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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2948_Библиотеки_им_академика_М_И_Перельмана
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395© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_93
Chapter 93
Differentiating Acute HBV fromanAcute
Exacerbation ofChronic HBV
JamesEsteban
A patient presents with fever and elevated transaminases—ALT of 350, AST of 260,
and total bilirubin of 5mg/dL.He has no past history of hepatitis but did use intra-
venous heroin several times, about 10years ago. One month before the presenta-
tion, he got a tattoo in a parlor. Labs show a positive hepatitis B surface antigen
(HBsAg), positive hepatitis B core antibody (anti-HBc) IgM and total, and elevated
HBV DNA of greater than 20million IU/mL.
Are you able to say if this is a case of acute hepatitis B infection or an exac-
erbation of chronic hepatitis B infection?
Chronic hepatitis B is dened as the persistence of HBsAg or positive HBV
DNA for at least 6months [1, 2]. Without prior HBV serologic testing, we have not
established HBV chronicity for this patient. I would make sure to look for signs of
liver disease chronicity and portal hypertension on the physical exam and abdomi-
nal ultrasound.
The presence of anti-HBc IgM is a strong indicator of acute hepatitis B infection,
but some patients with chronic hepatitis B who are experiencing an acute are-up or
exacerbation may also be anti-HBc IgM-positive.
Would you start antiviral therapy?
First, I would examine him for hepatic encephalopathy, obtain hepatitis B enve-
lope antigen (HBeAg), and antibody (anti-HBe), check his international normalized
ratio (INR), and obtain abdominal ultrasound to determine if he has cirrhosis and
portal hypertension.
J. Esteban (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jesteban@mcw.edu
https://t.me/medicina_free
396
If he has acute liver failure, dened as severe liver injury with hepatic synthetic
dysfunction (coagulopathy, INR>1.5), and hepatic encephalopathy within 26weeks
of disease onset, in a person without a history of cirrhosis, I will start antiviral
therapy in addition to getting him evaluated for liver transplantation.
If he does not have acute liver failure, I would follow him up closely and obtain
liver chemistries and INR frequently (every 1–2weeks for 1–2months). If he has
persistent hyperbilirubinemia (total bilirubin > 3 mg/dL) or coagulopathy
(INR>1.5), which indicate severe disease, for greater than 4weeks, then I will start
antiviral therapy because he has a protracted course of severe acute HBV infection.
The preferred antiviral therapies are the nucleos(t)ide analogs entecavir, tenofo-
vir disoproxil fumarate, and tenofovir alafenamide. Interferon is contraindicated in
acute hepatitis B infection due to risk of exacerbating liver inammation.
If he has neither of these, then close monitoring and expectant management are
appropriate. More than 95% of immunocompetent patients with acute hepatitis B
infection will recover spontaneously and lose HBsAg over time. In a large clinical
trial of patients with severe acute hepatitis B infection, lamivudine was no better
than placebo in terms of biochemical improvement and rates of HBsAg loss (both
~93% at 12months) [3].
He is HBeAg-positive and anti-HBe-negative. His INR is 1.3. On exam, he was
alert and oriented. He did not have spider angiomas, abdominal distention, uid
wave, or asterixis. Abdominal ultrasound shows a normal-appearing liver, without
splenomegaly or ascites. You decided that he does not require immediate initiation
of antiviral therapy. You monitor his liver chemistries and INR weekly. In week 4, his
liver chemistries showed the following: ALT of 120, AST of 100, total bilirubin of
1.8mg/dL, and INR of 1.2.
How would you follow him up?
I would continue following his liver chemistries, and I will, in addition, be fol-
lowing his HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV DNA periodically
because we need to know if he will “clear” the HBV infection or if he will go on to
develop chronic hepatitis B infection. I will obtain hepatitis B serologies at 3 and/or
6months. If he remains HBsAg positive at 6months or more, then we have estab-
lished that he has chronic hepatitis B infection. Management of chronic hepatitis B
is discussed in other chapters in the book.
References
1. Terrault N, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, etal. Update on pre-
vention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
Hepatology. 2018;67(4):1560–99.
2. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the
management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98.
3. Kumar M, Satapathy S, Monga R, Das K, Hissar S, Pande C, etal. A randomized controlled
trial of lamivudine to treat acute hepatitis B.Hepatology. 2007;45(1):97–101.
J. Esteban
https://t.me/medicina_free
397© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_94
Chapter 94
Acute HBV andRisk ofHBV Reactivation
JamesEsteban
A 25-year-old male gets acute hepatitis B from a sexual encounter. He completely
clears the infection spontaneously, without treatment.
Is there a need for extended follow-up of any kind?
Clearance of hepatitis B surface antigen (HBsAg) and formation of hepatitis B
surface antibody (HBsAb) denes functional cure. Loss of HBsAg is associated
with durable suppression of viral replication. Thus, he will not require extended
follow-up [1].
What if, 25years from now, he needs to receive rituximab-based regimen for
lymphoma, will he need special precautions?
After entry into the hepatocyte, hepatitis B virus (HBV) translocates into the
nucleus, where the double-stranded HBV DNA (dsDNA) is repaired into an
extremely stable covalently closed circular DNA (cccDNA). cccDNA persists in
hepatocytes long after loss of HBsAg. HBV dsDNA may also integrate with the
human genome as HBV integrated or iDNA.The persistence of cccDNA and iDNA
in hepatocytes, despite complete suppression of HBV replication and even loss of
HBsAg, is the reason why true virologic cure is not achievable in hepatitis B infec-
tion with current medical therapies.
Immunosuppressive therapy may release immunologic control over HBV, lead-
ing to resumption of transcription of HBV cccDNA and/or iDNA. This leads to
reappearance of HBsAg and HBV DNA in serum and hepatitis ares in some cases.
This is called HBV reactivation. Risk of HBV reactivation varies by intensity of
immunosuppression. B-cell depleting agents such as rituximab, or prolonged use of
J. Esteban (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jesteban@mcw.edu
https://t.me/medicina_free
398
Table 94.1 Risk of HBV reactivation according to immunosuppressive agent and HBsAg status
HBsAg+/
HBcAb+
HBsAg−/
HBcAb+
B-cell depleting therapy (e.g., rituximab, belimumab,
alemtuzumab, etc.)
High High
High-dose steroids (pred >20mg/day×>4weeks) High Moderate
Med-dose steroids (pred 10–20mg/day×>4weeks) Moderate Low
Low-dose steroids (pred <10mg/day), intra-articular steroids Low Low
Anthracycline-based systemic chemotherapy High Moderate
Non-anthracycline systemic chemotherapy Moderate Moderate
Immune checkpoint inhibitors (e.g., pembrolizumab,
nivolumab, ipilimumab)
High Moderate
Anti-TNF agents (e.g., iniximab, adalimumab,
certolizumab, golimumab)
High Moderate
Cytokine therapies (e.g., ustekinumab, abatacept,
natalizumab, vedolizumab)
Moderate Moderate
TK inhibitors (e.g., imatinib, nilotinib) Moderate Moderate
Proteosome inhibitors (e.g., bortezomib) Moderate Moderate
Histone deacetylase inhibitors (e.g., romidepsin) Moderate Moderate
Calcineurin inhibitors (e.g., tacrolimus, cyclosporine) Moderate Moderate
Antimetabolites (e.g., 6-MP, azathioprine, methotrexate,
mycophenolate)
Low Low
High risk, >10% risk of HBV reactivation; Moderate risk, 1–10% risk of HBV reactivation; Low
risk, <1% risk of HBV reactivation
high-dose corticosteroids, are associated with the highest risk of HBV reactivation
(>10%). Patients with a history of hepatitis B infection, i.e., HBsAg and hepatitis B
core antibody (HBcAb) positive, who will be receiving high-risk immunosuppres-
sive agents (Table 94.1), should be provided with antiviral prophylaxis with
nucleos(t)ide analogs such an entecavir, tenofovir disoproxil fumarate, or tenofovir
alafenamide to prevent HBV reactivation [2, 3].
Some immunosuppressive agents, such as tumor necrosis factor inhibitors or
cytokine inhibitors, have a lower, but not negligible, risk of HBV reactivation. Some
patients who will be receiving these agents may be offered on-demand therapy
(Fig.94.1), where we periodically check (typically every 3months) HBV DNA,
transaminases, and HBsAg for HBV reactivation or a hepatitis are (i.e., ALT >3×
upper limit of normal). Patients would then be promptly treated with nucleos(t)ide
analogs upon diagnosis of HBV reactivation.
In patients who are HBsAg positive, reactivation may be dened as:
• 100× increase in HBV DNA
• HBV DNA 1000IU/mL if previously undetectable
• HBV DNA 10,000IU/mL if previous level unknown
In patients who are HBsAg negative and HBcAb positive, reactivation may be
dened as:
• Any detectable HBV DNA
• Reverse seroconversion to HBsAg positive
J. Esteban
https://t.me/medicina_free
399
Fig. 94.1 Algorithm for prevention and management of HBV reactivation in patients receiving
immunosuppressive therapy
References
1. Terrault N, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, etal. Update on pre-
vention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
Hepatology. 2018;67(4):1560–99.
2. Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck-Ytter Y, AGA Institute. American
Gastroenterological Association Institute guideline on the prevention and treatment of
hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology.
2015;1480:215–9.
3. Loomba R, Liang TJ.Hepatitis B reactivation associated with immune suppressive and bio-
logical modier therapies: current concepts, management strategies, and future directions.
Gastroenterology. 2017;152(6):1297–309.
94 Acute HBV andRisk ofHBV Reactivation
https://t.me/medicina_free
401© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_95
Chapter 95
Complicated HCV
KiaSaeian
Patient is a 35-year-old female with a history of IV drug abuse from age 18–25 who
comes in with jaundice and weakness. She is overweight with a BMI of 33 and has
no history of signicant alcohol use. On exam, she has no stigmata of chronic liver
disease. Her liver enzymes are as follows: ALT of 240, AST of 150, bilirubin of 3.2,
and Alk phos of 120. Her US shows marked steatosis of the liver. Hepatitis panel is
positive for HCV ab, and her HCV PCR is (+) 1.2 million. ANA returns positive
at 1:640.
What is your impression, and how would you manage this patient?
One of the rst things I would like to do is check the gamma globulin level to
corroborate the positive ANA and substantiate the impression of AIH.I would con-
sider doing a liver biopsy. There would be two reasons to consider a liver biopsy.
First, would be to conrm a diagnosis of AIH, assuming her IgG level comes back
elevated. Personally, I like to have a biopsy conrmation of AIH before initiating
therapy, although not everyone agrees.
The second would be to evaluate for brosis from HCV.Since her HCV exposure
was probably over 10years ago, there is a good chance she could have brosis from
the chronic HCV.Most of the time with HCV we don’t need a liver biopsy, we sim-
ply treat the HCV, but in this case, we might.
An interesting question in this case is whether the patient has two distinct disor-
ders—both HCV and AIH (as well as potentially NAFLD). This question comes up
because some patients with HCV may have a positive ANA and features of autoim-
mune disease without having AIH.The distinction used to be much more of a quan-
dary when we used interferon to treat HCV, because interferon would dramatically
exacerbate AIH.
K. Saeian (*)
Division Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: ksaeian@mcw.edu
https://t.me/medicina_free
402
Now in this case, even if the patient has AIH, I don’t think it is urgent that we
start corticosteroids immediately, seeing how there is only a moderate level of trans-
aminase elevation. You can argue to hold off on biopsy, treat the HCV rst, and see
what happens with the autoimmune ndings.
The other interesting question about this case is the interplay between HCV and
NAFLD.I would check the HCV genotype, and if it is genotype 3, it might also
explain the degree of fat in the liver. Her BMI alone is probably adequate to explain
it, but genotype 3 has been associated with more signicant steatosis.
You talk about brosis, if you weren’t going directly to biopsy, would you do
a FibroScan
®
?
I do use the FibroScan
®
, although I do not use it as liberally as some. But the fact
is that it’s available and it’s pretty easy to do. Now I perform a signicant proportion
of the liver biopsies done in our institution, and I have a healthy appreciation for the
potential complications associated with liver biopsy. Therefore, I don’t rush into
doing liver biopsies as quickly as some others do. So, if the only reason for doing a
liver biopsy is to establish the diagnosis of brosis, I would try FibroScan
®
rst.
However, there are confounding issues, like obesity, that can make FibroScan
®
less reliable. In the aforementioned patient, because she has a BMI of 33, FibroScan
®
would be of limited benet. But if I have a case of chronic HCV (uncomplicated by
autoimmune features), where the patient is not obese and doesn’t have other con-
founding factors, I have a very low threshold to spend the few minutes doing the
FibroScan
®
. Then, if I don’t see any indication of brosis, I can treat their hepatitis
C and not need to arrange for follow-up, because I’m comfortable that brosis is
absent, and surveillance for HCC unnecessary.
What about the utility of FibroScan
®
in congestive heart failure? What if
you have a patient with congestive heart failure and elevated liver enzymes,
will you get a FibroScan
®
in that setting?
I would absolutely not use it in that setting because you’re likely to get a false
reading. If you look at the concept of elastography, it’s based on elasticity of the
tissue, and if you have elevated back pressures from CHF, pulmonary hypertension,
or hepatic vein obstruction, you lose that elasticity. Whether or not brosis is pres-
ent, the FibroScan
®
will imply advanced brosis.
K. Saeian
https://t.me/medicina_free
403© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_96
Chapter 96
Acute Liver Failure
KiaSaeian
A patient presents with acute liver failure. A 27-year-old female college student,
who had complained to her roommate that she felt weak and nauseated for several
days, is now found lying in bed in her dorm room, extremely lethargic. The room-
mate calls her parents who urge her to call an ambulance. She is sent to the ER.On
the physical exam, she is responsive but keeps drifting off to sleep. Her BP is 90/70,
pulse is 90, and temperature is 99. She has no signs of portal hypertension on exam.
Liver and spleen are not palpable.
WBC, 12,000; Hbg 11.5; platelets, 180,000; AST, 1700; ALT, 2200; ALK phos,
140; Bili, 8; INR, 2.5
How would you address this problem?
This pattern of enzymes is suggestive of zone three necrosis, and a common
cause of this is acetaminophen overdose, even though there isn’t a history of her
taking that. The other things you would think about in a young woman like this (not
necessarily involving zone 3 necrosis) are acute presentations of autoimmune hepa-
titis, other drug induced injuries, or an unknown viral infection. Those are the most
likely explanations for her presentation.
The fact that she is already presenting with synthetic dysfunction and encepha-
lopathy qualies her as having acute liver failure, so she absolutely must be at a
transplant center. Even if you think she has autoimmune hepatitis and you’re going
to treat her, you absolutely need to be prepared for the possibility of transplantation,
and that needs to be done pronto because these patients can deteriorate very rapidly.
K. Saeian (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: ksaeian@mcw.edu
https://t.me/medicina_free
404
Now, we’ve had some patients present like this who turned out to have autoim-
mune hepatitis who we’ve been able to treat and have them recover without trans-
plant. But once they’ve developed encephalopathy, it’s more unlikely that they will
turn around and improve quickly enough to avoid listing them.
We have a specic liver failure protocol in which we screen for the routine viral
hepatidites—HAV, HBV, HCV.We also include lab tests looking for alternative
viruses like CMV, EBV, and hepatitis E.In addition, we would certainly do toxicol-
ogy screens and check the autoimmune markers.
We also monitor the AFP because it can be a marker of the ability of the liver to
regenerate. Factor V can also be a marker so we monitor that as well. If the patient
becomes acidotic, that is a poor prognostic factor and we get even more concerned.
So that’s our lab work.
In terms of the imaging studies, we get a CT scan of the head to make sure there
is no midline shift or cerebral edema, which would necessitate more aggressive
measures, including hypernatremia, hypothermia, and occasional osmotic diuresis
with mannitol, although we don’t use that or hyperventilation as frequently as we
used to.
We would consider initiating n-acetyl-cysteine (NAC) even in the absence of
known acetaminophen overdose. The evidence is less robust in ALF not related to
acetaminophen, but there is some decent data that it can help in that setting.
Directing our attention to the alkaline phosphatase, it is not elevated in propor-
tion to the transaminases in this patient. In cases of viral hepatitis and autoimmune
hepatitis, usually the alkaline phosphatase elevation is proportional to the transami-
nase elevation. But it is possible that the alk phos is on a slower upward course, it’s
still early on, and it could take longer for that alk phos to get transcribed.
The elevated bilirubin/alkaline phosphatase ratio raises the possibility of Wilson’s
disease. However, if this was Wilson’s, I would expect her Hbg to be lower, and the
alkaline phosphatase might be even lower than it is in this case. Regardless, if this
was acute Wilson’s, you’re probably headed for transplant.
However, in cases of zone 3 necrosis of the liver, the transaminases tend to be
proportionally higher than the alkaline phosphatase. Other things that could cause
zone 3 injury include hypotension and heat stroke. Heat stroke can sometimes fool
you, although in this case, the AST being lower than the ALT makes that less likely.
Would you start steroids in this patient with acute liver failure?
We are reluctant to start steroids. Our transplant surgeons prefer to avoid steroids
in a patient headed for transplant. We would certainly wait for our autoimmune
markers to come back. But even if the ANA came back elevated, I would want to see
an elevated IgG as well, because we do see elevated ANA in a number of cases that
are not autoimmune liver disease. And even with an elevated ANA and IgG, I would
prefer to have a liver biopsy before starting steroids for AIH.
Now if this patient was somewhat more stable, not encephalopathic, and time
was more on our side, I would consider doing a liver biopsy. We have done tran-
sjugular liver biopsies in some patients with an INR in this range. If a biopsy con-
rmed the diagnosis of AIH, I would be much more inclined to start steroids.
K. Saeian
https://t.me/medicina_free
405© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_97
Chapter 97
Delayed Presentation ofTylenol Overdose
KiaSaeian
A patient with a history of taking a large dose of Tylenol 5days earlier is brought
into the hospital now. She is lethargic on presentation, ALT is 3000, AST is 2400,
INR is 2.5, bilirubin is 2.2, and Alk phos is 140.
Is there any role for NAC at this late point?
I think almost everyone would give it, even 5days after the overdose. The ques-
tion of whether it will benet the patient is a valid one, because we don’t have many
studies on initiating NAC in this subset of patients who are presenting this late in the
clinical course. One thing about this case is that it’s unusual for the numbers to be
this high on day ve. The numbers tend to peak on day three, so it is possible that
the transaminases might have been higher, say even 10,000, and are now trending
down. The patient may be recovering from the injury, but the fact that the numbers
decrease is not necessarily a good sign. It could be a sign of fulminant hepatic
necrosis.
The traditional teaching now is that you give NAC until the transaminases drop
below 1000. I would treat her as someone we might possibly be able to salvage, so
in this patient, even though it may be too late, we would start NAC and continue
until the numbers dropped to at least below 1000. The one reassuring thing in this
case is that the bilirubin is not extremely high. Treatment with NAC is generally
very safe, but some patients do develop nausea and vomiting, particularly with the
oral formulation.
K. Saeian (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: ksaeian@mcw.edu
https://t.me/medicina_free
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