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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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371© 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_87
Chapter 87
Autoimmune Hepatitis
JamesEsteban
The patient is a 28-year-old female with a history of hypothyroidism due to
Hashimoto’s disease, who presents with weakness and anorexia for 4weeks. She
has one or two cocktails per weekend. Her only medication is levothyroxine. Her
physical exam is fairly unremarkable with a BMI of 20. She has ALT of 420U/L,
AST of 300U/L, Alk phos of 70U/L, and a total bilirubin of 1.2mg/dL.Her viral
hepatitis panel is negative. She has elevated IgG at 2200mg/dL, elevated titers of
ANA 1:640, and anti-smooth muscle antibody of 1:160. Anti-mitochondrial anti-
body is negative.
This case seems fairly clear-cut, in terms of the strongly positive autoim-
mune markers. What is your approach to the patient with suspected autoim-
mune hepatitis (AIH)?
Even though the patient has classic liver biochemistries (hepatocellular) and
autoantibodies, I will still obtain a liver biopsy. The liver biopsy is necessary to
establish the diagnosis, evaluate concurrent liver disease (for example, NASH or
alcohol), and dene a baseline for future comparisons if the patient does not respond
to corticosteroids and rst-line immunomodulator therapy.
This patient’s liver biopsy shows interface hepatitis with a dense inltrate of
plasma cells. She has minimal hepatic steatosis and hepatic brosis (stage 1). You
start the patient on prednisone 60mg a day, and the patient’s liver enzymes start
improving immediately, but the patient also complains of mood swings and insomnia.
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
372
How would you manage this adverse side effect?
I would see how she does on a slightly lower dose of prednisone, perhaps 40mg
a day. I will do labs weekly and try to taper her prednisone dose further as soon as
her transaminases improve. I start azathioprine once I have prednisone down to
20–30mg a day, and this may help speed up the prednisone taper.
Another option is budesonide. A 9mg dose of budesonide is 30–40mg of pred-
nisone, but due to 90% rst-pass metabolism in the liver, budesonide is considered
a “topical” steroid and has much fewer steroid-related side effects than prednisone.
Budesonide is at least as effective (possibly more effective based on trials) than
prednisone in inducing and maintaining biochemical remission in non-cirrhotic
patients with AIH [1].
The patient is started on budesonide 9mg a day, and the steroid side effects
cease. Her liver enzymes continue improving.
Would you add azathioprine at this point? If so, what dose do you give? Do
you bother to check the TPMT status?
Once I verify a positive response to corticosteroids, I add on azathioprine (or
6-mercaptopurine, 6-MP). Since azathioprine can cause drug-induced liver injury
(either related to 6-MMP metabolites or as an idiosyncratic reaction), I prefer to
start azathioprine only when transaminases are normal to prevent diagnostic
confusion.
I start azathioprine at 50 mg a day. I send off a thiopurine methyltransferase
(TPMT) activity to identify that rare patient who will have zero or near-zero TPMT
activity who will suffer from severe myelosuppression with azathioprine. Because
this test takes time to result, I send it out as soon as AIH is diagnosed. The AASLD
recommends sending TPMT activity [2].
The intent is for azathioprine (or 6-MP) to be the long-term, steroid-sparing
maintenance regimen for AIH. For this reason, I continue to taper prednisone
down to a dose of prednisone 5mg. I try to discontinue prednisone altogether to
keep patients on azathioprine (or 6-MP) monotherapy for maintenance, and I have
reasonable success. Azathioprine at a dose of 50mg is often sufcient, but I have
gone up to 75–150mg of azathioprine if patients experience small are-ups in
their transaminases. In some cases, the only way to keep patients in remission is
through combination therapy of azathioprine and low-dose prednisone,
5–10mg daily.
The patient’s TPMT phenotype returns normal, and you start azathioprine 50mg
a day. However, 2weeks later the patient develops severe pain, goes to the ER, and
is found to have acute pancreatitis. Azathioprine is stopped.
Do you have any experience using mycophenolate or tacrolimus in this
situation?
Mycophenolate mofetil (MMF) and mycophenolic acid (MPA) are my second-
line agents for patients who do not tolerate or do not respond to azathioprine.
Mycophenolate is particularly effective if the reason for withdrawing azathioprine
was intolerance, rather than treatment nonresponse. However, mycophenolate is a
category X drug in pregnancy, thus at our patient’s age, she needs to use at least two
forms of effective contraception.
J. Esteban
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373
Calcineurin inhibitors (CNI), like tacrolimus and cyclosporine, and biologics are
also second-line agents for patients who are refractory to or intolerant of azathio-
prine or steroids. I almost never have had to use these agents in my non-transplant
AIH patients, but there are studies showing CNIs as effective agents in normalizing
transaminases.
Working in the community, we do not have much experience with mycophe-
nolate. What is the dose you use, and what are the side effects?
You can use a bottom-up approach, starting at 500mg BID of MMF (or 360mg
BID of MPA), and then gradually make your way up to 1000mg BID of MMF (or
720mg BID of MPA) based on the patient’s response. You can also use a top-down
approach, especially if the patient has higher transaminase levels, where you start at
1000mg BID of MMF until you’re able to induce and maintain biochemical remis-
sion, and then gradually make your way down to the minimum effective dose. The
most common side effects of MMF are GI upset (e.g., nausea, vomiting, abdominal
pain, diarrhea) and cytopenias.
The patient says she hopes to get pregnant in the next year or two. What
options do you have?
If she hopes to get pregnant, my options are to either keep her on steroid mono-
therapy, since she responded to that, or use CNIs such as tacrolimus or cyclosporine
instead of mycophenolate. Both are pregnancy category C. Azathioprine is category
D but may be continued during pregnancy to prevent a are-up.
For tacrolimus, a good starting dose is 0.1mg/kg/day divided into two doses,
which roughly translates to 2–3mg BID [3]. For cyclosporine, a good starting dose
is 2–3mg/kg/day, which roughly translates to 100–150mg BID [4]. Both tacroli-
mus and cyclosporine require drug-level monitoring to ensure efcacy and prevent
toxicities. Drug-level monitoring requires blood testing at the same time of day,
typically in the morning before taking the rst dose of the day. Patients would likely
need higher drug levels to induce remission (tacrolimus 6–8ng/dL, cyclosporine
100–150ng/dL), which could be lowered after a few months to a year of remission
for maintenance (tacrolimus 4–6ng/dL, cyclosporine 100–150ng/dL).
The main side effects of CNIs are nephrotoxicity, neurotoxicity, and metabolic
dysfunction, such as diabetes, hyperlipidemia, hypertension, and weight gain.
There are patients with AIH who have cirrhosis on their initial liver biopsy,
occurring in about 30% of cases. Is this fairly uncommon in young patients
presenting with AIH?
It is. Cirrhosis as the presenting phenotype of AIH is usually seen in older
patients and African-Americans.
Is it true that if you have full-blown cirrhosis, you may already have burned
out AIH and you may choose not to treat it?
Some patients with AIH and cirrhosis will have normal to mildly elevated trans-
aminases and minimal inammation on biopsy and would be labeled as “burned
out” AIH.I think it would be reasonable to withhold immunosuppressive treatment
for these patients because any potential benet is not worth treatment-related side
effects. These patients should continue to have periodic assessment of liver
chemistries.
87 Autoimmune Hepatitis
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374
Some patients will have normal transaminases but will continue to have inam-
matory activity on biopsy. I would treat these patients with maintenance immuno-
suppression to prevent progression of brosis (and thus portal hypertension and
hepatic decompensation) and a severe, acute are-up of AIH.We avoid azathioprine
in patients with decompensated cirrhosis.
References
1. Manns M, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, et al. Budesonide
induces remission more effectively than prednisone in a controlled trial of patients with auto-
immune hepatitis. Gastroenterology. 2010;139(4):1198–206.
2. Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, etal. Diagnosis and manage-
ment of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from
the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671–722.
3. Hanouneh M, Ritchie MM, Ascha M, Ascha MS, Chedid A, Sanguankeo A, et al. A review
of the utility of tacrolimus in the management of adults with autoimmune hepatitis. Scand J
Gastroenterol. 2019;54(1):76–80.
4. Fernandes NF, Redeker AG, Vierling JM, Villamil FG, Fong TL. Cyclosporine therapy in
patients with steroid resistant autoimmune hepatitis. Am J Gastroenterol. 1999;94(1):241–8.
J. Esteban
https://t.me/medicina_free
375© 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_88
Chapter 88
Primary Sclerosing Cholangitis
JuanTrivella
A 38-year-old male is referred because of elevated liver enzymes. He has one or two
drinks a week, does not use any drugs, and is on no medications. He has mild itch-
ing, no belly pain, and no jaundice. He has an alkaline phosphatase of 240, GGT of
200, ALT of 60, AST of 45, bilirubin of 0.9, INR of 1.1, WBC of 4.3, Hgb of 11.8,
platelets of 180,000, and albumin of 3.5. Ultrasound of the liver shows normal-
appearing liver, normal gallbladder, and CBD of 8mm in diameter. Hepatitis panel
is negative, ANA is (+)1:16, ASMA is (−), and AMA is (−). An MRCP is performed
and this demonstrates ductal narrowing both intra- and extrahepatic.
What is your diagnosis and what other tests would you want?
The presence of cholestasis and intra- and extrahepatic ductal narrowing on
MRCP in a male patient who has no other previous history of biliary or liver pathol-
ogy suggests the diagnosis of PSC, but careful exclusion of secondary causes of
sclerosing cholangitis is required—especially in the absence of IBD.The negative
AMA and the presence of intra- and extrahepatic ductal beading makes PBC
unlikely. It is not uncommon to have a slight elevation of transaminases in PSC, like
in the case presented above. The diagnosis of overlap AIH-PSC should be consid-
ered only when the transaminases approach ve times the upper limit of normal or
when these are the predominant pattern of elevation. It would also be important to
order an IgG4 to exclude IgG4 sclerosing cholangitis as a potential diagnosis. A
baseline CA19-9 and a colonoscopy to evaluate for inammatory bowel disease
should also be obtained [1].
J. Trivella (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jtrivella@mcw.edu
https://t.me/medicina_free
376
What is the current role of colonoscopy in PSC, both IgG4 positive and
negative?
In patients with PSC without a known history of IBD, a diagnostic colonoscopy
with histologic sampling should be performed at the diagnosis of PSC and then
every 5years if IBD is not initially detected, or earlier if the patient develops gas-
trointestinal symptoms to suggest IBD.Colon cancer surveillance should begin at
age 15years in patients with PSC and IBD and should be repeated yearly, given
their higher risk for developing colorectal cancer.
Is that true for IgG4 sclerosing cholangitis?
No. Although there is paucity of data regarding the course of IgG4 sclerosing
cholangitis, given its rarity, no strong association with IBD and/or colorectal cancer
has been established. Therefore, surveillance colonoscopy is not currently recom-
mended for these patients.
What is the role of ursodeoxycholic acid in PSC?
The efcacy of UDCA in PSC has not been consistent, despite this being the
most studied drug for this particular disease. Low-dose UDCA (13–15mg/kg/day)
has shown an improvement in ALP (in those with baseline elevated ALP) but has
shown no benets on liver histology or transplant-free survival. High-dose UDCA
(28–30mg/kg/day) should be avoided in patients with PSC, given the high risk for
serious adverse events.
Intermediate-dose UDCA (17–23mg/kg/day) has shown both ALP and histo-
logical improvement in a proportion of patients with PSC, but research has failed to
demonstrate a statistically signicant reduction in the need for liver transplantation,
cholangiocarcinoma, or overall mortality. This is with the caveat that most of these
reports have been underpowered. Medical societies like the AASLD currently sup-
port trials of intermediate-dose UDCA in PSC patients with baseline elevated
ALP.This medication can be continued lifelong if the patient experiences improve-
ment of symptoms and/or a meaningful alkaline phosphatase reduction after
12months of treatment [1].
How do you do surveillance studies in PSC?
Cholangiocarcinoma and gallbladder carcinoma surveillance should be per-
formed annually and include MRI/MRCP and a CA19-9. Surveillance is currently
not recommended for patients with PSC who are younger than 18years of age or in
those with exclusively small duct PSC.
In this case, the patient remains stable for a couple of years, with a stable MRCP
and CA19-9, and then, without explanation, his alkaline phosphatase goes up to
350, and his bilirubin goes up to 3. Another MRCP is performed, and there’s a
dominant stricture in the common bile duct.
How would you manage this?
This patient was found to have a relevant stricture on MRI/MRCP and should
receive an ERCP. ERCP is indicated for the evaluation of relevant strictures as well
as for the evaluation of new onset or worsening of pruritus, unexplained weight loss,
worsening serum liver chemistry abnormalities, rising CA19-9, recurrent bacterial
cholangitis, or progressive ductal dilatation on MRI/MRCP surveillance.
J. Trivel la
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377
On ERCP brushings of the stricture are performed. Cytology returns suspicious
and FISH cytology is pending.
The rst step should be to wait for the FISH analysis to return. If negative, then
the patient should receive a repeat ERCP in 3months. If positive, this case should
be discussed with a multidisciplinary team that includes pancreaticobiliary and
transplant surgery. Depending on the location of the stricture (intrahepatic vs. hilar
vs. distal CBD), this patient may qualify for resection or liver transplantation.
Can you do a liver transplant in a PSC patient who has a
cholangiocarcinoma?
The management of cholangiocarcinoma in patients with PSC depends on sev-
eral factors. The size and the location of the primary tumor in the biliary tree is one
of them. Well-selected patients with PSC and perihilar early-stage cholangiocarci-
noma can be considered for liver transplantation and can even qualify for exception
points after a rigorous process that involves close monitoring for metastatic disease,
neoadjuvant chemoradiation, and pretransplant staging laparoscopy. This is com-
monly referred to as the “Mayo protocol” and has shown an overall survival of
around 65% and a recurrence-free survival close to 80% at 5years [2].
Early studies evaluating liver transplantation in patients with intrahepatic chol-
angiocarcinoma showed a posttransplant recurrence in up to 25% and an overall
survival of about 40% at 5years, making this approach undesirable for quite some
time. Most recently, retrospective data looking at liver explants of patients with PSC
and an incidentally found, small (<3cm), solitary intrahepatic cholangiocarcinoma
showed an overall survival of around 61% and a recurrence-free survival of 75% at
5years. This has prompted different centers around the country to develop prospec-
tive research protocols to reevaluate LT as a possibility for those with a single small
liver lesion. Results from these trials are eagerly awaited.
Distal cholangiocarcinomas are best treated with surgical resection when possi-
ble, removing the bile duct, gallbladder, head of the pancreas, and the rst portion
of the duodenum (pancreaticoduodenectomy). There is currently no role for liver
transplantation in patients with distal cholangiocarcinoma.
References
1. Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez
M, Sapisochin G, Shroff R, Tabibian JH, Assis DN.AASLD practice guidance on primary
sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2023;77(2):659–702. https://doi.
org/10.1002/hep.32771.
2. Rosen CB, Heimbach JK, Gores GJ.Surgery for cholangiocarcinoma: the role of liver trans-
plantation. HPB (Oxford). 2008;10(3):186–9. https://doi.org/10.1080/13651820801992542.
88 Primary Sclerosing Cholangitis
https://t.me/medicina_free
379© 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_89
Chapter 89
PBC-AIH Overlap
JuanTrivella
A 35-year-old female is referred for lethargy and elevated LFTs. Her alkaline phos-
phatase is 320, AST is 289, ALT is 391, and bilirubin is 1.2. He is in no ETOH or
meds. AMA +1:320, ANA +1:160, ASMA +1:80, IgG 2200.
What is your diagnosis, and do you want a liver biopsy?
The information provided suggests a diagnosis of PBC-AIH overlap syndrome.
Although there is no standardized denition, this clinical entity is commonly char-
acterized by clinical, histologic, and serologic features of both autoimmune hepati-
tis and PBC, ensuing either simultaneously or sequentially.
According to the Paris criteria, which has a sensitivity of 92% and specicity of
97% for the diagnosis of overlap syndrome, two out of three key features for the
diagnosis of PBC and AIH, respectively, should be met to establish the diagnosis.
One of these is the presence of interface hepatitis and/or the presence of orid bile
duct lesions on histology. A liver biopsy in the case presented is not only indicated
to establish the diagnosis of overlap syndrome but also to exclude other potential
explanations for her elevated liver chemistries and to stage the brosis status of her
liver [1].
Liver biopsy is performed and shows granulomas with bile duct inammation
and also mild interface hepatitis with lymphocytes and plasma cells.
Would you start the patient on ursodeoxycholic acid alone, steroids alone, or
a combination?
The therapeutic approach for overlap syndrome has not been completely dened
because its low prevalence prevents the performance of large randomized clinical
trials. Most agree that the treatment should be directed toward the predominant
J. Trivella (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jtrivella@mcw.edu
https://t.me/medicina_free
380
component, particularly when patients do not completely meet Paris criteria. The
rationale for this approach comes from the premise that rather than being two sepa-
rate disorders occurring in parallel, overlap syndrome appears to be the result of a
single disease with atypical features. In these circumstances, steroids or UDCA
induce biochemical response when selected toward the predominant phenotype. In
those who meet Paris criteria, combination therapy with immunosuppression and
UDCA has proven to be superior in achieving biochemical response than either of
them alone. Since this patient meets all Paris criteria, then combination therapy
would be more appropriate [2, 3].
What steroid would you use?
Both prednisone and prednisolone can be used for the management of overlap
syndrome in combination with UDCA.Steroids should be tapered slowly to about
10mg daily after 4weeks of treatment to decrease the risk of adverse events.
Would you add azathioprine as you attempt to taper steroids?
Yes, I would attempt this. Given the low prevalence of PBC-AIH overlap syn-
drome, guidelines for its long-term treatment lack robust evidence. Despite this,
azathioprine has successfully been used as the long-term immunosuppressive agent
of choice for those with AIH.It would be reasonable to extrapolate this information
to patients with overlap syndrome, especially when considering the adverse events
that are commonly associated with long-term steroid use.
References
1. Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M.Primary biliary cholangitis: 2018 prac-
tice guidance from the American Association for the Study of Liver Diseases. Hepatology.
2019;69(1):394–419.
2. Chazouilleres O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R.Primary
biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to
therapy. Hepatology. 1998;28:296–301.
3. Kuiper EM, Zondervan PE, van Buuren HR.Paris criteria are effective in diagnosis of primary
biliary cirrhosis and autoimmune hepatitis overlap syndrome. Clin Gastroenterol Hepatol.
2010;8:530–4.
J. Trivel la
https://t.me/medicina_free
381© 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_90
Chapter 90
Immune-Tolerant Chronic HBV
JamesEsteban
A 24-year-old male, born in the United States and whose parents emigrated from
Taiwan, is evaluated in the clinic for a hepatitis B infection. This was detected when
he went to donate blood at a blood drive. He has no history of intravenous drug use,
tattoos, or blood transfusions. He is in a monogamous sexual relationship with a
female spouse. He is asymptomatic and has normal transaminases. He is hepatitis
B surface antigen (HBsAg) positive with an HBV DNA of 10 million IU/mL.His
total hepatitis B core antibody (anti-HBc total) is positive, and the anti-HBc IgM is
negative. He is hepatitis B envelope antigen positive (HBeAg).
How would you describe the phase of the patient’s hepatitis B infection?
We rst have to establish the chronicity of hepatitis B infection. Chronic hepati-
tis B is the presence of hepatitis B surface antigen and HBV viremia for at least
6months. The absence of signicant hepatocellular liver injury and anti-HBc IgM
strongly suggests chronic hepatitis B.I would make sure to repeat HBV serologies,
HBV DNA, and liver enzymes in the next 3–6months to verify chronic hepatitis B.
After we have established chronic hepatitis B, we need to determine the phase of
HBV infection the patient is experiencing. In the immune-tolerant phase, there is
normal ALT, minimal to no hepatic inammation, and high HBV DNA viral load.
Immune-tolerant hepatitis B is commonly seen in perinatally or vertically acquired
infection, which is potentially the route of transmission for our patient. These
patients are typically HBeAg-positive.
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
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