Keywords
acute liver failure - hepatic encephalopathy - PTLF - TIPSS
Introduction
Post TIPSS liver decompensation may adversely affect the clinical outcome and if severe
it may also require TIPSS reduction, liver transplant or may lead to death. No definition
for PTLF is currently available in clinical guidelines to identify these subsets of
patients. Post procedure the enzymes show transient rise which tends to get stabilized
within a few days. An exaggerated increase or delayed increase in enzyme levels may
indicate irreversible liver cell injury or failure. Gradually the synthetic liver
function also decreases due to diversion of blood flow from hepatocytes. According
to International Study Group of Liver Surgery (ISGLS) post-hepatectomy liver failure
is defined by an abnormal or increasing serum bilirubin and INR on or after postoperative
day 5, and further stratified into subgroups based on clinical outcomes.[1] However, post TIPSS liver failure is yet to be properly defined in literature.
Case 1
A 26-year-old female presented with gradual abdominal distension of 1-year duration
with history of multiple large volume paracentesis for last 3 months. Viral markers
and autoantibodies were negative. Ceruloplasmin and ferritin levels were normal. Doppler
examination was done, which showed heteroechoic cirrhotic liver with diffuse obliteration
of all three hepatic veins and normal IVC. Few small intrahepatic collaterals were
seen. No recanalizable hepatic vein could be identified. There was gross ascites and
gross right pleural effusion. The diagnosis of Budd Chiari syndrome with diffuse involvement
of all three hepatic veins was made. Patient was worked up in hematology for hypercoagulable
state which was negative. Due to recurrent tense ascites direct transjugular intrahepatic
portosystemic shunt was planned. Routine investigations showed TLC 4400, Hb: 6.8 g%,
platelet count (65,000), bilirubin 1.1, INR: 2.1, albumin: 3.9 g%, urea: 32 mg%, and
creatinine 1.1 mg%. Her pre-procedure MELDNa score was 11 and CPS was eight. Serum
electrolytes and echocardiography were normal.
As hepatic vein stump was not identified, direct intrahepatic portosystemic shunt
was done through inferior vena cava ([Fig. 1]). The procedure was uneventful, and the patient was started on low molecular weight
heparin. Day after, patient developed hypotension which later required inotropic support.
There was no evidence of sepsis and USG did not reveal hemothorax, hemopericardium,
or hemoperitoneum. Later she developed serial progressive increase in bilirubin from
1.1 to 3.5 mg%, liver enzyme levels peaked to eight times above baseline with INR
of 5.5. On day three, she developed hepatic encephalopathy which worsened from grade
1 to grade 4 within next 24 hours despite treatment. Work-up revealed normal electrolytes
with no evidence of gastrointestinal bleed. Serum ammonia levels showed a gradual
rising trend and later she was unable to maintain glucose levels and eventually died
on day six, post TIPSS.
Fig. 1 Case 1: (A) DSA image post DIPSS creation in patient of cirrhosis due to diffuse BCS with no
recanalizeable HV and a patent IVC and (B) post TIPSS USG Doppler showing typical phasic flow with velocity of 90 cm/s. IVC,
inferior vena cava; USG, ultrasonography.
Case 2
A 55-year-old female with type II diabetes, chronic hepatitis C-related chronic liver
disease requiring recurrent large volume paracentesis twice a week was referred for
TIPSS. There was no history of upper gastrointestinal bleed and hepatic encephalopathy.
USG Doppler revealed CLD with PHTN. All three hepatic veins and inferior vena cava
(IVC) were normal. Her liver function tests showed total bilirubin of 1.9 mg% and
serum albumin of 3.2 g%, serum sodium of 139 (mEq/L), and creatinine of 1.5 mg%. There
was mild anemia (Hb: 9.1 g%) and thrombocytopenia (55,000/mL). There was no history
of cardiac illness. Her MELDNa score was nine and CPS was seven. TIPSS was performed
as standard described technique with 10-mm shunt diameter. Ascites disappeared in
three following days; however, the patient developed grade 2 to 3 HE which was managed
medically. Patient recovered very gradually and was discharged after 10 days of medical
management. She continued to have grade 1 HE at home after discharge and after another
week patient relapsed with grade two-thirds HE and was re-admitted. Her work-up revealed
no sepsis, electrolyte imbalance and there was no evidence of GIB. She was treated
medically with lactulose, bowel wash, rifampicin, and hepamerz. Despite all conservative
efforts serum ammonia levels continue to rise and this time patient required prolonged
hospitalization for around 2 weeks. Due to distress caused by unresponsive high grade
HE, TIPSS reduction was planned. A 14-Fr long sheath was inserted into TIPSS via jugular
route and two 6-mm SEMS were simultaneously deployed in the tract over two wires.
One of the stents was closed with Amplatzer plug ([Fig. 2]) leaving other stent patent, reducing the TIPS shunt diameter to 50%. After shunt
reduction, patient started developing ascites again and patient showed only some degrees
of improvement in the status of hepatic encephalopathy. However, she continued to
be in waxing and waning state of HE.
Fig. 2 CASE 2: (A) FluoroSpot image post TIPSS in HCV-related CLD with refractory ascites (note post
cholecystectomy clips in situ). (B) Fluoro image showing two parallel wires after deployment of two separate smaller
6 mm × 60 mm SEMS deployed within the pre-placed 10-mm TIPSS stent. (C) Post shunt reduction image: Reduction done by occlusion of one of the stents with
Amplatzer plug (arrow). Note hand artifact (Asterix).
Careful history revealed past history of hypothyroidism, for which she took treatment
for a couple of years and left around 2 years back. Her repeat thyroid profile revealed
TSH of 46.4 and undetectable fT3 and fT4. She was initially started with 100 µg intravenous
thyroxine followed by oral thyroxine, after which she showed rapid improvement in
next 48 hours. She was discharged in stable condition after 7 days and remained symptom
free for next 2 months. Thereafter, she started requiring repeated paracentesis and
eventually developed spontaneous bacterial peritonitis followed by progressive sepsis
and multiorgan failure.
Discussion
Liver failure after TIPS insertion is a rare but fatal complication. Typical presentation
is marked elevation in liver enzymes, coagulopathy, and severe hepatic encephalopathy.
The risk of 3-month mortality after elective TIPS creation is 35%, 16%, and virtually
nil in patients with a MELDNa score of 18, between 11 and 17 and with model for end-stage
liver disease (MELD) score of 10 or less,[2]
[3] respectively.
The actual etiology of hepatic decompensation after TIPS insertion is variable, but
generally involves insult to an already-compromised liver in one or more of the following
manners[4]:
-
TIPS insertion reduces or reverses portal perfusion resulting in some degree of hepatocyte
ischemia.
-
Possible compression or occlusion of hepatic artery by the metallic stent at porta
resulting in ischemia or potential infarction.
-
The covered portion of the TIPS can occlude one or more hepatic veins, particularly
when there are shared origins, resulting in a HVOTO type of picture.
If no evidence of vessel occlusion or thrombosis is present on multiphase CT, the
etiology may be most likely related to the altered portal venous flow dynamics, and
thus urgent TIPS reduction/occlusion with coils or plugs should be attempted. Emergency
liver transplant should be reserved for cases that deteriorate after conservative
measures.
There are two limbs to prevent liver decompensation after a TIPSS creation. One is
to identify high-risk patients prior to the procedure and the other is early identification
of any treatable cause of impending PTLF. In patients with marginal hepatic functional
status, one should be very careful in reducing the portosystemic gradient, since a
large decrease may increase the risk of developing acute liver failure.
To identify patients at high risk of developing PTLF several prognostic scores are
used in literature. Clinical and biochemical factors identified to be associated with
poorer outcome including advanced age, history of encephalopathy, ascites, increased
prothrombin time, elevated bilirubin level, low sodium and albumin levels, and emergent
indication for TIPS rather than elective. Scoring systems like Child-Pugh score, MELD
score, Emory score, and APACHE II scores have been used to help prognosticate and
counsel patients being considered for TIPSS. In general, poorer post TIPSS outcome
is expected with a Child-Pugh score >12, MELD score >18, Emory score >3, or an APACHE
II score >18. High serum total bilirubin, high HVPG, and low albumin are independent
factors for predicting mortality within 1 year[5]
[6] according to various studies. MELD and MELDNa have performed best amongst all scores
and form the criteria for patient selection in most of the centers.[7] A score less than 18 is taken as ideal cut-off for performing a TIPSS procedure.
Development of PTLF in a patient with normal MELD score like in our cases requires
careful consideration of other variables that may adversely affect the outcome as
seen in our first patient. There is relative paucity of literature on the development
of PTLF in patients having MELD score <12.[8] In a single center large retrospective study several other factors have been identified
predicting poorer outcome even in patients with normal MELD score. They concluded
that refractory ascites as indication versus GIB, low Hb, and platelet count, MELD
11 or 12 versus less than or equal to ten, and CPS more than seven carry higher risk
of developing PTLF. Moreover, there is no correlation between stent diameter and decrease
in portosystemic pressure gradient. This was common to both cases having normal MELD
score but severe anemia and thrombocytopenia that affected the outcome. In their study
post TIPS early liver failure in patients with refractory ascites and a baseline MELD
score of 11 or 12 varied from 14 to 60% according to change in the platelet count
and from 14 to 69% according to change in the hemoglobin level. The effect of low
platelet may reflect the severity of the hemodynamic abnormalities correlated with
portal hypertension that are not immediately corrected by TIPS creation and the association
of low hemoglobin and poor post TIPSS outcome is not well elaborated.
After appropriate pre-procedure patient selection, the second limb is early identification
of any treatable cause of PTLF. The criteria for PTLF is another matter of debate.
Different definitions have been proposed and a consensus criteria is yet to be universally
accepted. AASLD defined ALF as “evidence of coagulation abnormality international
normalized ratio for prothrombin time >1.5 and hepatic encephalopathy in a patient
with a disease that has only been recognized for less than 26 weeks.[9] Though ISGLS states the criteria for liver failure post resection, there is no consensus
guidelines on the definition of what constitutes post TIPSS acute liver failure. Gaba
and Lakhoo[10] in their review of 268 patients formulated the definition of PTLF and concluded
that PTLF was defined by ≥threefold bilirubin and/or ≥twofold INR elevation associated
with clinical outcomes of prolonged hospitalization/increase in care level (grade
1), TIPS reduction or liver transplantation (grade 2), or death (grade 3) within 30-days
of TIPS. The treatment remains primarily supportive and in extreme cases LTP is required.
After TIPSS rising ammonia causing HE as a part of liver decompensation is seen in
as many as 30% patients which remains a serious clinical concern. Usually, it responds
to conservative management and only rarely it requires TIPSS reduction/closure or
urgent liver transplant. Medically refractory HE first prompts complete clinical,
biochemical, and metabolic work-up to rule out GIB, sepsis, and electrolyte imbalance
which needs treatment. Our patient did not respond to all measures to reduce ammonia
levels. This led to search for other causes of hyperammonemia, which revealed severe
hypothyroidism as the possible cause. Till date there have been only few (eight) case
reports on hypothyroidism causing hyperammonemic coma and all except one were patients
of CLD.[11] This further emphasizes that hypothyroidism precipitates hyperammonemia of liver
dysfunction. However, none of them was post TIPSS creation though spontaneous portosystemic
shunt has existed in one of these case reports. All of them have responded well to
thyroxine replacement.
Inefficient urea synthesis during hypothyroidism is expected to result in an increased
ammonia level. In liver failure and/or in patients with portal-systemic shunts, ammonia
reaches the systemic circulation and the central nervous system. Ammonia is metabolized
to glutamine in astrocytes through the glutamine synthetase enzyme and both ammonia
and glutamine exert toxic effects on brain.[12] An increase in liver enzymes concentration, AST more than ALT, is often found to
be associated with hypothyroidism. Microscopic changes like central congestive fibrosis
have also been described in myxedema states.[13]
Studies have also shown that the mean FT3 and FT4 levels are significantly decreased
and the mean TSH levels were significantly increased in liver cirrhosis. Low levels
of FT3 also correlate with the severity of liver disease in the form of CTP or MELD.
TSH levels increase with increasing MELD score. Therefore, thyroid levels in cirrhotic
patients may be used as a prognostic marker. It has been proposed that low FT3 and
high TSH might be used as a predictor of mortality in liver cirrhosis.[14]
Though hypothyroidism rarely presents first as hyperammonemia but it may precipitate
HE in existing CLD, more so after creating a TIPSS which further increases systemic
ammonia levels as seen in our second case. Though there is no cut off value of TSH
or fT4 levels which is acceptable for creating a TIPSS, thyroid function should still
be evaluated and should be normalized before an elective TIPSS. Refractory HE work-up
should include a complete thyroid profile and immediate correction if hypothyroidism
is detected.
These discussed non-MELD factors, like severe anemia, thrombocytopenia, and hypothyroidism,
are important to be evaluated prior to the procedure so as to prevent liver decompensation
and reduce early post TIPSS mortality.
Conclusion
In our cases despite a favorable low MELD score ([Table 1]) both patients developed progressive liver failure and death implicating other causes
which are beyond consideration by MELD alone. Despite abundance of prognostic scores
available for post TIPSS survival in CLD patients, careful patient selection is crucial
for clinical success. In patients with normal MELD score low Hb, platelet and resistant
ascites as indication may pose additional risk for PTLF. Thyroid function should be
evaluated prior to shunt creation and euthyroid status should be ensured prior to
elective TIPSS. In cases of refractory hyperammonemia complete thyroid profile is
required in addition to the standard work-up. Unlike the traditional concept of refusing
TIPSS in patients with MELD score above 18 according to newer concept these patients
may be taken for TIPSS after careful patient selection and detailed discussion with
the family. The positive outcome and decrease in incremental risk of death ultimately
benefit this subgroup of patients as well as demonstrated in some of the newer studies.[15]
Table 1
Patient profile pre-procedure
|
Patient 1 baseline profile
|
Patient 2 baseline profile
|
|
CBC (Hb/TLC/Platelet)
|
6.8/4400/65,000
|
9.1/3300/55000
|
|
LFT (Bil/OT/PT/protein/alb)
|
1.1/48/68/7.2/3/9
|
1.9/186/180/7.1/3.2
|
|
KFT (Ur/Cr)
|
32/1/1
|
111/1.5
|
|
INR
|
2.1
|
1.3
|
|
MELDNa
|
11
|
9
|
|
CPS
|
8
|
7
|
|
Others
|
_
|
TSH: 46.4
|
