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Supplementary Material: Case Reports
Patient 1: A 42 year old non-Hispanic white woman with MS had asymptomatic
elevations of serum ALT levels at month 6 of interferon beta-1a therapy given in a dose of 30
mcg intramuscularly once weekly. Past medical history included Graves’s disease and a small,
stable pituitary tumor. She had no history of liver disease and liver biochemistry test results were
normal before starting interferon beta therapy. She had no known drug allergies. Other
medications were zolpidem, thyroid hormone, doxepin, ibuprofen, lorazepam, and tizanidine
which was started 2 months before the DILI onset. Over-the-counter and herbal products
included a multivitamin, omega-3 fatty acids and “Thyro-Balance”. She did not smoke or drink
alcohol. At presentation, physical examination was unremarkable and laboratory tests revealed
ALT 282 U/L, AST 169 U/L, Alk P 95 U/L, and total bilirubin 0.9 mg/dL. Serum albumin and
INR were normal and white blood cell count was 6.9 × 103/μL with 0.6% eosinophils. Viral
hepatitis and autoimmune serologies were negative, and liver imaging was normal. A liver
biopsy was not performed. The liver biochemical abnormalities improved over a 2 month period
without any intervention beyond discontinuation of interferon beta-1a. Comment: This patient
had an asymptomatic elevation of her serum aminotransferase levels which normalized after
stopping the treatment. The case was adjudicated as “very likely” by the DILIN Causality
committee and interferon beta-1a was scored as a 2 while tizanidine was as scored as a 4 or
“possible”. The DILIN severity score was 1+ (mild).
Patient #2: A 38 year old non-Hispanic white woman with a 10 year history of MS
developed mild elevations in serum enzymes during interferon beta-1b therapy which was
discontinued at 2 years when levels continued to rise: ALT (310 U/L), AST (278 U/L),and ALK
P (254 U/L). She subsequently had a relapse of MS symptoms and did not respond to a course of
corticosteroids and plasmapheresis. Because of intractable symptoms including gait disturbance,
neurogenic bladder and optic neuritis, she was restarted on interferon beta in a dose of 300 mcg
subcutaneously three times a week with careful monitoring of serum enzymes. After two weeks,
liver biochemistries were again abnormal and interferon beta was stopped. Concomitant
medications included zolpidem, clonazepam, gabapentin, hydrocodone, darifenacin, sumatriptan,
nitrofurantoin, prednisone, lansoprazole, bupropion and azithromycin. She was allergic to
morphine, doxycycline and tramadol, all of which caused itching. She also had depression, prior
cholecystectomy and gastric bypass surgery 3 years prior for morbid obesity. At the time of
presentation, physical examination was unremarkable except for a BMI of 29 kg/m2. Laboratory
results showed an ALT 366 U/L, AST of 737 U/L, Alk P 322 U/L and total bilirubin 0.5 mg/dL.
Viral hepatitis and autoimmune serologies were negative, and liver imaging was unremarkable.
An outpatient liver biopsy performed 40 days after DILI onset for persistent Alk P elevations
showed mild, non-specific changes. There were rare foci of lobular inflammation and clusters of
pigmented macrophages consistent with resolved hepatitis. There was minimal steatosis and no
cholestasis. Six and 24 months after DILI onset she was asymptomatic of liver disease but
continued to have Alk P elevations (158 U/L and 136 U/L respectively) with normal serum
bilirubin and ALT. At her 24 month study visit, liver imaging showed increased echogenicity of
the liver but no hepatosplenomegaly. Comment: This patient presented with a history of liver
enzyme elevations occurring while on interferon beta that improved with drug discontinuation.
Other diagnoses were excluded; although she had a history of obesity, liver biopsy did not show
evidence of fatty liver disease. The development of an acute flare in liver enzymes with a
positive rechallenge and improvement after discontinuation, led this case to be scored as definite.
The DILIN severity score was 1+.
Patient #3: A 52 year old non-Hispanic white woman was started on interferon beta-1a
(Rebif: Serono) for progressive multiple sclerosis with gradual increase in the dose from 8.8 to
44 mcg subcutaneously thrice weekly over a 6 week period. She complained of myalgias and
fatigue and at week 14 was found to have mild elevations in serum ALT and AST that prompted
discontinuation of the interferon beta. Her medical history included asthma, migraines and a
cholecystectomy for gallstones. She had no history of liver disease or known drug allergies.
Concomitant medications included ibuprofen, acetaminophen, prednisone, topiramate, and
alprazolam all of which were continued. Concomitant over-the-counter products included
vitamin C, vitamin D and omega 3 fatty acids. She was a non-smoker and did not drink alcohol.
Her physical examination at presentation was unremarkable. Laboratory test results included
serum ALT 220 U/L, AST 113U/L, Alk P 74 U/L and total bilirubin 0.3 mg/dL. Viral hepatitis
and autoimmune serologies were negative, and liver imaging was unremarkable. Her liver
enzymes fell into the normal range after discontinuation of interferon beta, and a liver biopsy
was not performed. Comment: This patient presented with asymptomatic laboratory
abnormalities that developed following initiation of interferon beta and resolved after its
discontinuation. There were no other likely causes for the liver injury. Although she was taking
multiple other medications, these had been used for years and were continued. The DILIN
adjudication score for interferon beta hepatotoxicity was “very likely” and the DILIN severity
score was 1+ (mild).
Patient #4 : A 62 year old non-Hispanic white woman who had been on varying dose of
interferon beta-1a (Rebif)for multiple sclerosis for over 4 years developed asymptomatic
elevations in liver enzymes 4 months after the dose was increased from 22 to 44 mcg
subcutaneously, three times per week. She had a medical history of hypertension, skin cancer,
gastroesophageal reflux disease and osteoporosis. She reported multiple drug sensitivities
including reactions to epinephrine (tachycardia and palpitations), erythromycin (rash),
cephalexin (vaginal candidiasis), and morphine and codeine (pruritus). She was also taking
alendronate, hydrocholorthiazide, lansoprazole, diazepam and chlorpheniramine-phenylephrine.
Concomitant over-the-counter products included calcium, glucosamine-chondroitin, vitamin C
and omega 3 fatty acids. She did not smoke or drink. Her physical examination at presentation
was normal. Serum ALT was 240 U/L, AST 185 U/L, Alk P 83 U/L and total bilirubin 0.4
mg/dL. Viral hepatitis and autoimmune serologies were negative. A liver ultrasound revealed
increased echogenicity suggestive of mild fatty infiltration. As a result of the liver enzyme
elevation, the dose of interferon was reduced to 22 mcg three times per week, but then was
discontinued 2 months later when ALT levels did not improve. Two months later, serum enzyme
levels were normal. A liver biopsy was not performed. Comment: This patient presented with an
asymptomatic increase in liver enzymes after the dose of interferon beta 1a was increased. Her
aminotransferases improved with dose reduction but normalized only after the interferon-beta
was discontinued. The DILIN adjudication process rated the likelihood of interferon beta as
“probable”. The DILIN severity score was 1+ (mild).
Patient #6: A 47 year old African American woman developed asymptomatic liver
enzyme elevations on routine monitoring 3 months after starting interferon beta in a dose of 30
mcg subcutaneously, once weekly for MS. She had no history of liver disease or drug allergies.
Other medical conditions included hypertension for which she was taking bisoprololhydrochlorothiazide. For her MS, she received two monthly injections of dexamethasone before
starting interferon beta. She denied use of over-the-counter or herbal products. She was a non-
smoker and did not use alcohol. Physical examination at presentation was unremarkable.
Laboratory testing showed a serum ALT 850 U/L, AST 620 U/L, Alk P 91 U/L and total
bilirubin 0.7 mg/dL. Viral hepatitis and autoimmune serologies were negative, and liver imaging
was unremarkable. Interferon beta was stopped 4 days after identification of the enzyme
elevations, while her antihypertensive medications were continued. Her serum enzymes
continued to rise for 3 weeks and she developed associated nausea and jaundice. Peak values of
liver tests were ALT 1,484, ALK 150 U/L, and total bilirubin 3.9 mg/dL, while the INR
remained normal. Subsequently, her serum aminotransferase levels and bilirubin decreased and
were normal at 5 months later. A liver biopsy at 2 months after the onset of DILI showed zone 3
necrosis and mild inflammation but with a prominence of plasma cells. There was focal bridging
necrosis between some portal areas and the central necrosis. The viable parenchyma showed
hepatocyte rosettes and many foci of lobular inflammation. She was not hospitalized and
received no treatment for the liver injury. Comment: This patient presented with marked serum
aminotransferase elevations 3 months after starting interferon beta and subsequently developed
jaundice. Her liver enzymes normalized within 56 months of stopping interferon beta. Serologic
work up for competing liver disease was negative as was imaging. Her liver biopsy did revealed
zonal necrosis with plasma cells consistent with a drug or autoimmune injury. Despite the
concern for an underlying unexplained chronic hepatitis, the temporal relationship of interferon
treatment with liver injury, and improvement with discontinuation was suggestive of DILI. The
DILIN adjudication process rated the likelihood of interferon beta as the cause of DILI as
=definite. The DILIN severity score was 2 + based on liver enzyme elevation with
hyperbilirubinemia.