to deficiencies in activity goal of bariatric surgery,4 leading to up-regulation
of one or more of the enzymes required for nor- of hepatic ALA synthase 1, as a result of the loss
mal heme synthesis (Fig. 2). Most types of porphyr- of carbohydrate repression of this rate-control-
ia are inherited, although the most common type, ling enzyme for heme synthesis in the liver (Fig.
porphyria cutanea tarda, is usually an acquired dis- 2).5-8 I am aware of two other cases in which acute
order associated with liver disease and iron over- porphyria became manifest after bariatric surgery.
load. The porphyrias are categorized according to Acute attacks can also be triggered by drugs and
either the main source of overproduction of por- chemicals, leading to uncontrolled up-regulation
phyrins and porphyrin precursors (the bone mar- of ALA synthase 1.9 Unfortunately, this patient’s
row or the liver) or according to the clinical pre- disease may have been exacerbated by drugs ad-
sentation (cutaneous or neurovisceral) (Table 4). ministered for management of her symptoms,
Patients with any of the four types of acute por- including tramadol, trimethoprim–sulfamethox-
phyria may present with neurovisceral features in azole, and phenytoin.2,10,11 Sulfonamides, barbitu-
the same way as the patient in this case, with rates, and hydantoins are among the most danger-
colicky abdominal pain, more often in the lower ous drugs for patients with acute porphyria.9,11,12

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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

Figure 2. The Pathway of Hepatic Heme Synthesis and Its Regulation by Heme, Showing the Eight Enzymes and Porphyrias
Associated with Deficiencies.
The first and rate-controlling step is the condensation of glycine and succinyl–coenzyme A (CoA) to form 5-aminolevulinic acid (ALA).
This step is catalyzed by the enzyme ALA synthase-1, which is encoded by a nuclear gene. The messenger RNA (mRNA) of this gene
forms pre–ALA synthase-1 on the rough endoplasmic reticulum. C O LA OR leader
FIGU sequence
RE is cleaved as this protein is processed and taken up
by mitochondria. The ALA formed is transported into the cytoplasm, where the second enzyme, ALA dehydratase (also known as por-
Draft 4 06/05/08
phobilinogen synthase), condenses two molecules of ALA to form the monopyrrole porphobilinogen. The third enzyme, porphobilino-
Author Flotte
gen deaminase (also known as hydroxymethylbilane synthase), forms a linear tetrapyrrole, hydroxymethylbilane, which is normally rapid-
Fig # 2
ly converted, mainly to the cyclic intermediate uroporphyrinogen
Title III, by the enzyme uroporphyrinogen III synthase (also known as
uroporphyrinogen cosynthase). When uroporphyrinogen ME III synthase is deficient, as in congenital erythropoietic porphyria (Guenther’s
disease), hydroxymethylbilane rapidly undergoes nonenzymatic
DE ring closure to form uroporphyrinogen I. The enzyme uroporphyrinogen
decarboxylase carries out the stepwise decarboxylation
Artist of uroporphyrinogen
SBL I or III to form intermediates with 7-, 6-, 5-, and 4-carboxyl
groups. Coproporphyrinogen is the common name for the 4-carboxyl–containing
AUTHOR PLEASE NOTE: intermediate. Coproporphyrinogen III is transported
Figure has been redrawn and type has been reset
back into mitochondria, where the enzyme coproporphyrinogen III check
Please oxidase
carefully carries out the stepwise oxidative decarboxylation of two of
the remaining propionate beta side chains, at positions 2 and 4 (on rings A and B, respectively), to vinyl groups, forming protoporphy-
Issue date
rinogen IX. Next, the enzyme protoporphyrinogen oxidase carries out the oxidation of protoporphyrinogen IX to form protoporphyrin IX,
after which the enzyme ferrochelatase (also called heme synthase) inserts ferrous iron into the protoporphyrin IX macrocycle to form
the end product heme. Heme regulates the overall flux through the pathway by down-regulating levels of ALA synthase-1, which is
achieved by decreasing the stability of the ALA synthase-1 mRNA and inhibiting the uptake of the enzyme into mitochondria. Heme may
also decrease transcription of the ALA synthase-1 gene, although this suggestion is still controversial.

Female sex hormones, particularly progesterone, Management of Attacks of Acute Porphyria

are porphyrogenic; thus, the acute porphyrias are
more often clinically manifested in women than
in men, and it is rare for symptoms to develop
before puberty. However, this woman had under-
gone oophorectomy in the past.
How can this patient be treated? The treatment
of choice for acute porphyria is the intravenous
administration of heme.13-15 The heme is taken up
by hepatocytes, replenishes the regulatory heme
pool, and down-regulates ALA synthase 1. Heme

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 case records of the massachuset ts gener al hospital

Table 4. Classification of the Porphyrias.*

Type of Porphyria According to
Clinical Presentation
Cutaneous
Congenital erythropoietic
porphyria
Hepatoerythropoietic por-
phyria
Porphyria cutanea tarda
Erythropoietic protoporphyria
Neurovisceral (acute attacks)
ALA dehydratase–deficiency
porphyria
Acute intermittent porphyria
Hereditary coproporphyria†
Variegate porphyria†
Intermediates Chiefly
Enzyme Deficiency
Uroporphyrinogen-III synthase Uroporphyrin I
Uroporphyrinogen decarbox­
ylase
Uroporphyrinogen decarbox­
ylase
ALA dehydratase
Porphobilinogen deaminase
Coproporphyrinogen oxidase
Protoporphyrinogen oxidase
Major Source of
Overproduction
Overexcreted of Heme Precursors Comments
Bone marrow Onset in infancy, variable
severity
Liver Onset in infancy, usually
very severe
Uroporphyrin III, he- Liver Onset in adulthood,
patocarboxylpor- about 25% of cases
phyrin are hereditary
Protoporphyrin Bone marrow Onset in infancy
ALA, coproporphyrin Liver Onset in childhood, very
severe
ALA, porphobilinogen, Liver Onset in adulthood, es-
coproporphyrin pecially in women
ALA, porphobilinogen, Liver Onset in adulthood, es-
coproporphyrin pecially in women;
usually less severe
than acute intermit-
tent porphyria
ALA, porphobilinogen, Liver Onset in adulthood, es-
coproporphyrin, hard- pecially in women;
eroporphyrin, pro- usually less severe
toporphyrin than acute intermit-
tent porphyria

* ALA denotes 5-aminolevulinic acid.

† This type of porphyria may also have cutaneous features.

repletion may also improve 5-hydroxytryptophan
and serotonin metabolism, which has been sug-
gested to play a role in central nervous system
disease.16 If given early, heme can prevent irre-
versible axonal death.17 Cessation or avoidance of
porphyrogenic drugs, treatment of infections with
safe drugs, and maintenance of adequate carbo-
hydrate and energy intake are essential. This pa-
tient is likely to have slow and less-than-complete
recovery. Reversing the gastric bypass would prob-
ably not affect her neurologic status, but it could
decrease the risk of further attacks.
Biopsy specimens of the sural nerve and gas-
trocnemius muscle showed findings consistent
with but not diagnostic of the changes seen in
porphyria. I suspect that the diagnostic test result
was the report of urinary or serum levels of ALA
or porphobilinogen, requested earlier in this pa-
tient’s hospitalization.
Dr. Nancy Lee Harris (Pathology): Dr. Buonanno,
would you describe the thinking at the time of
the diagnostic testing?
Dr. Ferdinando S. Buonanno (Neurology): This
patient’s early symptoms of pelvic pain and red
urine appeared to her caregivers to be explained
by the presence of urinary tract infection. When
I saw her, I considered the diagnosis of an acute
porphyria; however, the primary clinical diagno-
sis of the neurology team was the Guillain–Barré
syndrome, and she was treated for that, while the
results of other tests, including those for porphy-
rins, were awaited.
Dr. Harris: Could we have the medical students’
diagnosis?
A Medical Student: On the basis of the presenta-
tion with abdominal pain, red urine, hypertension,
seizure, hyponatremia, and progressive axonal
polyneuropathy, our leading diagnosis was acute
porphyria, particularly acute intermittent porphyr-
ia. We also considered hereditary coproporphyria

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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

and variegate porphyria. Our differential diagno-

A sis included polyarteritis nodosa, amyloidosis, and
sarcoidosis.

Cl inic a l Di agnosis

Guillain–Barré syndrome.

Dr . Her ber t L . Bonkovsk y ’s

Di agnosis

Acute porphyria (acute intermittent porphyria, he-

reditary coproporphyria, or variegate porphyria).
B
Pathol o gic a l Dis cus sion

Dr. E. Tessa Hedley-Whyte: Light-microscopical ex-

amination of the sural-nerve biopsy specimen re-
vealed extensive axonal degeneration with numer-
ous myelin ovoids (Fig. 3A). The teased nerve-fiber
preparations revealed classic wallerian degenera-
tion (Fig. 3B). The ultrastructural preparation con-
firmed the presence of axonal degeneration, with
preservation of the basal lamina of the Schwann
C cell, which is characteristic of axonal degeneration
(Fig. 3C). No evidence of a demyelinating disorder
was detected. The findings are those of acute axo-
nal degeneration, but they do not reveal the cause.
Acute axonal degeneration is the characteristic
finding in porphyric neuropathy,18 but the mech-
anism remains unknown.19,20 Although porphyric
neuropathy is primarily a motor neuropathy, the
sural nerve, which is primarily a sensory nerve, is
also affected. In contrast to most axonal neuropa-
thies, porphyric neuropathy is often associated
with more proximal, rather than distal, limb in-
volvement as was true for this woman’s legs but
not for her arms.
Dr. Harris: Dr. Bloom, will you tell us about the
diagnostic test result?
Figure 3. Sural-Nerve–Biopsy Specimen. Dr. Bloom: Serum and 24-hour urinary speci-
Gomori’s trichrome staining (Panel A) shows a marked mens were sent to another laboratory for analysis
loss of myelin, with numerous myelin ovoids (purple), of porphyrin levels (Table 5). After these results
ICM AUTHOR Bonkovsky RETAKE 1st
indicative of wallerian degeneration. A teased-fiber prep-
REG F FIGURE 3a-c 2nd were received, additional tests were obtained in an
aration (Panel B), in which the specimen from the sural- 3rd attempt to classify the porphyria.
CASE TITLE
nerve biopsy is fixed in osmium tetroxide and then
Revised
EMail
teased into single myelinated axons, 4-C
Line shows multiple
Dr. Bonkovsky: The classification of porphyrias
Enon SIZE my-
elinFILL
ARTIST: mst
ovoids and varying stages H/T H/T
of disintegrating myelin
16p6
requires integration of clinical and laboratory fea-
Combo
(black) along the length of several fibers. A 400-Å-thick tures, especially urinary and fecal levels and pat-
AUTHOR, PLEASE NOTE:
section of the
Figure hasspecimen, fixed
been redrawn andintype
glutaraldehyde
has been reset.and os- terns of ALA, porphobilinogen, and porphyrins,
mium tetroxide and stained
Please with
check lead citrate (Panel C),
carefully. and levels of activities of ALA dehydratase and
shows a degenerating myelinated axon and Schwann
cell JOB:
still surrounded
35826 by a basal lamina, indicating
ISSUE: 6-26-08 axonal
porphobilinogen deaminase in erythrocytes. The
degeneration rather than demyelination. results in this patient are consistent with acute
intermittent porphyria, with normal activity of

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 case records of the massachuset ts gener al hospital

Table 5. Results of Porphyrin and Porphyrin-Precursor Studies.

Analyte Reference Range* Result

Blood
Total porphyrin (μg/dl) <1.1 39.6
Uroporphyrin (μg/dl) <1.1 9.7
Heptacarboxylporphyrin (μg/dl) <1.1 6.3
Hexacarboxylporphyrin (μg/dl) <1.1 6.9
Pentacarboxylporphyrin (μg/dl) <1.1 13.7
Coproporphyrin (μg/dl) <1.1 2.1
Protoporphyrin (μg/dl) <1.1 1.0
Uroporphyrinogen synthase (nmol/sec/liter) >6.9 13.1
Aminolevulinic acid dehydratase (nmol/sec/liter) >3.9 6.0
Urine†
Total volume (ml/24 hr) 975
Porphobilinogen (mg/24 hr) 0–2.7 29.9
Total porphyrin (μg/24 hr) 12–190 10,900
Uroporphyrin (μg/24 hr) 3.3–29.5 3,950
Heptacarboxylporphyrin (μg/24 hr) 0–6.8 2,150
Hexacarboxylporphyrin (μg/24 hr) <1.0 78.8
Pentacarboxylporphyrin (μg/24 hr) 0–4.7 1,510
Coproporphyrin (μg/24 hr) 0–155 3,210
ALA (mg/gram of creatinine) ≤3.6 38.5
Total porphyrins (μg/gram of creatinine) 31.0–139.0 15,000
Heptaporphyrin (μg/gram of creatinine) ≤4.6 2,560
Hexaporphyrin (μg/gram of creatinine) Not detected 36.0
Pentaporphyrin (μg/gram of creatinine) ≤1.7 690
Coproporphyrin (μg/gram of creatinine) 23.0–130.0 2,250
Stool
Uroporphyrin (μg/24 hr) <80 Not detected
Heptacarboxylporphyrin (μg/24 hr) <20 Not detected
Coproporphyrin (μg/24 hr) <640 498
Protoporphyrin (μg/24 hr) <1830 1,328

* Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at the Massachusetts General Hospital are for adults who are not pregnant and do not have medical con-
ditions that could affect the results. They may therefore not be appropriate for all patients. ALA denotes 5-aminolevulin-
ic acid.
† Two types of urine samples were collected: 24-hour samples and random samples (which are expressed per gram of
creatinine).

erythrocyte porphobilinogen deaminase; this oc-
curs in 5 to 10% of patients with this disease, who
have a mutation in the second exon of the porpho-
bilinogen deaminase (PBGD) gene, which is not
expressed in erythrocytes.21 Unfortunately, in this
country, unlike in many European countries,
there are no federally funded reference laborato-
ries that perform DNA-based studies to deter-
mine the genetic bases for the porphyrias.
Dr. Harris: After the diagnosis was made, he-
matin infusions were immediately begun, with
gradual improvement in the patient’s neurologic
status. She regained consciousness and respiratory
function, and the trachea was extubated. Three

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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

were treated with hematin infusions. One year

A after discharge, weekly hematin infusions were
begun. Thirteen months after discharge, bullous
skin lesions developed on her hands and feet. Dr.
Gonzalez, would you describe the findings?
Dr. Ernesto Gonzalez (Dermatology): This patient
had blisters on sun-exposed areas of the body,
primarily on the dorsal aspect of the hands, which
is typical of porphyria (Fig. 4A). She also had in-
creased pigmentation of the face and other areas
exposed to sunlight. The porphyrias that produce
skin lesions include porphyria cutanea tarda and,
B
less frequently, variegate porphyria and copropor-
phyria; acute intermittent porphyria does not have
skin manifestations. I performed biopsies of sev-
eral lesions.
Dr. Thomas J. Flotte: The skin biopsies showed
thickening of the walls of blood vessels (Fig. 4B)
with deposition of type 4 collagen and immuno-
globulins. The pathological changes associated
with porphyrias include thickening of the blood-
vessel walls and, if a blister is biopsied, subepider-
mal bullae, with retention of dermal papillae (Fig.
4C). The findings in this patient are consistent
C with porphyria.22-24 We were unable to identify the
type of porphyria.
Dr. Bonkovsky: The presence of skin lesions sug-
gests that this patient has hereditary copropor-
phyria or variegate porphyria. However, iron over-
load from the hematin infusions could result in
secondary porphyria cutanea tarda in a patient
with acute intermittent porphyria.
Dr. Harris: It has been approximately 2 1/2 years
since the bariatric surgery was performed. The
patient has lost 45 kg in weight. She lives with her
daughter, uses a motorized wheelchair, requires
Figure 4. Cutaneous Manifestations of Porphyria. in-home assistance, and has not returned to work.
There is hyperpigmentation of the skin on the hand She can raise her arms and legs and use her hands
(Panel A), with denuded areas reflecting ruptured blis- with a brace to eat and perform other tasks. Sen-
ICM AUTHOR Bonkovsky RETAKE 1st
ters. The skin-biopsy specimen shows thickening of
REG F FIGURE
blood-vessel 4a-c
walls (highlighted
2nd
by staining with period-
sation in her hands is normal, but she has de-
3rd
CASE TITLE
ic acid–Schiff), which is characteristic of porphyria
Revised
creased sensation in her feet. She believes she is
EMail
(Panel B). A stain for type IV Line
collagen4-C(inset) shows a
SIZE
continuing to have improvement with physical
Enon
thickenedARTIST: mst
basement-membrane H/T zone H/Taround16p6
blood therapy. Recent genetic testing in the Porphyria
FILL Combo
vessels. A specimen from a biopsy of a blister in anoth- DNA Testing Laboratory of Dr. Robert J. Desnick,
AUTHOR, PLEASE NOTE:
er patient with porphyria (Panel C, hematoxylin and
Figure has been redrawn and type has been reset.
eosin) shows a subepidermal bulla with little inflam-
Department of Genetics and Genomic Sciences,
Please check carefully.
mation and retention of the architecture of the dermal Mount Sinai School of Medicine, New York, dis-
papillae,
JOB: a35826
phenomenon known asISSUE: festooning.
6-26-08 closed normal genes for the enzymes responsible
for all acute porphyrias except for that of varie-
gate porphyria; the gene for protoporphyrinogen
months after admission, she was transferred to a oxidase was found to have a splice site mutation,
rehabilitation facility. During the next 6 months, IVS11+G→C, which is consistent with a diagnosis
she was readmitted to this hospital several times of variegate porphyria. Analysis of the uroporphy-
for pneumonia and flares of porphyria, which rinogen decarboxylase gene showed no mutations,

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 case records of the massachuset ts gener al hospital

a finding that rules out hereditary but not acquired
porphyria cutanea tarda.
The contrast between the difficulty that this
patient’s caregivers had in making the diagnosis
and the ease with which the discussant (invited
because of his expertise in porphyrias) and the
medical students made it, when the entire course
was laid out for them, illustrates the challenge of
pulling important details out of a large amount
of information, when viewed from the ground in
real time. The patient and her caregivers believed
that it was important to report her case, so that
others could learn from this experience.
A nat omic a l Di agnosis
Acute porphyria (variegate porphyria).
Dr. Bonkovsky reports receiving consulting fees from Boeh-
ringer Ingelheim, Novartis, and Ovation; lecture fees from Ova-
tion; and grant support from Novartis. No other potential con-
flict of interest relevant to this article was reported.

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Copyright © 2008 Massachusetts Medical Society.

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