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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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291© 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_59
Chapter 59
Increased LFTs withLow Ceruloplasmin
JoseFranco
A 27-year-old male is referred for elevated liver enzymes. His only complaint is
mild chronic fatigue and difculty concentrating at work. His AST is 100, ALT is
120, Alk phos is 40, and bilirubin is 1.2. His Hbg is 12.2. and iron saturation is
25%. Hepatitis panel is negative, while ANA, AMA, and ASMA are all negative.
Serum ceruloplasmin is 17 (normal 20–40). The diagnosis of Wilson’s is consid-
ered. He is sent to an ophthalmologist, who does a slit lamp exam and does not see
K-F rings.
How would you evaluate this patient further?
In this young male with elevated liver enzymes and a decreased ceruloplasmin,
Wilson’s disease is a consideration. The absence of K-F rings does not rule out
Wilson’s. The next step would be to do a 24-h urine copper. I don’t think there is any
value in getting a serum copper or a spot urine copper; these tests are not useful.
Whatever the result of the 24-h urine copper, we should do a liver biopsy. In
Wilson’s, the 24-h urine copper should be high, > 40μg. If it is high, this is likely
Wilson’s, and we do the biopsy for quantication of copper in liver tissue. More
than 250μg of copper/g dry weight is diagnostic for Wilson’s. If, for some reason,
the level is lower, between 50 and 250μg/g dry weight, then molecular/genetic test-
ing is indicated. If the 24-h urine copper is not elevated, I would do a liver biopsy
for histology, and if signicant copper is present, do quantitative copper levels.
When you send quantitative copper studies, you need to send tissue in a dry tube to
an institution capable of performing this test.
One interesting thing in this case is the low alkaline phosphatase. No one seems
to know why this is low in Wilson’s, but the only condition you ever really see a low
alkaline phosphatase is in Wilson’s disease.
J. Franco (*)
Department of Medicine-Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jfranco@mcw.edu
https://t.me/medicina_free
292
If Wilson’s is present, would you do further neuropsychiatric evaluation?
I'm not sure that doing further neuropsychiatric evaluation would help if the
patient is already reporting difculty concentrating at work. He’s 27, and, obvi-
ously, this is a genetic disorder, so he has already had a couple of decades worth of
disease, and I would attribute those symptoms to Wilson’s disease. I don't know
what further neuropsychiatric evaluation would tell me, and it's not going to alter
my treatment, which is, of course, to treat the condition.
If Wilson’s is diagnosed, how would you treat the patient?
Historically, penicillamine was the agent we used the most, but today, it is hardly
ever used because there are less toxic options. Trientine is another agent that works
like penicillamine, helping to increase the urinary excretion of copper. But my agent
of choice is zinc, which has lower toxicity than both penicillamine and trientine.
Zinc works to prevent absorption of copper from the GI tract. It is usually well toler-
ated. Occasionally, I'll use a combination of zinc and trientine because they work
via different mechanisms.
How do you monitor their response to therapy?
I mostly follow their liver enzymes, but you can also monitor their 24-h urine
copper. We tend to do that once a year. The urine copper should be low if the zinc is
doing its job. Some also follow the non-ceruloplasmin-bound copper (or “free cop-
per”), which can be calculated by subtracting ceruloplasmin-bound copper
(3.15×ceruloplasmin in mg/L equals the amount of ceruloplasmin-bound copper in
μg/L) from the total serum copper concentration (in μg/L; serum copper in
μmol/L×63.5 equals serum copper in μg/L). In order to simplify this, you can use
the following: total serum copper (in μg/L)−(3×ceruloplasmin in mg/L)=non-
ceruloplasmin- bound copper (to be more accurate, you can use 3.15). This can be
cumbersome, and it is difcult when results return without specic numerical val-
ues (e.g., serum copper <3).
How many cases of Wilson's would you say you've seen over the years?
I would say 40–50, but right now, I’m following three quite actively.
J. Franco
https://t.me/medicina_free
293© 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_60
Chapter 60
Normal Ceruloplasmin-Suspected Wilson’s
JoseFranco
A 37-year-old male is referred for elevated LFTs; AST is 120, ALT is 150, Alk phos
is 50, and Bili is 1.2.
The patient has had increased fatigue for the past 1month. ANA, ASMA, AMA,
celiac, alpha-1-AT, and Fe/TIBC are all normal. Ceruloplasmin is 20. Slit lamp
exam is positive, and 24-h urine copper is elevated.
Can you comment on the nding of a normal ceruloplasmin in a case of
likely Wilson’s?
In this case, KF rings are present but ceruloplasmin is normal. It is important to
remember that ceruloplasmin is an acute phase reactant. The elevated urinary cop-
per level conrms the diagnosis of Wilson’s. If the 24-h urine is normal or only
mildly elevated, a liver biopsy is indicated.
J. Franco (*)
Department of Medicine-Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jfranco@mcw.edu
https://t.me/medicina_free
295© 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_61
Chapter 61
Increased LFTs-Alpha 1 Antitrypsin
Deciency
JoseFranco
A 49-year-old female is seen for a history of elevated liver enzymes. Her AST is 55
and ALT is 80; alk phos and bilirubin are normal. Also, she is mildly obese. She
notes a family history of cirrhosis in her father and uncle, neither of whom were
smokers or drinkers, but both also suffered from lung disease, presumed COPD.She
has not had pulmonary problems. Because of the family history, alpha-1 antitrypsin
levels and genotype were sent off. She was found to have mild AAT deciency with
ZZ genotype.
What manifestations of A1AT have you seen in your liver patients?
I have seen symptoms of liver involvement including liver failure, more in the
pediatric patients. I have had one adult present with advanced liver disease requiring
liver transplant.
Do you nd it more as a primary disorder or a contributing disorder to some
other underlying liver disease?
I would say it is more commonly a contributing factor in a patient with some
other underlying liver disease.
Any treatments you have used?
While there is treatment for lung disease due to alpha-1 antitrypsin deciency,
there is none for liver disease. This is because of the different pathogenesis of the two.
The lung disease of alpha-1 antitrypsin deciency is due to proteolytic damage from
PMNs, which is usually inhibited by alpha-1 antitrypsin. Synthetic alpha-1 antitryp-
sin is available to prevent this damage. The liver disease, on the other hand, is due to
the retention of abnormal A1AT-Z molecules in the hepatocyte leading to cell dam-
age. Synthetic alpha-1 antitrypsin is of no benet here. Therefore, there is no treat-
ment for liver disease except transplant when end-stage complications have developed.
J. Franco (*)
Department of Medicine-Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jfranco@mcw.edu
https://t.me/medicina_free
297© 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_62
Chapter 62
Suspected Gilbert’s
JoseFranco
A 37-year-old male is seen because of an elevated bilirubin. He is asymptomatic.
His total bilirubin ranges from 2.2 to 2.9 with a direct of 0.4–1.0 over the last
3 months. Physical exam is normal. An US of the liver with Doppler is normal.
Hepatitis panel, autoimmune markers, iron saturation, ceruloplasmin, and alpha-1
antitrypsin are all normal. His reticulocyte count and LDH are normal.
Would you diagnose this as Gilbert’s? How do you approach cases of sus-
pected Gilbert’s, where the direct bilirubin is higher than expected?
In this case, where you have an elevated unconjugated bilirubin, I think you’re
either dealing with Gilbert’s or hemolysis, and you never want to miss hemolysis. I
check the reticulocyte count and haptoglobin and have them look at the red blood
cells on the smear to make sure there is no hemolysis.
Here, the elevated bilirubin is mostly unconjugated and ranges from 2.2 to 2.9.
But, from personal experience, I will tell you that it can go into the mid-three range.
I know this because I have Gilbert’s, and I’ll frequently be in that 3.5 range when
they have me go for blood tests. They’ll always call me back with a critical lab
value, and I have to explain it to them. The unconjugated bilirubin is worsened with
physiologic stress, and when you’re fasting. My wife can look at me when I get
home and tell whether I have skipped lunch, seeing whether I look jaundiced. But if
you are under the weather, if you have any viral syndrome, many things will increase
it. You’re supposed to check the bilirubin in a fasting state.
Now in this case, there is a mild elevation of the conjugated bilirubin. In cases
where it is predominantly conjugated bilirubin, rather than unconjugated, you may
be looking at those rare disorders—Rotor and Dubin-Johnson. In these two
disorders, the basic defect is in the transporter that gets the conjugated bilirubin out
J. Franco (*)
Department of Medicine-Division of Gastroenterology and Hepatology, Medical College of
Wisconsin, Milwaukee, WI, USA
e-mail: jfranco@mcw.edu
https://t.me/medicina_free
298
of the hepatocyte, into the bile duct. These conditions are very rare, Gilbert’s on the
other hand is very common, 6–7% of the population. But in a case like this, where
the vast majority is unconjugated, I think the mild elevation of the direct bilirubin is
probably a red herring.
There are certainly cases where you can have other underlying liver disease in
association with Gilbert’s, but then you usually see a rise in the AST and ALT or
alkaline phosphatase, in addition to the bilirubin. If it’s just a rise in bilirubin and
it’s mostly indirect with a slight elevation of the direct, it’s usually going to be
Gilbert’s.
J. Franco
https://t.me/medicina_free
299© 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_63
Chapter 63
The Signicance ofAST>ALT
FranciscoDurazo
A 42-year-old female is referred for abnormal liver enzymes with an AST of 52 and
ALT of 38. She has a normal BMI but mildly increased waist circumference. She has
two glasses of wine a night. An US shows some steatosis but is otherwise negative.
Does the AST>ALT send off any alarm bells?
Yes, we wonder if she is actually drinking more than two glasses of wine a day;
is alcohol-induced liver injury responsible for these numbers? The normal pattern
for transaminases is ALT > AST, which also holds true for most liver diseases,
including viral hepatitis, autoimmune hepatitis, and even fatty liver disease. But we
tend to see AST> ALT in patients with alcoholic liver disease, and we see it in
patients who have gone on to develop cirrhosis. In cirrhosis, the production of ALT
is decreased and so the AST>ALT.Therefore, in this patient, what is the explana-
tion for the AST>ALT? Is it coming from alcohol or from occult cirrhosis, or might
the elevated AST be coming from muscle damage or hemolysis?
We also note that the ultrasound shows steatosis. Anyone with fatty liver deserves
a workup for chronic hepatitis, which includes serology for hepatitis B, hepatitis C,
autoimmune hepatitis, Wilson’s disease (in the right age cohort), alpha-1 antitrypsin
deciency, and celiac disease.
If the workup for chronic hepatitis returns negative, would you pursue a
liver biopsy?
If all those labs return negative, we suspect the patient has alcoholic steatohepa-
titis. The only way to make this diagnosis is with liver biopsy. We would discuss
liver biopsy with the patient, elaborating on how it could alter management and help
with determining prognosis. In the meantime, we would suggest the patient stop
F. Durazo (*)
Division of Gastroenterology and Hepatology, Department of Medicine,
Medical College of Wisconsin, Milwaukee, WI, USA
e-mail: fdurazo@mcw.edu
https://t.me/medicina_free
300
drinking and recheck liver enzymes after 3 months. If the labs normalize, we would
probably cancel the biopsy. If they remain abnormal, we would proceed with biopsy.
An important pearl is that the biopsy appearance of NASH is identical to that of
alcoholic steatohepatitis, and the only way of distinguishing the two is by history.
But, as noted, the fact that the AST is higher suggests alcohol is the culprit; usually
in NASH, the ALT > AST, although the ratio has been noted to reverse in some cir-
rhotics with NASH.
F. D u r a z o
https://t.me/medicina_free
301© 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_64
Chapter 64
Marked Hyperbilirubinemia
KiaSaeian
A 75-year-old male presents to the ER with fever and elevated LFTs. An US shows
a stone in the CBD, with a very high bilirubin. His alk phos was 480, his AST was
160, and his ALT was 200. His total bilirubin is >30, and direct bilirubin was >20.
The patient had a normal bilirubin 1month earlier. MRI of the liver shows multiple
stones in the gallbladder, a common duct stone, and no suggestion of biliary stric-
ture, hepatobiliary, or pancreatic neoplasm. PMH is positive for mild CHF and
mild renal insufciency.
His abdominal pain started about a week before coming to the ER.He is mildly
hypotensive. His congestive heart failure is worsened. He is started on broad-
spectrum antibiotics and has an urgent ERCP and stone extraction with clearing of
the bile duct and pus. His blood cultures return positive, growing gram-negative
rods. After the procedure, all his liver enzymes are improving except his bilirubin.
He remains mildly hypotensive. Four days after the procedure, his bilirubin remains
>30, although all the other liver enzymes are returning toward baseline.
How can you get such a high bilirubin in this setting?
A good rule of thumb that I use is that it is atypical to have a bilirubin over 20
and, particularly, a bilirubin of over 30 with pure bile duct obstruction. In these
circumstances, I always consider other potential contributors that may lead to intra-
hepatic cholestasis and hemolysis. In this particular case, the history provides a
number of clues to other potential contributors. The mild congestive heart failure
can lead to cholestasis due to passive congestion. Renal insufciency can result in
more prolonged hyperbilirubinemia and slower clearance of the bilirubin. And,
most importantly, the positive blood cultures with gram-negative rods can result in
K. Saeian (*)
GI/Hepatology Division, Department of Medicine, Medical College of Wisconsin,
Milwaukee, WI, USA
e-mail: ksaeian@mcw.edu
https://t.me/medicina_free
302
cholestasis of sepsis, which can develop from impairment of bile transport in the
setting of sepsis. In this setting, continued hypoperfusion, either due to his low
blood pressure or passive congestion from his heart failure, can further prolong this
episode.
What are the different issues to keep in mind when you are confronted with
hyperbilirubinemia (in the 20s or 30s range) in patients who are septic, have
cardiac surgery, or have multisystem disease, often in an ICU setting?
By far, the most common scenario is due to infection or cholestasis of sepsis,
which, again, is believed to be, at least in part, due to a defect in bile transport due
to sepsis. The most severe form of this is cholangitis lenta, which has more com-
monly been reported in liver transplant patients and is commonly associated with a
poor overall prognosis. Cholangitis lenta itself is a histologic diagnosis in which
there is proliferation of dilated bile ductules and inspissated bile along with neutro-
phils and, on occasion, portal inammation with a lymphoplasmacytic inltrate. As
many physicians know, it is common to see episodes of cholestasis of sepsis, but
physicians rarely encounter cholangitis lenta because we rarely proceed with liver
biopsy in such settings. This is often because these patients are so critically ill and
the biopsy is not felt to alter management. This may also be why it is thought to be
more common in liver transplant patients, since those patients are much more likely
to undergo a liver biopsy when critically ill.
We already touched on a couple of scenarios outlined in the rst question of this
section that can result in hyperbilirubinemia, often with aminotransferase and alka-
line phosphatase elevations. Entities that can result in more of an isolated hyperbili-
rubinemia with mild alteration of other liver enzymes, albeit not always in the 20–30
range, include heart failure/passive congestion, medications (ceftriaxone for
instance is a common contributor), hemolysis (in the setting of indirect hyperbiliru-
binemia), and the effects of anesthesia. The latter is particularly an issue in patients
with underlying cirrhosis. It is not uncommon for us to see patients without known
prior liver disease who were subsequently diagnosed as having cirrhosis, because
they developed hyperbilirubinemia in response to undergoing anesthesia, particu-
larly for an abdominal or cardiac operation.
K. Saeian
https://t.me/medicina_free
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