Presentation of Case

Dr. Yin Ge (Medicine): A 69-year-old man with a history of diabetes mellitus, heart disease,
peripheral vascular disease, and renal transplantation was admitted to this hospital because of
increasing weakness, malaise, anorexia, diffuse pain, and a history of falling.
Twenty months before this admission, renal transplantation was performed because of renal
failure caused by diabetic and hypertensive nephrosclerosis; a myocardial infarction occurred
intraoperatively. Immunosuppression was begun with the administration of antithymocyte
globulin, tacrolimus, mycophenolate mofetil, and prednisone. The next month, coronary-artery
bypass grafting of three vessels was performed for unstable angina. During the next 18 months,
the patient was admitted to this hospital multiple times for recurrent sternal osteomyelitis;
cultures were positive for methicillin-sensitive Staphylococcus aureus, Candida tropicalis, and 3
months before admission, coagulase-negative staphylococcus. Treatment included antimicrobial
agents, surgical dbridement, and chest-wall reconstruction. Thirteen months before this
admission, testing of the blood for BK virus nucleic acids was positive. Two months later,
worsening renal failure and congestive heart failure occurred. Pathological examination of a
biopsy specimen of the allograft kidney showed glomerulitis, with mononuclear cells, scattered
neutrophils, and swollen endothelial cells; there were also dilated peritubular capillaries
containing mononuclear cells, plasma cells, and occasional neutrophils. Immunofluorescence
microscopy revealed widespread, intense staining of the peritubular capillaries for C4d; the
results were thought to represent acute cellular and humoral rejection. Plasmapheresis was
performed, and methylprednisolone, immune globulin, and rituximab were administered.
Five months before admission, increasing fatigue, anorexia, and failure to thrive developed. The
patient had recurrent fevers and chills and felt cold, all in association with sternal and central-
catheter infections. During this time, he saw numerous physicians, including generalists and
specialists; however, his condition continued to deteriorate. The results of testing 8 weeks before
admission are shown in Table 1Table 1 Laboratory Data.. Increasing fatigue and diffuse
weakness that was worse in the legs developed 6.5 weeks before admission. The patient tripped,
hit his head, and lacerated his parietal scalp on the right side; the results of computed
tomography (CT) of the head, performed at another hospital, were reportedly normal. During the
remaining weeks before this admission, chronic pain and anorexia worsened, associated with
weight loss of 9.1 kg. The patient reported pain in the lower abdomen, constipation, nausea with
recurrent retching, and decreased urination, and he required increasing narcotic analgesia. One
week before admission, he had difficulty arising from bed and fell several times. Four days
before admission, he saw his primary care physician for pain, weakness, and anorexia. The blood
pressure was 112/70 mm Hg and the pulse 70 beats per minute. The physician prescribed
megestrol acetate for anorexia. According to the patient's wife, he had had constipation, a
depressed mood, and hair loss for the past several months. The day before this presentation, his
wife noted slurred speech and increasing somnolence.
Diabetes mellitus had been diagnosed 16 years earlier. The patient also had hypertension,
hypercholesterolemia, hyperkalemia, peripheral vascular disease (for which angioplasty of the
left superficial femoral artery and bilateral stent placements in the common iliac arteries had
been performed), and prostatic hypertrophy. Medications on admission included tacrolimus (0.5
mg daily), mycophenolate mofetil (250 mg twice daily), prednisone (5 mg daily), fluconazole,
simvastatin, amlodipine, carvedilol, isosorbide mononitrate, acetylsalicylic acid, acetaminophen,
furosemide, fentanyl patch, tamsulosin hydrochloride, omeprazole, insulin, fludrocortisone
(prescribed 9 months earlier for hyperkalemia), megestrol acetate, polyethylene glycol, zinc
sulfate, sodium bicarbonate, ferrous sulfate, narcotic analgesia, trimethoprimsulfamethoxazole,
stool softeners, and fluticasone by inhalation. He lived with his wife and was retired. He drank
alcohol in moderation until this recent illness and had stopped smoking 7 years earlier; he had
not used illicit drugs. His mother had had diabetes mellitus and died at 81 years of age of throat
cancer; his father died at 80 years of age of prostate cancer.
On examination, the patient was somnolent but arousable. The blood pressure was 93/45 mm Hg,
the pulse 43 beats per minute and regular, the temperature 36.0C, the respiratory rate 16 breaths
per minute, and the oxygen saturation 99% while the patient was breathing ambient air. Trace
erythema over the inferior sternal incision and a healing laceration over the right parietal scalp
were noted. There were minimal crackles in the lung fields and diffuse muscle wasting; the
remainder of the examination was normal, although the neurologic examination was limited
owing to the patient's decreased ability to concentrate.
The platelet count and the activated partial-thromboplastin time were normal, as were blood
levels of calcium, total and direct bilirubin, aspartate and alanine aminotransferase, amylase,
lipase, and lactic acid. The tacrolimus level was 7.0 ng per milliliter; other test results are shown
in Table 1. Urinalysis revealed a pH of 5.0 and a specific gravity greater than 1.030; the results
were otherwise normal. An electrocardiogram showed sinus rhythm at a rate of 44 beats per
minute (decreased from 64 beats per minute 5 weeks earlier), with a PR interval of 200 msec, a
QRS complex of 88 msec, and QT and QTc intervals of 517 and 442 msec, respectively; new
nonspecific T-wave abnormalities appeared in leads V
1
, V
2
, and V
3
as compared with 5 weeks
earlier. A chest radiograph showed mild interstitial pulmonary edema, with surgical clips in the
mediastinum and a tortuous aorta with atherosclerotic calcification. CT of the head without the
administration of contrast material revealed periventricular and subcortical microangiopathic
changes and atherosclerosis in the carotid siphons, with no evidence of intracranial hemorrhage,
mass lesion, or territorial infarct. Ultrasonography of the transplanted kidney revealed resistive
indexes of the arcuate arteries throughout the kidney of 0.84 to 1.00 (normal range, 0.6 to 0.7),
which were increased as compared with a study from 5 months previously, which showed
indexes of 0.74 to 0.83; these findings suggested the possibility of transplant rejection.
Within 80 minutes after arrival, the patient's blood pressure decreased to 83/35 mm Hg and the
pulse to 40 beats per minute. Normal saline (4 liters intravenously within the first 6 hours),
vancomycin, cefepime, fluconazole, and methylprednisolone were administered. Hypotension
and bradycardia persisted. Calcium gluconate, atropine, dopamine (followed by norepinephrine),
vasopressin, glucagon, and ondansetron were added. Screening of the blood for toxins revealed
the presence of dextromethorphan, methylprednisolone, and amlodipine. The patient was
admitted to the coronary intensive care unit (ICU). Ciprofloxacin, metronidazole, sodium
bicarbonate, calcium gluconate, insulin, and glucose were administered intravenously. Anuria
occurred, despite bumetanide challenge, and continuous venovenous hemofiltration was begun.
Transthoracic echocardiography revealed a left ventricular ejection fraction of 64% and an
estimated right ventricular systolic pressure of 68 mm Hg, which were unchanged from a
previous study. Regional wall-motion abnormalities seen on the previous study were improved.
Cultures of the blood and urine were obtained.
Diagnostic tests were performed.
Differential Diagnosis
Dr. Jeffrey L. Greenwald: May we see the imaging studies?
Dr. Shaunagh McDermott: The chest radiograph obtained on admission shows perihilar fullness
and loss of definition of the pulmonary vasculature, features consistent with mild interstitial
pulmonary edema (Figure 1Figure 1 Chest Imaging.). The CT scan of the brain
without the administration of contrast material shows periventricular and subcortical white-
matter hypodensities, most likely representing chronic microangiopathic changes. There is also
mild prominence of the ventricles and sulci, a feature consistent with diffuse parenchymal
volume loss (Figure 2Figure 2 CT of the Brain.).
Ultrasonography of the transplanted kidney on admission shows resistive indexes of the arcuate
arteries of 0.84 to 1.00, as compared with 0.74 to 0.83 on ultrasonography performed 5 months
earlier (Figure 3A and 3BFigure 3 Renal Ultrasonography.). This increase in the
resistive index is worrisome with regard to transplant rejection.
Dr. Greenwald: This case is particularly challenging, since our patient presented with a several-
month course of the following largely nonspecific problems: weakness, fatigue, weight loss,
depressed mood, and malaise. According to the Institute of Medicine, our patient had the
geriatric clinical syndrome of failure to thrive, which is defined as weight loss, decreased
appetite and poor nutrition, and inactivity, often accompanied by dehydration, depressive
symptoms, impaired immune function, and low cholesterol. Occurring in both acute and chronic
forms, failure to thrive leads to impaired functional status, morbidity from infection, pressure
sores, and, ultimately, increased mortality.1 This syndrome is challenging to address, since it
often has multiple contributing causes, including clinical, psychosocial, and environmental
elements. Identifying potential causes requires bearing in mind that the principle of Occam's
razor may not apply. That is, multiple underlying contributing factors may coexist.
We are given several clues that I will use to help focus my differential diagnoses. The patient
was immunosuppressed, was taking 22 medications, and had a history of vascular disease,
diabetes, and recent hair loss. He had hypotension and bradycardia on presentation, and the
infusion of isotonic fluids, at least in the initial course, did not lead to hemodynamic
stabilization. He had hypercapnia and anemia characterized by notable variations in red-cell size,
shape, and staining. Finally, his echocardiogram showed pulmonary hypertension and a left
ventricular ejection fraction that were unchanged from earlier studies; however, the patient's
current study was performed while he was receiving pressor medications.
These factors all help to shape the differential diagnoses I will consider. These include
conditions related to four major domains medication effects, infections, malignant conditions,
and endocrinopathies.
Effects of Medication
This patient was prescribed numerous medications, including tacrolimus, mycophenolate mofetil,
and prednisone. The side effects of tacrolimus include abdominal pain, anorexia, alopecia, and
bradycardia. However, the patient's tacrolimus level was in the appropriate therapeutic range,
given the time since transplantation; in this range, these side effects are uncommon. Similarly,
the side effects of mycophenolate mofetil could explain the patient's myalgias, abdominal pain,
bradycardia, and weakness. However, the prescribed dose of mycophenolate mofetil in cases of
renal transplantation is typically lower than the dose in cases of transplantation of other solid
organs; therefore, side effects are less common. Certainly, the multiplicity of the patient's other
medications, such as the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (i.e., the
statin), the beta-blocker, the calcium-channel blocker, the diuretic, and the venodilators, could
also have contributed to the overall complex of symptoms. Given this patient's older age, the
question of symptomatic polypharmacy is one that we may not be able to rule out fully.2
Infections
Immunosuppression-associated infections and other infections must be considered, including
disseminated tuberculosis, EpsteinBarr virus, cytomegalovirus (CMV), and cryptococcal
meningitis. These infections can be manifested subacutely, can have protean manifestations, and
can be easily overlooked. In addition, given that this patient had BK virus, a testament to the
depth of his immunosuppression, we must consider other infectious causes. JC virus infection,
for example, is more common in patients who have received transplants and who are taking
mycophenolate mofetil; it can be manifested subacutely by slurred speech and weakness. This
condition is relatively rare in patients who have undergone renal transplantation and typically is
manifested by seizures, ataxia, visual disturbances, cranial-nerve abnormalities, or hemiparesis.3
Many of this patient's presenting symptoms could be explained by several of these infections, but
the infections do not clearly account for the bradycardia and hypotension, unless superimposed
sepsis developed at the time of presentation.
Malignant Conditions
Both immunosuppression-related cancers and other cancers common to a 69-year-old male
former smoker must be considered. Immunosuppressive medications increase the risk of cancers
such that approximately one in five renal- or liver-transplant recipients will have a cancer
detected within the first decade after transplantation.4 Skin cancer is the most common post-
transplantation cancer, but post-transplantation lymphoproliferative disorder (PTLD) occurs in
approximately 1% of recipients of solid-organ transplants5 and has a higher incidence among
those who received antithymocyte globulin and tacrolimus. This diagnosis must remain on our
list.
This patient's largely nonspecific presentation could also be explained in part by advanced
cancers, such as cancers of the lung, colon, or pancreas. We are given no information about
whether the patient had ever had a screening colonoscopy. The chest radiograph makes advanced
lung cancer unlikely. None of these cancers explain the hair loss, bradycardia, hypotension, or
lack of response to the administration of crystalloid fluids.
Endocrinopathies
Two endocrinopathies, adrenal insufficiency and hypothyroidism, warrant consideration.
Together, they may explain a large proportion of this patient's presentation. Adrenal
insufficiency in this patient would most likely be drug-induced (from long-term use of
glucocorticoids) or caused by an autoimmune disorder (Addison's disease). Infection with CMV
could also cause adrenal insufficiency.6 The current prednisone dose, 5 mg daily, is nearly
physiologic but may impair the ability of the adrenal glands to increase glucocorticoid
production in response to stress.7 Indeed, with the chronic sternal wound and bloodstream
infections that the patient has had for many months, it is curious that he had not shown signs of
hypoadrenalism previously. Or perhaps he had. Relative adrenal insufficiency caused by the
chronic stress of these infections may explain his weight loss, anorexia, nausea, and lack of
energy. However, if long-standing, clinically significant adrenal insufficiency had been present,
we might have expected the pigmentary changes that are often seen in the hands and other skin
folds in relation to coexpression of melanocyte-stimulating hormone and corticotropin secreted
from the pituitary gland. I believe this condition was present but was not the dominant cause of
his illness. Although glucocorticoid-replacement therapy was administered on presentation, it
could take hours to take effect, which could explain his initial lack of response to fluid
resuscitation.
Hypothyroidism might explain the patient's presentation and course better than all the other
diagnoses considered. Ironically, hypothyroidism is not related to the patient's status as a
transplant recipient, perhaps making the condition more difficult for focused clinicians to
identify. Hypothyroidism may develop during progression to end-stage renal disease, which is
thought to be caused by metabolic derangements associated with progressive uremia.8 Given the
poor functioning of the patient's graft before admission, perhaps hypothyroidism induced by end-
stage renal failure was a contributing factor. However, autoimmune hypothyroidism
(Hashimoto's disease) remains the most likely diagnosis and explains the patient's weakness
(although the typical elevations in the creatine kinase level that one would expect in cases of
hypothyroid myopathy are not seen in this patient because of his cachectic state),9 depressive
symptoms, generalized nonspecific pains, constipation, bradycardia, and hair loss. In fact,
thyroid hormone deficiency may prolong the effect of any existing adrenal glucocorticoid
hormones, potentially forestalling the manifestations of adrenal insufficiency.
Hypothyroidism, to some degree, would also help to explain the pulmonary hypertension,
cardiac dysfunction, hypercapnia, and anemia in this patient. The continually high pulmonary-
artery pressures are most likely related to ischemic heart disease in the patient. Hypothyroidism
is a recognized cause of pulmonary hypertension, but the mechanism is not well elucidated.
Indeed, treatment of hypothyroidism can lead to reductions in pulmonary pressures. 10 Similarly,
hypothyroidism may impair cardiac contractility, which improves with replacement therapy.
Like cardiac and other muscles, respiratory muscles are affected by hypothyroidism, potentially
explaining the hypercapnia.
Patients with hypothyroidism commonly have anemia, which is associated with lower metabolic
activity and leads to lower oxygen extraction by tissues and, therefore, less secretion of
erythropoietin. Although anemia is classically normocytic, it can be microcytic (caused in part
by a high frequency of concurrent iron deficiency due to malabsorption or blood loss) or
macrocytic (due to associated lipid abnormalities leading to incorporation of excess lipids in the
red-cell membrane or to the increased risk of concurrent pernicious anemia).6,7
I believe this patient's presentation with a failure to thrive was due to severe hypothyroidism with
relative, if not absolute, adrenal insufficiency.
Dr. Jeffrey L. Greenwald's Diagnosis
Severe hypothyroidism and relative adrenal insufficiency.
Clinical Impression
Dr. Eric S. Rosenberg (Pathology): Dr. Ge, what was your clinical impression when you saw this
patient?
Dr. Ge: This patient presented with profound shock, complicated by renal failure and electrolyte
abnormalities. Highest on our differential diagnosis list was distributive shock due to sepsis,
especially given his history of repeated infections and profound immunosuppression.
Cardiogenic causes of shock also were high on our list. The patient had a history of coronary
artery disease and had an elevated troponin level on presentation. Hypotension and bradycardia
can sometimes be seen in patients with an inferior myocardial infarction. In this patient with
nonspecific electrocardiographic changes, a bedside transthoracic echocardiogram revealed
grossly normal left and right ventricular function, making myocardial ischemia less likely.
Another cardiogenic possibility was adverse effects of medication, since profound hypotension
and bradycardia can occur with overdoses of beta-blockers and calcium-channel blockers, both
of which were on his home medication list. However, he did not have a response to the glucagon
therapy that was initiated in the emergency department earlier in the day.
The patient had been receiving long-term prednisone and fludrocortisone. Because he had acute
decompensation and chronic failure to thrive, the possibility of adrenal insufficiency was raised
and he was given an empirical stress dose of hydrocortisone. However, the profound bradycardia
was odd and had no readily identifiable cause. Since the patient also had anorexia and subacute
mental changes, another endocrinopathy severe hypothyroidism was raised as a possibility.
Pathological Discussion
Dr. Anand S. Dighe: The level of thyrotropin, measured on admission, was highly elevated at
132 U per milliliter (reference range, 0.4 to 5.0). Results of thyroid hormone tests showed a
profoundly low level of total thyroxine (T
4
) at 1.2 g per deciliter (15.4 nmol per liter; reference
range, 4.5 to 10.9 g per deciliter [57.9 to 140.3 nmol per liter]) and a low level of total
triiodothyronine (T
3
) at 26 ng per deciliter (0.40 nmol per liter; reference range, 60 to 181 ng per
deciliter [0.9 to 2.8 nmol per liter]). These values were consistent with primary hypothyroidism.
The patient was assessed for autoimmune thyroid disease by measurement of autoantibodies
directed against thyroid peroxidase. Antithyroid peroxidase antibodies were not detected. In
addition to the negative testing for antithyroid peroxidase antibodies, the patient did not have a
history of radiation exposure or neck surgery and was not taking medications implicated as a
cause of hypothyroidism. Thus, the cause of the patient's primary hypothyroidism is unclear.
In the afternoon on the day of admission to this hospital, the cortisol level was low, at 3.7 g per
deciliter (102.1 nmol per liter; reference range at noon to 8 p.m., 5 to 15 g per deciliter [138.0
to 413.8 nmol per liter]). Given the patient's critical status when the blood sample was drawn,
this level of cortisol could be interpreted as inappropriately low. However, afternoon cortisol
testing is of limited value in the diagnosis of adrenal insufficiency. Furthermore, the specimen
was obtained after the administration of methylprednisolone, which suppresses the secretion of
endogenous cortisol. Therefore, the low cortisol level, although suggestive of adrenal
insufficiency, is not diagnostic. Support for the diagnosis of adrenal insufficiency would be
present if a cortisol level obtained in the early morning had been low.
Follow-up
Dr. Ge: After we made the diagnosis of profound hypothyroidism, the patient was started on
intravenous levothyroxine. He was subsequently weaned off vasopressors on hospital day 3.
Continuous venovenous hemofiltration, which had been started for severe acidosis and
electrolyte imbalance, was discontinued on hospital day 4. After the administration of
levothyroxine was begun, intermittent fevers started to develop, which probably had been
masked by the hypothyroidism. On hospital day 5, because of the recurrent fevers, the patient
underwent CT of the chest; the scan showed bilateral ground-glass opacities, most markedly in
the left upper lobe. Sputum cultures eventually grew stenotrophomonas, pseudomonas, and
methicillin-resistant Staphylococcus aureus. He was given an extended course of vancomycin,
cefepime, trimethoprimsulfamethoxazole, and voriconazole.
On hospital day 8, the patient was transferred from the ICU to a general medicine ward.
Intermittent mucous plugging of the airways developed, and the patient returned to the ICU,
where he remained for hospital days 17 through 21; he was then transferred back to the ward. His
mental status slowly worsened during the next 10 days, in association with ongoing infections.
The medical team had a discussion with the family, and since the patient was declining from
both a physical and mental standpoint, the decision was made to transition his care to comfort
measures only. He died on hospital day 31.
A Physician: Would severe hypothyroidism alone explain the hypotension?
Dr. Lloyd Axelrod (Endocrinology): Not usually. In fact, in the typical ambulatory patient with
hypothyroidism, you would expect some hypertension, predominantly diastolic hypertension. In
myxedema coma, hypotension may occur. However, in general, you would not want to attribute
hypotension to hypothyroidism.
Dr. Greenwald: I'm going to stick to my guns and bet that there probably was some adrenal
insufficiency that could explain part of this.
A Physician: Is it possible that the patient had hypothyroidism at the time of his transplantation
and that that could have contributed to his perioperative event?
Dr. Greenwald: We know that patients who undergo major surgery while in a significantly
hypothyroid or hyperthyroid state have an increased risk of perioperative complications and
death. I think it is a bit of a stretch in this case, but it certainly is possible.
Anatomical Diagnosis
Severe primary hypothyroidism.



Terjemahan
Presentasi Kasus

Dr Yin Ge (Kedokteran): Seorang pria 69 tahun dengan riwayat diabetes mellitus, penyakit jantung,
penyakit pembuluh darah perifer, dan transplantasi ginjal dirawat di rumah sakit ini karena kelemahan
meningkat, malaise, anoreksia, nyeri menyebar, dan sejarah jatuh.

Dua puluh bulan sebelum masuk ini, transplantasi ginjal dilakukan karena gagal ginjal yang disebabkan
oleh diabetes dan hipertensi nephrosclerosis, infark miokard terjadi intraoperatively. Imunosupresi
dimulai dengan pemberian globulin antithymocyte, tacrolimus, mycophenolate mofetil, dan prednison.
Bulan berikutnya, koroner-bypass arteri grafting dari tiga kapal dilakukan untuk angina tidak stabil.
Selama 18 bulan ke depan, pasien dirawat di rumah sakit ini beberapa kali untuk osteomyelitis sternal
berulang, kultur positif untuk methicillin-sensitive Staphylococcus aureus, Candida tropicalis, dan 3
bulan sebelum masuk, staphylococcus koagulase-negatif. Pengobatan termasuk agen antimikroba,
debridement, dan dada-dinding rekonstruksi. Tiga belas bulan sebelum masuk ini, pengujian darah
untuk asam nukleat virus BK adalah positif. Dua bulan kemudian, memburuknya gagal ginjal dan gagal
jantung kongestif terjadi. Pemeriksaan patologis dari spesimen biopsi dari ginjal allograft menunjukkan
glomerulitis, dengan sel mononuklear, neutrofil tersebar, dan sel endotel bengkak, ada juga melebar
peritubular kapiler yang mengandung sel-sel mononuklear, sel plasma, dan neutrofil sesekali. Mikroskop
immunofluorescence mengungkapkan luas, pewarnaan kuat dari kapiler peritubular untuk C4D, hasilnya
dianggap mewakili penolakan seluler dan humoral akut. Plasmapheresis dilakukan, dan
metilprednisolon, immune globulin, dan rituximab diberikan.

Lima bulan sebelum masuk, kelelahan meningkat, anoreksia, dan gagal tumbuh berkembang. Pasien
memiliki demam berulang dan menggigil dan merasa dingin, semua dalam hubungan dengan infeksi
sternal dan pusat-kateter. Selama waktu ini, ia melihat dokter banyak, termasuk generalis dan spesialis,
namun kondisinya terus memburuk. Hasil pengujian 8 minggu sebelum masuk ditunjukkan pada Tabel
Data 1Laboratory 1Table .. Meningkatkan kelelahan dan kelemahan difus yang buruk di kaki maju 6,5
minggu sebelum masuk. Pasien tersandung, memukul kepalanya, dan terkoyak kulit kepala parietal nya
di sisi kanan, hasil computed tomography (CT) dari kepala, dilakukan di rumah sakit lain, dilaporkan
normal. Selama minggu-minggu yang tersisa sebelum masuk ini, nyeri kronis dan anoreksia memburuk,
terkait dengan penurunan berat badan dari 9,1 kg. Pasien melaporkan nyeri di perut bagian bawah,
sembelit, mual muntah dengan berulang, dan kencing berkurang, dan dia diperlukan analgesia narkotika
meningkat. Satu minggu sebelum masuk, ia mengalami kesulitan yang timbul dari tempat tidur dan jatuh
beberapa kali. Empat hari sebelum masuk, ia melihat dokter perawatan utamanya untuk nyeri,
kelemahan, dan anoreksia. Tekanan darah adalah Hg 112/70 mm dan denyut nadi 70 denyut per menit.
Dokter diresepkan asetat megestrol untuk anoreksia. Menurut istri pasien, ia memiliki sembelit, suasana
hati depresi, dan rambut rontok selama beberapa bulan terakhir. Sehari sebelum presentasi ini, istrinya
mencatat bicara cadel dan mengantuk meningkat.

Diabetes mellitus telah didiagnosa 16 tahun sebelumnya. Pasien juga mengalami hipertensi,
hiperkolesterolemia, hiperkalemia, penyakit pembuluh darah perifer (yang angioplasti dari arteri
femoralis kiri dangkal dan penempatan stent bilateral dalam arteri iliaka umum telah dilakukan), dan
hipertrofi prostat. Obat tentang penerimaan termasuk tacrolimus (0,5 mg per hari), mycophenolate
mofetil (250 mg dua kali sehari), prednison (5 mg sehari), flukonazol, simvastatin, amlodipine, carvedilol,
mononitrate mononitrate, asam asetilsalisilat, asetaminofen, furosemid, fentanil patch, tamsulosin
hidroklorida , omeprazole, insulin, fludrocortisone (diresepkan 9 bulan sebelumnya untuk hiperkalemia),
asetat megestrol, glikol polietilen, seng sulfat, natrium bikarbonat, sulfat besi, narkotika analgesia,
trimethoprim-sulfamethoxazole, pelunak tinja, dan flutikason terhirup. Dia tinggal bersama istri dan
sudah pensiun. Dia minum alkohol dalam jumlah sedang sampai penyakit ini baru-baru ini dan telah
berhenti merokok 7 tahun sebelumnya, ia tidak menggunakan obat-obatan terlarang. Ibunya memiliki
diabetes mellitus dan meninggal pada 81 tahun dari kanker tenggorokan, ayahnya meninggal di usia 80
tahun karena kanker prostat.

Pada pemeriksaan, pasien itu mengantuk tapi arousable. Tekanan darah 93/45 mmHg, denyut nadi 43
kali per menit dan teratur, suhu 36,0 C, tingkat pernapasan 16 napas per menit, dan saturasi oksigen
99% sedangkan pasien menghirup udara ambien. Melacak eritema atas sayatan sternal rendah dan
laserasi penyembuhan atas kulit kepala parietalis kanan dicatat. Ada minimal crackles dalam bidang
paru-paru dan pengecilan otot menyebar, sisa pemeriksaan normal, meskipun pemeriksaan neurologis
terbatas karena kemampuan pasien menurun untuk berkonsentrasi.

Jumlah trombosit dan waktu parsial tromboplastin diaktifkan-normal, seperti darah kadar kalsium, total
dan bilirubin langsung, aspartat dan asam aminotransferase, amilase, lipase, dan laktat alanin. Tingkat
tacrolimus adalah 7,0 ng per mililiter, hasil tes lain yang ditunjukkan pada Tabel 1. Urinalisis
mengungkapkan pH 5,0 dan berat jenis lebih besar dari 1,030, hasilnya dinyatakan normal.
Elektrokardiogram menunjukkan ritme sinus pada tingkat 44 denyut per menit (menurun dari 64 denyut
per menit 5 minggu sebelumnya), dengan interval PR dari 200 msec, kompleks QRS dari 88 msec, dan QT
dan interval QTc dari 517 dan 442 msec , masing-masing; baru nonspesifik T-gelombang kelainan muncul
di mengarah V1, V2, dan V3 dibandingkan dengan 5 minggu sebelumnya. Sebuah rontgen dada
menunjukkan edema paru interstisial ringan, dengan klip bedah di mediastinum dan berliku-liku dengan
kalsifikasi aorta aterosklerotik. CT kepala tanpa pemberian bahan kontras mengungkapkan perubahan
mikroangiopati periventricular dan subkortikal dan aterosklerosis di sifon karotis, tanpa bukti
perdarahan intrakranial, lesi massa, atau infark teritorial. Ultrasonografi transplantasi ginjal
mengungkapkan indeks resistif dari arteri arkuata seluruh ginjal 0,84-1,00 (rentang normal, 0,6 hingga
0,7), yang meningkat dibandingkan dengan studi dari 5 bulan sebelumnya, yang menunjukkan indeks
dari 0,74-0,83; ini Temuan menunjukkan kemungkinan penolakan transplantasi.

Dalam 80 menit setelah kedatangan, tekanan darah pasien menurun menjadi Hg 83/35 mm dan pulsa
sampai 40 denyut per menit. Saline normal (4 liter intravena dalam 6 jam pertama), vankomisin,
sefepim, flukonazol, dan metilprednisolon diberikan. Hipotensi dan bradikardi bertahan. Kalsium
glukonat, atropin, dopamin (diikuti oleh norepinefrin), vasopressin, glukagon, dan ondansetron
ditambahkan. Penyaringan darah untuk racun mengungkapkan adanya dekstrometorfan,
metilprednisolon, dan amlodipine. Pasien dirawat di unit perawatan koroner intensif (ICU).
Ciprofloxacin, metronidazol, natrium bikarbonat, kalsium glukonat, insulin, dan glukosa intravena.
Anuria terjadi, meskipun tantangan bumetanide, dan hemofiltration venovenous kontinyu dimulai.

Echocardiography transthoracic mengungkapkan fraksi ejeksi ventrikel kiri 64% dan diperkirakan
tekanan sistolik ventrikel kanan 68 mm Hg, yang tidak berubah dari studi sebelumnya. Regional dinding-
gerak kelainan yang terlihat pada studi sebelumnya yang ditingkatkan. Budaya dari darah dan urin
diperoleh.

Tes diagnostik dilakukan.
Differential Diagnosis

Dr Jeffrey L. Greenwald: Semoga kita melihat pencitraan?

Dr Shaunagh McDermott: The rontgen dada yang diperoleh saat masuk menunjukkan kepenuhan
perihilar dan hilangnya definisi pembuluh darah paru, fitur konsisten dengan edema paru ringan
interstisial (Gambar 1Figure 1Chest Imaging.). CT scan dari otak tanpa pemberian bahan kontras
menunjukkan periventricular dan subkortikal putih-materi hypodensities, kemungkinan besar mewakili
perubahan mikroangiopati kronis. Ada juga menonjol ringan dari ventrikel dan sulci, sebuah fitur yang
konsisten dengan kehilangan volume difus parenkim (Gambar 2Figure 2CT Otak.).

Ultrasonografi dari transplantasi ginjal pada masuk menunjukkan indeks resistif dari arteri arkuata 0,84
terhadap 1,00, dibandingkan dengan 0,74-0,83 pada ultrasonografi dilakukan 5 bulan sebelumnya
(Gambar 3A dan 3BFigure 3Renal Ultrasonografi.). Peningkatan indeks resistif mengkhawatirkan
berkaitan dengan transplantasi penolakan.

Dr Greenwald: Kasus ini sangat menantang, karena pasien kami disajikan dengan kursus beberapa bulan
dari masalah sebagian besar spesifik berikut: kelemahan, kelelahan, penurunan berat badan, perasaan
depresi, dan malaise. Menurut Institute of Medicine, pasien kami memiliki sindrom klinis geriatri dari
gagal tumbuh, yang didefinisikan sebagai "penurunan berat badan, penurunan nafsu makan dan gizi
buruk, dan tidak aktif, sering disertai oleh dehidrasi, gejala depresi, gangguan fungsi kekebalan tubuh,
dan rendah kolesterol. Terjadi dalam bentuk akut dan kronis, gagal tumbuh mengarah ke status
fungsional gangguan, morbiditas dari infeksi, luka tekanan, dan, akhirnya, kematian meningkat "1.
Sindrom ini menantang untuk mengatasi, karena sering memiliki penyebab-penyebab ganda, termasuk
klinis , unsur-unsur psikososial, dan lingkungan. Mengidentifikasi penyebab potensial membutuhkan
mengingat bahwa prinsip pisau cukur Occam mungkin tidak berlaku. Artinya, beberapa faktor yang
mendasari dapat hidup berdampingan.

Kami diberi beberapa petunjuk bahwa saya akan gunakan untuk membantu memfokuskan diagnosis
diferensial saya. Pasien imunosupresi, itu mengambil 22 obat, dan memiliki riwayat penyakit pembuluh
darah, diabetes, dan rambut rontok baru-baru ini. Dia memiliki hipotensi dan bradikardi pada
presentasi, dan infus cairan isotonik, setidaknya dalam kursus awal, tidak menyebabkan stabilisasi
hemodinamik. Dia hypercapnia dan anemia ditandai dengan variasi penting dalam merah-sel ukuran,
bentuk, dan pewarnaan. Akhirnya, echocardiogram nya menunjukkan hipertensi pulmonal dan fraksi
ejeksi ventrikel kiri yang tidak berubah dari studi sebelumnya, namun studi saat pasien dilakukan saat
dia menerima obat pressor.

Faktor-faktor ini semua membantu membentuk diagnosis diferensial saya akan mempertimbangkan. Ini
termasuk kondisi yang berkaitan dengan empat domain utama - efek obat, infeksi, kondisi ganas, dan
endocrinopathies.
Pengaruh Obat

Pasien ini diresepkan obat banyak, termasuk tacrolimus, mycophenolate mofetil, dan prednison. Efek
samping dari tacrolimus termasuk nyeri perut, anoreksia, alopecia, dan bradikardi. Namun, tingkat
tacrolimus pasien berada di kisaran terapi yang tepat, mengingat waktu sejak transplantasi, dalam
kisaran ini, efek samping ini jarang terjadi. Demikian pula, efek samping dari mikofenolat mofetil bisa
menjelaskan mialgia pasien, nyeri perut, bradycardia, dan kelemahan. Namun, dosis yang diresepkan
mikofenolat mofetil dalam kasus transplantasi ginjal biasanya lebih rendah daripada dosis dalam kasus
transplantasi organ padat lainnya, sehingga efek samping yang kurang umum. Tentu saja, banyaknya
obat lain pasien, seperti 3-hidroksi-3-methylglutaryl koenzim A inhibitor reduktase (yaitu, statin), beta-
blocker, blocker saluran kalsium, diuretik, dan venodilators, bisa juga telah memberikan kontribusi
untuk kompleks keseluruhan gejala. Mengingat usia ini pasien yang lebih tua, pertanyaan polifarmasi
merupakan salah satu gejala bahwa kita mungkin tidak dapat untuk menyingkirkan fully.2
Infeksi

Imunosupresi terkait infeksi dan infeksi lain harus dipertimbangkan, termasuk TB diseminata, Epstein-
Barr virus, cytomegalovirus (CMV), dan meningitis kriptokokus. Infeksi ini dapat diwujudkan subacutely,
dapat memiliki manifestasi protean, dan dapat dengan mudah diabaikan. Selain itu, mengingat bahwa
pasien ini memiliki BK virus, bukti kedalaman imunosupresi nya, kita harus mempertimbangkan
penyebab infeksi lainnya. Infeksi virus JC, misalnya, lebih sering terjadi pada pasien yang telah menerima
transplantasi dan yang mengambil mycophenolate mofetil, bisa diwujudkan oleh subacutely bicara cadel
dan kelemahan. Kondisi ini relatif jarang terjadi pada pasien yang telah mengalami transplantasi ginjal
dan biasanya dimanifestasikan oleh kejang, ataksia, gangguan penglihatan, tengkorak-saraf kelainan,
atau hemiparesis.3 Banyak gejala pasien ini menyajikan dapat dijelaskan oleh beberapa infeksi ini, tetapi
infeksi tidak jelas menjelaskan bradikardia dan hipotensi, kecuali sepsis ditumpangkan dikembangkan
pada saat presentasi.
Kondisi Ganas

Kedua imunosupresi terkait kanker dan kanker lainnya umum untuk perokok 69-tahun mantan pria
harus dipertimbangkan. Obat imunosupresif meningkatkan risiko kanker tersebut bahwa sekitar satu
dari lima penerima ginjal atau hati--transplantasi akan memiliki kanker terdeteksi dalam dekade
pertama setelah transplantation.4 Kanker kulit adalah kanker pasca-transplantasi yang paling umum,
namun pasca-transplantasi gangguan lymphoproliferative (PTLD) terjadi pada sekitar 1% dari penerima
solid-organ transplants5 dan memiliki insiden yang lebih tinggi di antara mereka yang menerima globulin
antithymocyte dan tacrolimus. Diagnosis ini harus tetap di daftar kami.

Presentasi ini pasien sebagian besar spesifik juga dapat dijelaskan sebagian oleh kanker stadium lanjut,
seperti kanker, paru-paru pankreas usus, atau. Kita tidak diberikan informasi tentang apakah pasien
pernah mengalami screening colonoscopy. The rontgen dada membuat kanker paru-paru lanjut
mungkin. Tak satu pun dari kanker ini menjelaskan rambut rontok, bradikardia, hipotensi, atau
kurangnya respon terhadap pemberian cairan kristaloid.
Endocrinopathies

Dua endocrinopathies, insufisiensi adrenal dan hipotiroidisme, perlu dipertimbangkan. Bersama-sama,
mereka dapat menjelaskan sebagian besar presentasi ini pasien. Insufisiensi adrenal pada pasien ini
kemungkinan besar akan obat-induced (dari penggunaan jangka panjang glukokortikoid) atau
disebabkan oleh gangguan autoimun (penyakit Addison). Infeksi CMV juga dapat menyebabkan adrenal
insufficiency.6 Dosis prednison saat ini, 5 mg sehari, hampir fisiologis namun dapat mengganggu
kemampuan kelenjar adrenal untuk meningkatkan produksi glukokortikoid dalam menanggapi stress.7
Memang, dengan luka sternal kronis dan aliran darah infeksi yang pasien telah selama berbulan-bulan,
itu aneh bahwa ia tidak menunjukkan tanda-tanda hypoadrenalism sebelumnya. Atau mungkin ia punya.
Insufisiensi adrenal relatif disebabkan oleh stres kronis dari infeksi ini dapat menjelaskan penurunan
berat badannya, anoreksia, mual, dan kekurangan energi. Namun, jika lama, insufisiensi adrenal secara
klinis signifikan telah hadir, kita boleh berharap perubahan pigmen yang sering terlihat di tangan dan
lipatan kulit lainnya dalam kaitannya dengan coexpression dari melanosit-stimulating hormone dan
corticotropin disekresikan dari kelenjar pituitari. Saya percaya kondisi ini hadir, tetapi bukanlah
penyebab dominan dari penyakitnya. Meskipun glukokortikoid-terapi penggantian diberikan pada
presentasi, bisa berlangsung berjam-jam untuk mengambil efek, yang dapat menjelaskan kurangnya
awalnya respon terhadap resusitasi cairan.

Hypothyroidism mungkin menjelaskan presentasi pasien dan tentu saja lebih baik daripada semua
diagnosis lain dipertimbangkan. Ironisnya, hipotiroidisme tidak berhubungan dengan status pasien
sebagai penerima transplantasi, mungkin membuat kondisi lebih sulit bagi dokter terfokus untuk
mengidentifikasi. Hypothyroidism dapat berkembang selama perkembangan ke stadium akhir penyakit
ginjal, yang diduga disebabkan oleh derangements metabolik yang berhubungan dengan uremia.8
progresif Mengingat fungsi miskin korupsi pasien sebelum masuk, mungkin hipotiroidisme disebabkan
oleh stadium akhir gagal ginjal adalah kontribusi Faktor. Namun, hipotiroidisme autoimun (penyakit
Hashimoto) tetap diagnosis yang paling mungkin dan menjelaskan kelemahan pasien (meskipun
ketinggian khas di tingkat creatine kinase yang satu akan mengharapkan dalam kasus miopati hipotiroid
tidak terlihat pada pasien ini karena negara kakeksia), 9 gejala depresi, sakit nonspesifik umum,
sembelit, bradycardia, dan rambut rontok. Bahkan, kekurangan hormon tiroid dapat memperpanjang
efek dari setiap hormon yang ada glucocorticoid adrenal, berpotensi forestalling manifestasi insufisiensi
adrenal.

Hipotiroidisme, untuk beberapa derajat, juga akan membantu untuk menjelaskan hipertensi paru,
disfungsi jantung, hypercapnia, dan anemia pada pasien ini. The paru-arteri terus tekanan tinggi yang
paling mungkin berhubungan dengan penyakit jantung iskemik pada pasien. Hypothyroidism adalah
penyebab diakui hipertensi paru, tetapi mekanisme ini tidak baik dijelaskan. Memang, pengobatan
hipotiroidisme dapat menyebabkan penurunan tekanan paru. 10 Demikian pula, hipotiroidisme dapat
mengganggu kontraktilitas jantung, yang meningkatkan dengan terapi pengganti. Seperti otot jantung
dan lainnya, otot-otot pernapasan dipengaruhi oleh hipotiroidisme, berpotensi menjelaskan
hypercapnia tersebut.

Pasien dengan hypothyroidism umumnya mengalami anemia, yang berhubungan dengan aktivitas
metabolik yang lebih rendah dan menyebabkan ekstraksi oksigen rendah oleh jaringan dan, karenanya,
sekresi kurang dari erythropoietin. Meskipun anemia normositik klasik, dapat mikrositik (disebabkan
sebagian oleh frekuensi tinggi kekurangan zat besi bersamaan karena malabsorpsi atau kehilangan
darah) atau makrositik (akibat kelainan lipid terkait mengarah ke penggabungan lipid kelebihan dalam
membran sel atau merah dengan peningkatan risiko anemia pernisiosa bersamaan) .6,7

Saya percaya presentasi ini pasien dengan gagal tumbuh adalah karena hipotiroidisme berat dengan
relatif, jika tidak mutlak, insufisiensi adrenal.
Dr Jeffrey L. Greenwald itu Diagnosis

Parah hipotiroidisme dan insufisiensi adrenal relatif.
Kesan Klinis

Dr Eric S. Rosenberg (Patologi): Dr Ge, apa kesan klinis Anda ketika Anda melihat pasien ini?

Dr Ge: Pasien ini disajikan dengan shock yang sangat serius, rumit oleh gagal ginjal dan kelainan
elektrolit. Tertinggi pada daftar diagnosis diferensial kami adalah kejutan distributif karena sepsis,
terutama mengingat sejarah infeksi berulang dan imunosupresi yang mendalam. Penyebab syok
kardiogenik juga yang tinggi di daftar kami. Pasien memiliki riwayat penyakit arteri koroner dan memiliki
tingkat troponin meningkat pada presentasi. Hipotensi dan bradikardi kadang-kadang dapat dilihat pada
pasien dengan infark miokard rendah. Pada pasien dengan perubahan elektrokardiografi nonspesifik,
echocardiogram transthoracic samping tempat tidur mengungkapkan fungsi ventrikel terlalu biasa kiri
dan kanan, membuat iskemia miokard kecil kemungkinannya. Kemungkinan lain kardiogenik adalah efek
samping dari obat-obatan, karena hipotensi mendalam dan bradikardi dapat terjadi dengan overdosis
beta-blockers dan calcium-channel blocker, yang keduanya dalam daftar obat rumahnya. Namun, ia
tidak memiliki respon terhadap terapi glukagon yang dimulai di gawat darurat pada hari sebelumnya.

Pasien telah menerima jangka panjang prednison dan fludrocortisone. Karena dia memiliki
dekompensasi akut dan kronis gagal untuk berkembang, kemungkinan insufisiensi adrenal dibesarkan
dan ia diberi dosis stres empiris hidrokortison. Namun, bradikardia mendalam aneh dan tidak memiliki
penyebab mudah diidentifikasi. Karena pasien juga memiliki anoreksia dan perubahan mental subakut,
lain endocrinopathy - hipotiroidisme parah - dibesarkan sebagai suatu kemungkinan.
Patologis Diskusi

Dr Anand S. Dighe: Tingkat thyrotropin, diukur pada masuk, itu sangat meningkat pada 132 U per
mililiter (referensi kisaran, 0,4-5,0). Hasil tes hormon tiroid menunjukkan tingkat mendalam rendah
tiroksin total (T4) sebesar 1,2 mg per desiliter (15,4 nmol per liter, kisaran referensi, 4,5-10,9 mg per
desiliter [57,9-140,3 nmol per liter]) dan tingkat rendah Total triiodothyronine (T3) pada 26 ng per
desiliter (0,40 nmol per liter, kisaran referensi, 60-181 ng per desiliter [0,9-2,8 nmol per liter]). Nilai-nilai
yang konsisten dengan hipotiroidisme primer. Pasien dinilai untuk penyakit tiroid autoimun dengan
pengukuran autoantibodi diarahkan terhadap peroksidase tiroid. Anti-antibodi tiroid peroksidase tidak
terdeteksi. Selain pengujian negatif untuk anti-tiroid antibodi peroksidase, pasien tidak memiliki riwayat
paparan radiasi atau leher operasi dan tidak mengambil obat terlibat sebagai penyebab hipotiroidisme.
Dengan demikian, penyebab hipotiroidisme primer pasien tidak jelas.

Pada sore pada hari masuk ke rumah sakit ini, tingkat kortisol rendah, sebesar 3,7 mg per desiliter (102,1
nmol per liter, referensi berkisar pada siang hari sampai 8 malam, 5 sampai 15 mg per desiliter [138,0-
413,8 nmol per liter ]). Mengingat status kritis pasien ketika sampel darah diambil, tingkat kortisol dapat
ditafsirkan sebagai tidak tepat rendah. Namun, sore pengujian kortisol adalah nilai terbatas dalam
diagnosis insufisiensi adrenal. Selain itu, spesimen diperoleh setelah pemberian metilprednisolon, yang
menekan sekresi kortisol endogen. Oleh karena itu, tingkat kortisol yang rendah, meskipun sugestif dari
ketidakcukupan adrenal, tidak diagnostik. Dukungan untuk diagnosis insufisiensi adrenal akan hadir jika
tingkat kortisol diperoleh di pagi hari sudah rendah.

Follow-up

Dr Ge: Setelah kita membuat diagnosis hipotiroidisme yang mendalam, pasien dimulai pada
levothyroxine intravena. Dia kemudian disapih dari vasopressors pada hari rumah sakit 3. Hemofiltration
venovenous terus menerus, yang telah dimulai untuk asidosis berat dan ketidakseimbangan elektrolit,
dihentikan pada hari rumah sakit 4. Setelah administrasi levothyroxine dimulai, demam intermiten mulai
berkembang, yang mungkin telah disembunyikan oleh hipotiroidisme tersebut. Pada hari rumah sakit 5,
karena demam berulang, pasien menjalani CT dari dada, scan menunjukkan bilateral tanah-kaca
kekeruhan, yang paling mencolok di lobus kiri atas. Kultur dahak akhirnya tumbuh stenotrophomonas,
pseudomonas, dan methicillin-resistant Staphylococcus aureus. Dia diberi kursus diperpanjang
vankomisin, sefepim, trimethoprim-sulfamethoxazole, dan vorikonazol.

Pada hari rumah sakit 8, pasien dipindahkan dari ICU ke bangsal kedokteran umum. Lendir Intermittent
penyumbatan pada saluran udara dikembangkan, dan pasien kembali ke ICU, di mana ia tinggal selama
hari di rumah sakit 17 sampai 21, ia kemudian ditransfer kembali ke bangsal. Status mental nya
perlahan-lahan memburuk selama 10 hari ke depan, berkaitan dengan infeksi yang sedang berlangsung.

Tim medis melakukan diskusi dengan keluarga, dan karena pasien mengalami penurunan baik dari sudut
pandang fisik dan mental, keputusan itu dibuat untuk transisi perawatan untuk menghibur langkah saja.
Dia meninggal pada hari rumah sakit 31.

Seorang Dokter: Apakah hipotiroidisme parah saja menjelaskan hipotensi?

Dr Lloyd Axelrod (Endokrinologi): Biasanya tidak. Bahkan, pada pasien rawat jalan khas dengan
hipotiroidisme, Anda akan mengharapkan beberapa hipertensi, terutama hipertensi diastolik. Dalam
myxedema koma, hipotensi dapat terjadi. Namun, secara umum, Anda tidak ingin atribut hipotensi
untuk hipotiroidisme.

Dr Greenwald: Aku akan tetap berpegang pada senjata saya dan bertaruh bahwa mungkin ada beberapa
kekurangan adrenal yang bisa menjelaskan bagian dari ini.

Sebuah Dokter: Apakah mungkin bahwa pasien mengalami hipotiroidisme pada saat transplantasi dan
bahwa yang bisa memberikan kontribusi untuk acara perioperatif nya?

Dr Greenwald: Kita tahu bahwa pasien yang menjalani operasi besar sementara di hipotiroid signifikan
atau negara hipertiroid memiliki peningkatan risiko komplikasi dan kematian perioperatif. Saya pikir itu
adalah sedikit peregangan dalam kasus ini, tapi jelas adalah mungkin.
Anatomi Diagnosis

Parah utama hipotiroidisme.