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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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Primary care providers are more aware of the disease. In turn, patients with
chronic cholestasis are referred earlier to the hepatology clinic, and treatment is
started before decompensated cirrhosis has ensued. This is why clinical signs and
symptoms of portal hypertension are a rather uncommon presentation in patients
with PBC nowadays.
Now, we are most aware of PBC occurring in females. Are you seeing it in
males, are they being diagnosed later? Is the course more severe in males?
PBC affects people of all sexes, races, and ethnicities. Earlier reports showed a
median female-to-male ratio of 10:1, but these were case-nding studies and, there-
fore, subjected to numerous biases. Modern literature from epidemiologic studies—
which, although not perfect, provide a more general vision of the actual number of
cases—have shown that the female to male prevalence ratio is closer to 4–6:1 [3, 4].
PBC in males is often diagnosed at an older age once the disease is more
advanced. It has also been associated with a lower biochemical response to ursode-
oxycholic acid (UDCA), greater progression to cirrhosis, higher rates of liver-
related death or transplantation, and higher risk for primary liver cancer [5].
It’s important that we continue to create awareness among providers that PBC
can affect people from all backgrounds. Being vigilant will lead to an earlier diag-
nosis, particularly in males and racial minorities, allowing for prompt treatment
initiation, which will in turn slow down the rate of progression to cirrhosis.
If patients are diagnosed early with PBC and started on ursodeoxycholic
acid immediately, do you nd that the vast majority will do well for years,
decades even?
Yes, the introduction of ursodeoxycholic acid in the mid-1990s has helped
reshape the transplant-free survival in patients with PBC.Those treated with the
medication have a survival rate of 90% at 5years and 66% at 15years. In the pre-
ursodeoxycholic acid era, these percentages were signicantly lower with a 79%
transplant-free survival at 5years and 32% at 15years [6].
Why does ursodeoxycholic acid work so remarkably well for PBC?
Ursodeoxycholic acid is a hydrophilic bile acid that is normally present in human
bile at a low concentration (around 3% of the total bile acid pool). When adminis-
tered orally, only 30–60% is absorbed by the bowel. In the hepatocytes and biliary
ducts, ursodeoxycholic acid has anti-inammatory properties, solubilizes the bile,
and stimulates bile ow [7].
When you see patients who are initially doing well but then take a turn for
the worse, what sort of symptoms do they usually present with?
Symptoms do not correlate well with the degree of cholestasis or brosis,
although, observationally, patients with more severe disease tend to have more
symptoms.
Symptoms can appear at any point in the disease course, with fatigue being the
most common one. It is experienced by about 80% of the patients, and it is very
disabling. Fatigue is also very challenging to manage, with no effective medications
currently approved for its treatment. The second most frequent symptom is pruritus.
It is more intense in the limbs, particularly in the palms and soles, and has a
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circadian rhythm. It is more intense in the evening and overnight. Pruritus is associ-
ated with sleep deprivation, worsening fatigue, depression, social isolation, and
self- mutilation, thus leading to signicant impairment in quality of life [1].
Sicca complex symptoms, including dry mouth and dry eyes, are usually under
reported by patients but are highly prevalent in PBC.Providers should proactively
ask about them when following patients with PBC and treat them accordingly [1].
Right upper quadrant abdominal pain is present in about 25–30% of patients.
This is a very nonspecic symptom, and other etiologies like gallbladder or pancre-
atic disease and abdominal/chest wall pathology would have to be excluded before
attributing the pain solely to PBC [1].
How do you like to manage pruritus in PBC?
My initial approach consists of utilizing commercially available skin moisturiz-
ers, emollients, and topical agents with camphor or menthol. The only currently
approved treatment for pruritus in PBC is cholestyramine. This is a bile acid binding
resin. It is usually started at a dose of 4g by mouth per day and can be increased to
a maximum of 16g per day. It is important to remember that cholestyramine can
inadvertently bind other medications—particularly ursodeoxycholic acid—when
taken at the same time, preventing their absorption. Therefore, it is recommended
that cholestyramine should be taken 3–4h before or after other prescribed drugs. A
recent trial utilizing bezabrate (400mg by mouth per day) for the management of
cholestatic itch showed a 50% reduction in the severity of pruritus in PBC patients
treated with this brate. This medication can be considered an alternative to chole-
styramine, where it is available. Rifampin (150–300mg PO BID) enhances the rate
of bile acid metabolism and increases the excretion of pruritogens. This medication
works well in PBC, but its use is off-label, and although very rare, it has been asso-
ciated with severe hepatitis.
Now, if you have a patient who doesn’t tolerate cholestyramine, does colesti-
pol work for pruritus?
Colestipol can be used for PBC since this is also a bile acid binding resin, but it
has not been FDA-approved for this particular indication.
She is started on UDCA at a dose of 13–15mg/kg per day.
When you start ursodeoxycholic acid, when do you want to recheck liver
enzymes?
Liver chemistries should be rechecked every 3–6months in patients treated with
ursodeoxycholic acid. Alkaline phosphatase has a log linear association with the
risk of liver transplant and death and can be used to monitor response to therapy.
There are multiple other scores like the UK-PBC and the GLOBE score that are
excellent at estimating outcomes and can be found online. In clinical practice, the
goal should be to normalize or near normalize the ALP after 1year of treatment
with UDCA.This is only possible in about two thirds of the patients. Those who do
not respond may require the combination of UDCA with other drugs, like obeticho-
lic acid or brates, where it is available [8].
In this case, recheck of the alkaline phosphatase at 6 months returns 160
(nl<80).
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Would you change your management?
Although the ALP is still elevated, it is much improved in comparison to her
baseline numbers. Since the patient has only been on UDCA for 6months, I would
keep her on this medication. I would make sure that the dose is appropriate to her
weight and that she is being compliant with the medication. It is also important to
assess for side effects like stomach upset, hair thinning, and weight gain each fol-
low-up visit.
Will you go to a higher dose of ursodeoxycholic acid?
No, the dose of UDCA should range between 13 and 15 mg/kg per day, and
higher doses have not shown any benet in terms of biochemical response or mor-
tality. I would only increase the dose of this medication if it has been miscalculated
previously and the patient is being undertreated [9].
The patient remains on ursodeoxycholic acid, and at the end of 1year, the alka-
line phosphatase is 150.
Would you change your treatment?
This is a difcult question to answer since the patient responded well to the
medication but did not completely normalize her ALP.Data supports that this near
normalization of her ALP should decrease her rate of PBC progression, transplant-
free survival, and overall mortality. I would have a discussion with the patient
regarding her overall prognosis and pros and cons of starting obeticholic acid (OCA)
and come up with a collaborative plan after [10].
Do patients tend to have problems tolerating ursodeoxycholic acid or toler-
ating obeticholic acid?
Patients usually tolerate ursodeoxycholic acid well. Some patients complain of
hair thinning, stomach upset (particularly bloating and diarrhea), and weight gain.
UDCA should be taken with food. If patients can’t tolerate a single dose of the
medication per day, then UDCA can be split into two doses.
OCA is a synthetic bile acid, which acts as a very potent farnesoid X receptor
agonist. It was approved by the FDA for the management of PBC patients who
respond inadequately to UDCA after 1 year of therapy. Although over 45% of
patients achieve a signicant ALP improvement with the concomitant use of OCA
and UDCA, this medication is associated with pruritus in a dose-dependent fashion,
leading to the discontinuation of the drug in up to 25% of patients. This is why OCA
should be started at a dose of 5mg per day and then slowly increase the dose up to
10mg PO daily. OCA also decreases HDL cholesterol and increases LDL choles-
terol independently of the dose. Providers should be aware that OCA is contraindi-
cated in patients with cirrhosis with a Child-Pugh score of B or C and in those with
a Child-Pugh score of A who have previous or current clinical evidence of portal
hypertension [8].
Can you use it in a grade A cirrhosis?
Yes, you can use it in cirrhotic patients with a Child-Pugh score of A, as long as
there is no evidence of portal hypertension. In these patients, the recommended
maximum dose is 5mg PO/daily.
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Is it known why OCA might precipitate hepatic decompensation?
I don’t think this has been fully claried. The current black label warning is
based on post-marketing reports.
In this case, the alkaline phosphatase drops down to 100 on the combination of
OCA and ursodeoxycholic acid.
So, I assume you just continue the two medicines indenitely?
Yes, I would continue both medications indenitely.
Besides tracking liver enzymes, how are you following your PBC patients?
The holistic management of PBC should include four different aspects. The rst
one is the disease treatment per se, which includes the utilization of UDCA and
monitoring liver chemistries for response every 3–6months. The second important
aspect is to stage the disease in terms of brosis status via elastography. Elastography
should be performed every 2–3years in those PBC patients without evidence of
advanced brosis at baseline and on a yearly basis in those with evidence of
advanced brosis at baseline or on follow-up. In general, a liver stiffness measure-
ment below 6.5kPa or above 11kPa measured by transient elastography accurately
discriminates between the absence or presence of advanced brosis respectively
with high sensitivity and specicity. Surveillance for hepatocellular carcinoma and
esophageal varices should follow the same guideline recommendations that apply
for cirrhotic patients from other etiologies. A third important aspect is to address
and manage symptoms directly derived from PBC like pruritus, fatigue, and sicca
complex. Lastly, patients with cholestasis should be screened and treated for bone
disease, dyslipidemia, and liposoluble vitamin deciencies, particularly if jaundice
has ensued [8].
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. Prince MI, Chetwynd A, Craig WL, Metcalf JV, James OF.Asymptomatic primary biliary
cirrhosis: clinical features, prognosis, and symptom progression in a large population based
cohort. Gut. 2004;53(6):865–70.
3. Lu M, Zhou Y, Haller IV, Romanelli RJ, VanWormer JJ, Rodriguez CV, etal. Increasing preva-
lence of primary biliary cholangitis and reduced mortality with treatment. Clin Gastroenterol
Hepatol. 2018;16:1342–50.e1.
4. Lleo A, Jepsen P, Morenghi E, Carbone M, Moroni L, Battezzati PM, etal. Evolving trends
in female to male incidence and male mortality of primary biliary cholangitis. Sci Rep.
2016;6:25906.
5. John BV, Aitcheson G, Schwartz KB, Khakoo NS, Dahman B, Deng Y, etal. Male sex is asso-
ciated with higher rates of liver related mortality in primary biliary cholangitis and cirrhosis.
Hepatology. 2021;74:879–91.
6. Lammers WJ, van Buuren HR, Hirscheld GM, Janssen HL, Invernizzi P, Mason AL,
etal. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of
84 Managing Primary Biliary Cholangitis
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patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology.
2014;147(6):1338–49.e5; quiz e15.
7. Gulamhusein AF, Hirscheld GM.Primary biliary cholangitis: pathogenesis and therapeutic
opportunities. Nat Rev Gastroenterol Hepatol. 2020;17(2):93–110.
8. Trivella J, John BV, Levy C.Primary biliary cholangitis: epidemiology, prognosis, and treat-
ment. Hepatol Commun. 2023;7(6):e0179. https://doi.org/10.1097/HC9.0000000000000179.
9. Angulo P, Jorgensen RA, Lindor KD.Incomplete response to ursodeoxycholic acid in primary
biliary cirrhosis: is a double dosage worthwhile? Am J Gastroenterol. 2001;96(11):3152–7.
10. Corpechot C, Poujol-Robert A, Wendum D, Galotte M, Chretien Y, Poupon RE, et al.
Biochemical markers of liver brosis and lymphocytic piecemeal necrosis in UDCA-treated
patients with primary biliary cirrhosis. Liver Int. 2004;24(3):187–93.
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Switzerland AG 2023
W. H. Sobin et al. (eds.), Managing Complex Cases in Gastroenterology,
https://doi.org/10.1007/978-3-031-48949-5_85
Chapter 85
Advanced PBC
JuanTrivella
A 55-year-old female, who hasn’t seen a doctor in years, comes in with the com-
plaint of severe itching and fatigue. She drinks only on weekends, two beers a day.
She has no stigmata of chronic liver disease on exam. However, her alkaline phos-
phatase is elevated to 360 (fractionation shows the increase is from the liver), bili-
rubin is 1.8, albumin is 3.2, AST is 40, ALT is 70, Hbg is 11, platelets is 100k, and
AMA is+1:160. US shows mild nodularity of liver. LSM (liver stiffness measure-
ment) is 11kPa on transient elastography.
Would you want a liver biopsy in this case?
This female patient with classic symptoms for PBC, a predominantly cholestatic
pattern of elevated liver chemistries, and a positive AMA does not require a biopsy
to make the diagnosis of PBC.Despite this, if the possibility of a concomitant diag-
nosis is also being considered, for example, metabolic associated steatohepatitis
(MetASH), or there are concerns for overlap syndrome with autoimmune hepatitis
on additional serologies, then a liver biopsy may be necessary. The combination of
ndings on US and elastography are concerning for progression to cirrhosis, and the
thrombocytopenia could imply the development of portal hypertension. I would feel
comfortable managing the patient as such and would obtain the appropriate screen-
ing per guidelines and monitor closely her liver chemistries [1].
This patient has an EGD, and there are no varices and no GAVE.
A normal endoscopy in the above scenario would not change the diagnosis of
PBC or the presence of at least advanced brosis (given the results on elastography).
The only aspect that would require further investigation is the thrombocytopenia,
since initially this was believed to be secondary to portal hypertension—and
J. Trivella (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jtrivella@mcw.edu
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although this may still be true—the normal upper endoscopy makes this possibility
somewhat less likely. An alternative explanation for the low platelets would have to
be ruled out.
Would you want to start ursodeoxycholic acid, even if there is advanced
cirrhosis?
Yes, absolutely. UDCA improves liver chemistries, delays histological progres-
sion, and delays the development of varices. Furthermore, improved survival with
the use of UDCA has been shown regardless of sex, brosis stage, or even in those
with an inadequate response to the medication [2].
Do you monitor the AMA levels during treatment?
No, AMA titers do not correlate with disease activity, severity, or response to
therapy and are devoid of prognostic signicance. AMA should not be followed
longitudinally since its value will not change the patient’s management [3].
In this patient, ursodeoxycholic acid is started and the alkaline phosphatase
doesn’t drop.
Would you add OCA?
To answer this question accurately, additional clinical information is needed, but
in general, OCA is indicated in patients with an inadequate response to UDCA after
1year of monotherapy with this drug. This is exclusively for non-cirrhotics or for
those with cirrhosis and a Child’s Pugh score no worse than A without previous or
current evidence of portal hypertension or decompensated disease [1].
What do you think about using brates instead of OCA?
You can consider using brates as an off-label add-on therapy for the manage-
ment of inadequate responders. The caveat is that bezabrate is not currently com-
mercially available in the United States. Most of the data on the effectiveness of
bezabrate in combination with UDCA comes from Europe and Japan, where this
medication has been repurposed for the treatment of PBC and cholestatic itch for
years [4]. In the United States, only fenobrate is available in retail, and data on its
use for the management of inadequate responders is considerably less robust.
Although gastrointestinal and musculoskeletal side effects, like myalgias and
arthralgias, are more common in patients with PBC on dual UDCA-brates, no
signicant difference in the frequency of serious side effects (including elevations
of aminotransferases >5 times the ULN) has been reported when comparing the
combined treatment with those on UDCA monotherapy, making this a relatively
safe drug for use in PBC.
In this case, the cholesterol comes back 290. LDL is 160.
Is it unusual to see lipid levels like this in PBC, and would you start a statin?
Hyperlipidemia is very common among patients with PBC.At initial presenta-
tion, around three quarters of patients with PBC have a cholesterol level>200mg/
dL with a proportion of them also experiencing milder elevations of low-density
lipoproteins (LDL) and marked elevations in high-density lipoproteins (HDL).
Late-stage disease is associated with marked LDL elevations. Clinically, dyslipid-
emia alone does not appear to increase the risk of cardiovascular events in patients
with PBC and therefore, its management should follow the same criteria that is used
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to treat lipid disorders in other populations with no history of PBC.In other words,
statins are not contraindicated in patients with PBC and should be used as needed
and according to the regular dyslipidemia guidelines used in preventive medicine
and primary care [5, 6].
So, to summarize, you are going to add OCA to ursodeoxycholic acid and
probably start a statin. Are there any other treatments you would start in the
meantime?
If this patient is conrmed to have cirrhosis and portal hypertension and her
numbers fail to normalize on combination therapy, then a conversation regarding
the potential need for liver transplantation will be necessary. This is especially
important if her synthetic function continues to deteriorate, or she clinically decom-
pensates. She will also need appropriate hepatocellular carcinoma and esophageal
varices screening according to guidelines. The patient will also require symptomatic
management for pruritus, sicca complex, and fatigue. Lastly, she should receive
appropriate screening for bone disease and liposoluble vitamin deciencies (the lat-
ter only if jaundice is present) and her hepatitis A virus (HAV) and hepatitis B virus
(HBV) vaccination status should be addressed.
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. Shi J, Wu C, Lin Y, Chen YX, Zhu L, Xie WF.Long-term effects of mid-dose ursodeoxycho-
lic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials. Am J
Gastroenterol. 2006;101(7):1529–38.
3. Levy C, Bowlus CL. Role of antinuclear antibodies in primary biliary cholangitis. Am J
Gastroenterol. 2020;115(10):1604–6.
4. Tanaka A, Hirohara J, Nakano T, Matsumoto K, Chazouilleres O, Takikawa H, etal. Association
of bezabrate with transplant free survival in patients with primary biliary cholangitis. J
Hepatol. 2021;75:565–71.
5. Assis DN.Chronic complications of cholestasis: evaluation and management. Clin Liver Dis.
2018;22:533–44.
6. Chalifoux SL, Konyn PG, Choi G, Saab S.Extrahepatic manifestations of primary biliary chol-
angitis. Gut Liver. 2017;11:771–80.
85 Advanced PBC
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369© 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_86
Chapter 86
Autoimmune Hepatitis
FranciscoDurazo
The patient is a 24-year-old female with a history of hypothyroidism who presents
with weakness. She is on no medications, except oral contraceptives. Her labs
reveal an ALT of 520, AST of 319, Alk phos of 80, and bilirubin of 1.0. Hepatitis
panel is negative, ANA returns+1:160, and ASMA is+1:80. Gamma globulin is two
times normal.
How do you manage this patient?
All things point to this being autoimmune hepatitis, but we want to send the rest
of our chronic hepatitis workup for completeness. We need to do a liver biopsy to
conrm the diagnosis.
Liver biopsy is consistent with AIH.
What treatment do you recommend for AIH?
We like to start with prednisone monotherapy. Once we see a denite response to
steroids, with the liver enzymes improving, we add on azathioprine. We don’t start
azathioprine initially because we want to ensure that the hepatitis is steroid respon-
sive. If it is not steroid responsive, we may be dealing with a different diagnosis. We
start azathioprine at 50mg. Once azathioprine is started, the goal is to taper the
steroids and hopefully maintain the patient on azathioprine monotherapy. Unlike
IBD, where doses of azathioprine may be 150 or 200mg or more, in AIH hepatolo-
gists generally don’t go above 50mg. And, unlike in IBD, many hepatologists do
not bother checking TPMT status before starting azathioprine.
What about the patient who has autoimmune hepatitis and cirrhosis?
We tend to avoid steroids in the patients with AIH and cirrhosis. The steroids are
more likely to promote sodium retention, ascites, and decompensation. So, in
F. Durazo (*)
Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: fdurazo@mcw.edu
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cirrhotics, we generally use azathioprine monotherapy, or CellCept (mycopheno-
late), or just maintenance therapy. In younger patients, AIH tends to present as a
more acute hepatitis with very high transaminases and jaundice. In older patients,
the disease usually presents as a more chronic hepatitis and a more subacute course,
and these patients are more likely to have well-established brosis or cirrhosis and
portal hypertension.
F. D u r a z o
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