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Case Records of the Massachusetts General Hospital
Founded by Richard C. Cabot
Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Alyssa Y. Castillo, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors
Case 15-2019: A 55-Year-Old Man
with Jaundice
Esperance A. Schaefer, M.D., M.P.H., Mark A. Anderson, M.D.,
Arthur Y. Kim, M.D., and Maroun M. Sfeir, M.D.​​
Pr e sen tat ion of C a se
Dr. Joseph D. Planer (Medicine): A 55-year-old man with a history of opioid use disorder and hepatitis C virus (HCV) infection presented to this hospital with jaundice.
Four months before the current presentation, the patient was released from
prison after a 2-year incarceration. After he left prison, he resumed injecting
heroin and had three episodes of overdose. He was evaluated at another hospital
for symptoms of depression and was admitted for psychiatric treatment. During
that admission, sublingual buprenorphine–naloxone therapy was initiated, and the
patient was discharged.
One day after discharge and 5 weeks before the current presentation, headache,
body aches, sweats, diarrhea, and nausea developed. The patient presented to a
clinic for substance use disorder that is affiliated with the other hospital and reported that he had been unable to obtain sublingual buprenorphine–naloxone
from a pharmacy after discharge. The temperature was 36.6°C, the pulse 70 beats
per minute, and the blood pressure 100/68 mm Hg. The weight was 72 kg. He
appeared to be restless, but the remainder of the physical examination was normal.
Urine toxicologic screening was positive for buprenorphine, norbuprenorphine,
and norfentanyl; buprenorphine–naloxone therapy was resumed.
Three weeks before the current presentation, dark urine and light-headedness
developed and did not improve with increased fluid consumption. The patient also
noticed slow thinking and arthralgias in the hands, wrists, and elbows. He was
evaluated by a new primary care provider. The temperature was 36.7°C, the pulse
53 beats per minute, and the blood pressure 104/66 mm Hg. The joints of the
hands, wrists, and elbows were normal. The neurologic examination was normal,
as was the remainder of the physical examination. Blood levels of electrolytes and
glucose were normal, as were the complete blood count, differential count, and
results of renal-function tests. Urinalysis revealed clear, dark-yellow urine, with a
specific gravity of 1.020 (reference range, 1.00 to 1.030), a pH of 7.5 (reference
range, 5.0 to 9.0), trace ketones (reference value, negative), and 2+ urobilinogen
n engl j med 380;20
From the Departments of Medicine
(E.A.S., A.Y.K.), Radiology (M.A.A.), and
Pathology (M.M.S.), Massachusetts
General Hospital, and the Departments
of Medicine (E.A.S., A.Y.K.), Radiology
(M.A.A.), and Pathology (M.M.S.), Har‑
vard Medical School — both in Boston.
N Engl J Med 2019;380:1955-63.
DOI: 10.1056/NEJMcpc1900592
Copyright © 2019 Massachusetts Medical Society.
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Table 1. Laboratory Data.
Prothrombin time (sec)
Prothrombin-time international normalized ratio
3 Wk before
Alanine aminotransferase (U/liter)
Aspartate aminotransferase (U/liter)
Bilirubin (mg/dl)†
Alkaline phosphatase (U/liter)
Protein (g/dl)
C-reactive protein (mg/liter)
Hepatitis C virus antibody
Hepatitis C virus RNA (IU/ml)
Human immunodeficiency virus p24 antigen
and type 1 and type 2 antibodies
*Reference values are affected by many variables, including the patient population and the laboratory methods used. The
ranges used at Massachusetts General Hospital are for adults who are not pregnant and do not have medical conditions
that could affect the results. They may therefore not be appropriate for all patients.
†To convert the values for bilirubin to micromoles per liter, multiply by 17.1.
(reference value, negative). Other laboratory test
results are shown in Table 1.
One week before the current presentation, the
patient noticed yellowing of the eyes and skin.
One week later, he was seen by his primary care
provider and was immediately transported by
ambulance to the emergency department of this
hospital for evaluation.
On evaluation, the patient reported 2 weeks
of anorexia, malaise, nausea with dark-brown
emesis, profuse nonbloody watery diarrhea, intermittent abdominal cramping, poor sleep, blurry
vision, and episodes of forgetfulness and loss of
concentration. He had no fevers, chills, bleeding,
or pulmonary or genitourinary symptoms and
had no sick contacts. There was a history of
osteoarthritis, depression, and anxiety. HCV infection had been diagnosed but not treated while
the patient was incarcerated. He reported that
when he used intravenous heroin, he did not
reuse, share, or lick needles. Allergies included
penicillin, aspirin, and sulfonamide-containing
n engl j med 380;20
antibiotic agents. The only medication was sublingual buprenorphine–naloxone.
The patient was divorced and had no children. He had not been sexually active in 2 years.
He was born in the northeastern United States
and had not traveled outside the country. Since
his release from prison, he was unemployed,
homeless, and sleeping in a shelter. He had no
known exposure to rodents or rodent excreta.
He smoked cigarettes daily and had done so for
20 years. He had previously consumed 2 liters of
vodka daily but had quit 6 years earlier. His parents were deceased; he was estranged from his
siblings, and their medical history was unknown.
On physical examination, the temperature
was 36.3°C, the pulse 57 beats per minute, the
blood pressure 113/72 mm Hg, the respiratory
rate 18 breaths per minute, and the oxygen saturation 97% while the patient was breathing ambient air. The weight was 68 kg. The patient appeared jaundiced and had marked scleral icterus.
The mucous membranes were moist, and there
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Case Records of the Massachuset ts Gener al Hospital
was no cervical lymphadenopathy. The abdomen
was soft and nondistended, with no evidence of
ascites. There was mild tenderness on palpation
of the upper right quadrant of the abdomen,
with no hepatosplenomegaly. The patient had no
gynecomastia, caput medusae, or spider angiomas. He was alert and fully oriented and had no
asterixis. There was no rash or leg edema. The remainder of the physical examination was normal.
Blood levels of electrolytes, glucose, and lipase
were normal, as were the complete blood count,
differential count, and results of renal-function
tests. Serum toxicologic screening did not detect
acetaminophen, salicylates, tricyclics, or ethanol.
Other laboratory test results are shown in Table 1.
Dr. Mark A. Anderson: Limited ultrasonography
of the right upper quadrant (Fig. 1) revealed no
bile-duct dilatation, a patent main portal vein
with hepatopetal flow, and normal hepatic parenchymal echotexture. Diffuse, hypoechoic gallbladder-wall thickening was present, without
gallbladder distention, cholelithiasis, or pericholecystic fluid. Murphy’s sign was negative. There
was trace perihepatic ascites.
Dr. Planer: Additional diagnostic tests were
Differ en t i a l Di agnosis
Dr. Esperance A. Schaefer: The first question to address in the assessment of this patient is whether his syndrome is due to acute liver injury or
acute-on-chronic liver failure in the presence of
established cirrhosis.1 The patient had a history
of heavy alcohol use and HCV infection. In patients with chronic HCV infection, fibrosis can
progress slowly, with cirrhosis developing after
20 years in 16%; however, the progression of
fibrosis is influenced by host and environmental
factors and is accelerated by alcohol use.2 Clinical clues that point away from cirrhosis in this
case include the absence of gynecomastia and
spider angioma on physical examination, the normal platelet count, and the absence of nodular
liver contour and splenomegaly on ultrasonography.3 The magnitude of his elevated alanine
aminotransferase level also argues against advanced liver disease, because it suggests the
presence of a substantial volume of viable hepatocytes that are susceptible to injury, a feature
that is uncommonly seen in cirrhosis.
n engl j med 380;20
In the absence of underlying cirrhosis, it is
critical to rule out acute liver failure. In adults,
the diagnosis of acute liver failure requires synthetic dysfunction with an international normalized ratio of more than 1.5, as well as a disease
duration of less than 26 weeks and the presence
of hepatic encephalopathy. This patient reported
mild cognitive change, but his examination did
not reveal hepatic encephalopathy. Thus, his
clinical diagnosis at presentation is most consistent with severe acute liver injury, rather than
acute liver failure.
A long-held dogma regarding the differential
diagnosis of severe acute liver injury is that most
cases are due to vascular, viral, or toxic causes.
A recent multicenter study examined the causes
of severe acute liver injury in patients with an
aspartate aminotransferase or alanine aminotransferase level of more than 1000 U per liter
and confirmed the leading causes to be ischemic
hepatitis, pancreaticobiliary disease, drug-induced
liver injury, and viral hepatitis.4
Ischemic Hepatitis
Does this patient have a vascular or ischemic
process that is causing acute liver injury? Ische­
mic hepatitis is defined as a decrease in hepatic
blood flow that results in hepatocyte death and
necrosis. This condition is commonly seen in
critically ill patients, and in many cases, a clear
hypotensive episode is not documented, which
suggests that the insulting event may be fleeting
or subclinical.5 Recent data further suggest that
elevated central venous pressure and cardiac
pressures on the right side are important predisposing factors.6 The elevation in aminotransferase levels tends to be dramatic but brisk, with
the rise and fall occurring over a period of 24 to
48 hours, and it is usually followed by a rise in
the bilirubin level. This patient does not have
ischemic injury, given the sustained and persistent rise in the alanine aminotransferase level
over a period of several weeks.
Pancreaticobiliary Disease
The absence of bile-duct dilatation, gallstones,
and pancreatic abnormality on ultrasonography
provides evidence against a pancreaticobiliary
cause of this patient’s liver injury. The magnitude of hyperbilirubinemia and the kinetics of
elevation in aminotransferase levels are also not
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Case Records of the Massachuset ts Gener al Hospital
Figure 1 (facing page). Abdominal Ultrasound Images.
Grayscale images (Panels A, B, E, and F) and color
Doppler images (Panels C and D) of the right upper
quadrant show no intrahepatic or extrahepatic bileduct dilatation (Panels A and B), a patent main portal
vein with flow in the correct direction (Panel C, arrow),
trace perihepatic ascites (Panel D, arrows), and a col‑
lapsed gallbladder with diffuse, hypoechoic wall thicken‑
ing (Panels E and F, plus signs). FF denotes free fluid.
suggestive of biliary disease; the alanine aminotransferase level tends to rise and fall rapidly,
and it is uncommon to have a peak bilirubin
level of more than 10 mg per deciliter (171 μmol
per liter).7
Drug-Induced Liver Injury
Drug-induced liver injury must be considered in
all cases of severe acute liver injury or failure;
studies have determined it to be the most common cause of acute liver failure in the United
States and most of Europe.8 In a large study that
involved patients with this condition, severe hepatocellular disease was common, with a mean
alanine aminotransferase level of 1200 U per liter
and a mean international normalized ratio of 1.6.
The leading offending agents were antibiotics
and herbal and dietary supplements.9 In this case,
the only new medication was buprenorphine–
naloxone, which is an exceedingly rare cause of
drug-induced liver injury. One report identified
buprenorphine–naloxone as the cause of severe
liver injury in two patients with chronic HCV
infection; the drug had been injected at high
doses, and symptomatic hepatitis had occurred
within 4 days after the injection.10 In this patient,
there is no reported history of use of injection
buprenorphine–naloxone, and the symptoms had
appeared just 1 day after initiation of the medication.
Viral Hepatitis
This patient’s clinical presentation is strongly suggestive of acute viral hepatitis. The acute viral
infections that most commonly cause severe
liver injury are HCV infection (in 8.0% of cases)
and hepatitis B virus (HBV) infection (in 2.1% of
cases). Hepatitis A virus (HAV), hepatitis delta
virus (HDV), Epstein–Barr virus, and cytomega-
n engl j med 380;20
lovirus infections are much less common causes
(in 0.3% of cases combined).4 These findings are
in keeping with 2016 data from the Centers for
Disease Control and Prevention, which showed
41,000 new cases of HCV infection, 20,900 new
cases of HBV infection, and 4000 new cases of
HAV infection.11
Acute HCV Infection
Symptoms associated with acute HCV infection
occur approximately 9 weeks after exposure.
There is a very low level of viremia in the first
2 months after infection, followed by a brisk and
exponential increase in viremia over a period of
8 to 10 days. In the subsequent phase, the host
immune system responds to the viremia: the
aminotransferase levels rise, the HCV RNA viral
load plateaus, and symptoms develop.12 Symptoms include fatigue, abdominal pain, jaundice,
muscle and joint aches, mood disturbances, and
diarrhea.13 During this phase, the viral load and
alanine aminotransferase level fluctuate. The viral
load may be intermittently or persistently negative. It is common for the alanine aminotransferase level to be more than 10 times the upper
limit of the normal range, but marked hyperbilirubinemia and an elevated prothrombin time
are rare.14
Could this patient have acute HCV infection?
Although he reportedly had a history of HCV
infection, we have not seen an HCV viral load
obtained before this presentation. A positive test
for HCV antibodies alone suggests previous exposure but does not confirm a chronic infection.
An estimated 25% of persons with exposure to
HCV have successful viral clearance; female sex,
symptomatic infection, and favorable host genetic factors are associated with spontaneous
clearance.15 A landmark finding in the understanding of the immune response to HCV was the
identification of single-nucleotide polymorphisms
in the IL28B gene that are strongly associated
with both interferon response16-18 and spontaneous viral clearance.19-21 Such favorable singlenucleotide polymorphisms have also been shown
to increase the clearance of repeat infection.
In the absence of chronic HCV infection, many
of the features in this case are strongly suggestive
of acute HCV infection. The patient reported that
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n e w e ng l a n d j o u r na l
he had not shared needles, but sharing of flushes,
cooking apparatus, or other elements during
injection may pose a risk of exposure. The time
frame from presumed exposure, the diffuse
symptom complex, and the fluctuating viral load
would support a diagnosis of acute HCV infection; however, the degree of hyperbilirubinemia
and the coagulopathy are not characteristic of
this diagnosis.14
Acute HBV Infection
The clinical presentation and outcome of acute
HBV infection are strongly influenced by the patient’s age; in neonates, viral clearance is exceedingly rare, occurring in less than 5% of cases,
whereas in adults, the infection is successfully
controlled in more than 95% of cases.22 The virus
itself is noncytopathic, and the symptoms and
liver injury are consequences of the host immune response. Liver failure is rare but occurs in
approximately 1% of cases. Even in the absence
of liver failure, liver injury can be severe; in one
case series, the mean alanine aminotransferase
level was 1419 U per liter, and the mean bilirubin
level 6.5 mg per deciliter (111 μmol per liter).23
In classic cases of HBV infection, there is a subacute rise and fall in the alanine aminotransferase level, occurring over a period of 2 to 8 weeks,
with the viral DNA and surface antigen levels
falling after the alanine aminotransferase level
has peaked. The hallmark serologic test for
acute HBV infection is the test for IgM antibodies to HBV core antigen, which can remain positive for up to 6 months after exposure.
If the patient’s status regarding previous exposure to HBV is unknown, it can be challenging to distinguish reactivation of chronic HBV
infection from new acute HBV infection. Reactivation occurs when the virus transitions from a
state of low viral replication to a period of increased replication that is accompanied by a vigorous immune response and is clinically manifested by jaundice or decompensated liver disease.
Peak alanine aminotransferase and bilirubin
levels tend to be lower in patients with reactivation than in patients with primary infection, and
IgM antibodies to HBV core antigen are present
in less than half of patients with reactivation.24
In this patient, hepatitis was more severe
than is commonly seen in persons with acute
HBV infection, and this finding raises the question of whether additional factors contributed to
n engl j med 380;20
m e dic i n e
his condition. Underlying HCV infection can
precipitate a more severe clinical presentation of
HBV infection; in one small case series, severe
hepatitis was observed in 34.5% of the patients
with HCV and HBV coinfection, as compared
with 6.9% of the patients with acute HBV infection alone.25 All the patients with preexisting
HCV infection had an undetectable HCV viral
load 3 to 6 weeks after the onset of symptoms,
a finding that suggests that infection with another hepatotropic virus may prompt a strong
anti-HCV immune response that results in viral
clearance.26,27 The clinically significant decline
in this patient’s HCV viremia supports the possibility of a superinfection with a second virus.
However, it does not provide insight into which
viral agent may be involved.
Acute HDV Infection
What other factors could explain this patient’s
severe acute liver injury? HDV infection is dependent on and exacerbates HBV infection. There
are two clinical patterns of infection with HDV:
coinfection, in which exposure to HDV and to
HBV are simultaneous; and superinfection, in
which acute HDV infection occurs in a person
with established chronic HBV infection. In cases
of coinfection, HDV infection relies on the successful development of HBV infection, which is
uncommon in adults, and thus chronic coinfection is rare. The clinical presentation of acute
coinfection varies in severity. Superinfection is
most likely to be clinically severe and is thought
to be a major cause of acute liver failure in patients with chronic HBV infection. In cases of
superinfection, chronic coinfection is commonly
established. As with acute HBV infection, the
diagnosis of HDV infection is made with the use
of serologic tests. In patients with acute coinfection, tests for IgM antibodies to both HDV and
HBV core antigen are positive. The HBV DNA
level is more commonly elevated in patients with
acute coinfection than in patients with superinfection, in whom the HBV DNA level can be quite
low because of an anti-HDV immune response.28
HDV infection remains rare in the United
States. Among the persons who participated in
the National Health and Nutrition Examination
Survey (NHANES) from 1999 to 2012 and had
positive tests for HBV core antibodies and surface antigen, the estimated overall prevalence of
HDV infection was 0.02%.29 NHANES data
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Case Records of the Massachuset ts Gener al Hospital
tained from 2011 to 2016 showed a slightly higher
prevalence of HDV infection, of 0.11%.30 However, the NHANES did not include several highrisk populations, such as homeless and incarcerated persons. In addition, the prevalence of HDV
infection may be higher among persons who
inject drugs. In one cohort of persons who inject
drugs, testing for HDV antibodies and RNA was
performed in participants who had a positive
test for HBV surface antigen, and HDV infection
was identified in 35.6% of the participants with
chronic HBV infection.31 Thus, although the overall prevalence of HDV infection is very low, the
rate may be higher in certain high-risk cohorts.
HAV Infection
HAV infection is a classic cause of severe acute
viral hepatitis. Similar to HBV infection, HAV
infection has a clinical presentation that varies
according to the patient’s age; children are often
asymptomatic, whereas more than 70% of adults
have symptoms, such as fever, malaise, nausea,
vomiting, and abdominal discomfort, that last
2 to 8 weeks. Jaundice is usually short-lived, occurring over a period of less than 2 weeks, but a
small fraction of patients may have a relapsing
course.32 Before 2017, only 1600 cases of HAV
infection were reported annually, due in large
part to a highly effective vaccine. However, since
2017, a multistate outbreak of HAV infection has
led to a sharp rise in the number of cases, with
7000 cases reported in 12 states33 and 350 outbreak-associated cases reported in the state of
Massachusetts by early 2019. Of the patients who
had these outbreak-associated cases, 48% were
homeless, 90% were engaged in illicit drug use,
and 63% had HCV coinfection.34 In light of this
epidemic, HAV infection is an important consideration in this case. However, in this patient,
jaundice had progressed over a period of 5 weeks,
whereas in patients with HAV infection, icteric
hepatitis lasts less than 2 weeks.
The diagnosis in this case will depend entirely
on the results of serologic tests. In the presence
of severe acute liver injury and probable viral
hepatitis, a biopsy is unlikely to yield additional
information.35 This patient probably has chronic
HCV infection. However, the severity and duration
of the acute icteric hepatitis are most consistent
with acute HBV infection, which, superimposed
n engl j med 380;20
on chronic HCV infection, can lead to severe hepatitis. Because the patient’s presumed exposure was
injection drug use, HDV coinfection should be
considered; however, since it occurs rarely, it is
unlikely in this case.
Dr . E sper a nce A . Sch a efer’s
Di agnosis
Acute hepatitis B virus infection in the presence
of chronic hepatitis C virus infection.
Pathol o gic a l Discussion
Dr. Maroun M. Sfeir: This patient was tested for
HAV and hepatitis E virus. Both tests were negative, ruling out these two causes of acute viral
Testing for HBV was also performed. The
patient’s blood tests were negative for HBV surface antibodies and positive for HBV surface antigen, IgM antibodies to HBV core antigen, and
HBV e antigen. These test results, in conjunction
with a plasma HBV DNA level of 999,000 IU per
milliliter, are diagnostic of acute HBV infection.
A negative test for HBV surface antibodies is
expected in cases of acute HBV infection.
Finally, because HDV relies on HBV for replication, a test for HBV surface antigen, which
constitutes the protein coat of the defective virus, would be positive during HDV infection.36
As noted previously, HBV and HDV coinfection
occurs when a patient becomes infected with the
two viruses simultaneously. HDV antibodies are
detectable 3 months after exposure in 85% of
patients with coinfection and decline to undetectable levels after the infection resolves, as reflected by a rise in the level of HBV surface antibodies.36,37 Serum HDV RNA is detected early but
is transient during HBV and HDV coinfection.
This patient’s blood tests were positive for HDV
RNA viremia, confirming the diagnosis of acute
HDV infection. Taken together, these results are
diagnostic of acute HBV and HDV coinfection.
Discussion of M a nagemen t
a nd Fol l ow-up
Dr. Arthur Y. Kim: Daily measurements of the alanine aminotransferase level and prothrombin
time revealed a steady decline. In immunocompetent adults, acute HBV infection typically
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n e w e ng l a n d j o u r na l
solves spontaneously, and antiviral treatment is
usually not given during this stage.38 However,
because this patient had ongoing symptoms and
a markedly elevated HBV viremia and there were
concerns regarding the rapid progression of liver
disease due to multiple viral infections, therapy
with tenofovir disoproxil fumarate was initiated
on hospital day 4. The bilirubin level peaked at
24.6 mg per deciliter (421 μmol per liter) on
hospital day 6; the patient felt better and was
discharged. One month after presentation, the
alanine aminotransferase level had normalized.
Six months after discharge, the patient continued to receive tenofovir, and the HBV DNA level
had declined to 462 IU per milliliter. The HCV
RNA viral load rebounded to 76,200 IU per milliliter. The patient therefore had triple infection
with HBV, HCV, and HDV.
Currently in the United States, particularly in
the northeast region, there is a “syndemic” (synergistic epidemic) of opioid use and associated
infectious diseases, with each overlapping epidemic further exacerbating the prognosis and
burden of disease.39 Unstable housing is an additional factor, as observed in this case. HCV infection is common in persons who inject drugs,
whereas HBV infection is more rare. Exposure to
HDV in persons with chronic HBV infection is an
increasing concern,30,31 and as mentioned previously, the prevalence of HDV is particularly high
among persons with HBV infection who inject
drugs.31 Moreover, the rates of bacterial infections,
HAV infection, and human immunodeficiency
virus type 1 infection have been rising in this
population.34,40 Responses to such a syndemic are
multipronged and include addressing social factors such as homelessness, preventing certain
infectious diseases (e.g., HAV and HBV) by means
of vaccination, and enhancing access to opioidagonist therapy and syringe-services programs.
1. Hernaez R, Solà E, Moreau R, Ginès P.
Acute-on-chronic liver failure: an update.
Gut 2017;​66:​541-53.
2. Westbrook RH, Dusheiko G. Natural
history of hepatitis C. J Hepatol 2014;​61:​
3. Udell JA, Wang CS, Tinmouth J, et al.
Does this patient with liver disease have
cirrhosis? JAMA 2012;​307:​832-42.
4. Breu AC, Patwardhan VR, Nayor J, et al.
A multicenter study into causes of severe
m e dic i n e
Although the interactions of all three viruses
in this patient are complex, treatment should be
considered for all three, because each chronic
infection contributes to the risk of future complications, such as cirrhosis and hepatocellular
carcinoma. HCV is considered to be curable with
safe and effective combination antiviral therapies that are typically administered for 8 or 12
weeks. Trials of such agents in patients with a
recent history of intravenous drug use have
shown excellent cure rates and relatively low reinfection rates.41,42
HDV is a defective virus that depends on the
presence of HBV. The patient’s antiviral therapy
directed against HBV should therefore be continued, but it is unlikely to resolve the HDV. Available therapies for HDV are based on interferonalfa but are associated with substantial side
effects and have had varied results. New experimental agents, such as prenylation inhibitors
and entry inhibitors, show promise but are not
yet approved for use.43
Ten months after presentation, the patient’s
housing had stabilized, he was no longer using
injection drugs, and he was employed. He continued to be adherent to the tenofovir and buprenorphine–naloxone regimens. He had yet to
be treated specifically for either HCV or HDV
Fina l Di agnosis
Acute hepatitis B virus and hepatitis delta virus
coinfection in the presence of chronic hepatitis
C virus infection.
This case was presented at the Medical Case Conference.
Dr. Kim reports receiving consulting fees from BioMarin. No
other potential conflict of interest relevant to this article was
Disclosure forms provided by the authors are available with
the full text of this article at
acute liver injury. Clin Gastroenterol
Hepatol 2018 August 10 (Epub ahead of
5. Tapper EB, Sengupta N, Bonder A.
The incidence and outcomes of ischemic
hepatitis: a systematic review with metaanalysis. Am J Med 2015;​128:​1314-21.
6. Lightsey JM, Rockey DC. Current concepts in ischemic hepatitis. Curr Opin
Gastroenterol 2017;​33:​158-63.
7. Bangaru S, Thiele D, Sreenarasim-
n engl j med 380;20
haiah J, Agrawal D. Severe elevation of
liver tests in choledocholithiasis: an uncommon occurrence with important clinical implications. J Clin Gastroenterol
8. Hadem J, Tacke F, Bruns T, et al. Etiologies and outcomes of acute liver failure
in Germany. Clin Gastroenterol Hepatol
9. Chalasani N, Bonkovsky HL, Fontana
R, et al. Features and outcomes of 899 pa-
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Case Records of the Massachuset ts Gener al Hospital
tients with drug-induced liver injury: the
DILIN prospective study. Gastroenterology 2015;​148(7):​1340-1352.e7.
10. Peyrière H, Tatem L, Bories C,
Pageaux GP, Blayac JP, Larrey D. Hepatitis
after intravenous injection of sublingual
buprenorphine in acute hepatitis C carriers: report of two cases of disappearance
of viral replication after acute hepatitis.
Ann Pharmacother 2009;​43:​973-7.
11. Viral hepatitis:​2016 surveillance. Atlanta:​Centers for Disease Control and
Prevention, 2016 (https://www​.cdc​.gov/​
12. Sharma SA, Feld JJ. Acute hepatitis C:
management in the rapidly evolving world
of HCV. Curr Gastroenterol Rep 2014;​16:​
13. Santantonio T, Sinisi E, Guastadi­
segni A, et al. Natural course of acute
hepatitis C: a long-term prospective study.
Dig Liver Dis 2003;​35:​104-13.
14. Loomba R, Rivera MM, McBurney R,
et al. The natural history of acute hepatitis C: clinical presentation, laboratory findings and treatment outcomes. Aliment
Pharmacol Ther 2011;​33:​559-65.
15. Grebely J, Page K, Sacks-Davis R, et al.
The effects of female sex, viral genotype,
and IL28B genotype on spontaneous clearance of acute hepatitis C virus infection.
Hepatology 2014;​59:​109-20.
16. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C
treatment-induced viral clearance. Nature
17. Suppiah V, Moldovan M, Ahlenstiel G,
et al. IL28B is associated with response to
chronic hepatitis C interferon-alpha and
ribavirin therapy. Nat Genet 2009;​
18. Tanaka Y, Nishida N, Sugiyama M, et al.
Genome-wide association of IL28B with
response to pegylated interferon-alpha
and ribavirin therapy for chronic hepatitis
C. Nat Genet 2009;​41:​1105-9.
19. Page K, Mirzazadeh A, Rice TM, et al.
Interferon lambda 4 genotype is associated with jaundice and elevated aminotransferase levels during acute hepatitis C
virus infection: findings from the InC3
Collaborative. Open Forum Infect Dis 2016;​
20. Thomas DL, Thio CL, Martin MP, et al.
Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature
21. Tillmann HL, Thompson AJ, Patel K,
et al. A polymorphism near IL28B is associated with spontaneous clearance of
acute hepatitis C virus and jaundice. Gastroenterology 2010;​139(5):​1586-92, 1592.e1.
22. Trépo C, Chan HL, Lok A. Hepatitis B
virus infection. Lancet 2014;​384:​2053-63.
23. Du X, Liu Y, Ma L, et al. Virological
and serological features of acute hepatitis
B in adults. Medicine (Baltimore) 2017;​
24. Kunnathuparambil SG, Vinayakumar
KR, Varma MR, Thomas R, Narayanan P,
Sreesh S. Bilirubin, aspartate aminotransferase and platelet count score: a novel
score for differentiating patients with
chronic hepatitis B with acute flare from
acute hepatitis B. Ann Gastroenterol 2014;​
25. Sagnelli E, Coppola N, Pisaturo M, et al.
HBV superinfection in HCV chronic carriers: a disease that is frequently severe but
associated with the eradication of HCV.
Hepatology 2009;​49:​1090-7.
26. Shin EC, Sung PS, Park SH. Immune
responses and immunopathology in acute
and chronic viral hepatitis. Nat Rev Immunol 2016;​16:​509-23.
27. Coffin CS, Mulrooney-Cousins PM,
Lee SS, Michalak TI, Swain MG. Profound
suppression of chronic hepatitis C following superinfection with hepatitis B virus.
Liver Int 2007;​27:​722-6.
28. Genesca J, Jardi R, Buti M, et al. Hepatitis B virus replication in acute hepatitis
B, acute hepatitis B virus-hepatitis delta
virus coinfection and acute hepatitis delta
superinfection. Hepatology 1987;​7:​569-72.
29. Njei B, Do A, Lim JK. Prevalence of
hepatitis delta infection in the United
States: National Health and Nutrition Examination Survey, 1999-2012. Hepatology
30. Patel EU, Thio CL, Boon D, Thomas
DL, Tobian AAR. Prevalence of hepatitis B
and hepatitis D virus infections in the
United States, 2011-2016. Clin Infect Dis
2019 January 3 (Epub ahead of print).
31. Mahale P, Aka PV, Chen X, et al. Hepatitis D viremia among injection drug users in San Francisco. J Infect Dis 2018;​217:​
n engl j med 380;20
32. Shin EC, Jeong SH. Natural history,
clinical manifestations, and pathogenesis
of hepatitis A. Cold Spring Harb Perspect
Med 2018;​8(9):​a031708.
33. Foster M, Ramachandran S, Myatt K,
et al. Hepatitis A virus outbreaks associated with drug use and homelessness —
California, Kentucky, Michigan, and Utah,
2017. MMWR Morb Mortal Wkly Rep 2018;​
34. Current hepatitis A outbreak. Boston:​
Public Health Commission, Massachusetts
Department of Public Health, 2019 (https://
35. Fyfe B, Zaldana F, Liu C. The pathology of acute liver failure. Clin Liver Dis
36. Hughes SA, Wedemeyer H, Harrison
PM. Hepatitis delta virus. Lancet 2011;​
37. Olivero A, Smedile A. Hepatitis delta
virus diagnosis. Semin Liver Dis 2012;​32:​
38. Kumar M, Satapathy S, Monga R, et al.
A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology
39. Valdiserri R, Khalsa J, Dan C, et al.
Confronting the emerging epidemic of
HCV infection among young injection
drug users. Am J Public Health 2014;​104:​
40. Cranston K, Alpren C, John B, et al.
Notes from the field: HIV diagnoses
among persons who inject drugs —
Northeastern Massachusetts, 2015-2018.
MMWR Morb Mortal Wkly Rep 2019;​68:​
41. Dore GJ, Altice F, Litwin AH, et al.
Elbasvir-grazoprevir to treat hepatitis C
virus infection in persons receiving opioid
agonist therapy: a randomized trial. Ann
Intern Med 2016;​165:​625-34.
42. Grebely J, Feld JJ, Wyles D, et al. Sofosbuvir-based direct-acting antiviral therapies for HCV in people receiving opioid
substitution therapy: an analysis of phase
3 studies. Open Forum Infect Dis 2018;​
43. Koh C, Heller T, Glenn JS. Pathogenesis of and new therapies for hepatitis D.
Gastroenterology 2019;​156(2):​461-476.e1.
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