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105]

Review Article

Low‑Volume Plasma Exchange and Low‑Dose Steroid to Treat

Severe Liver Injury
Uday Zachariah, Santhosh E. Kumar, Vijay Alexander, Lalji Patel1, Ashish Goel, C. E. Eapen
Departments of Hepatology and 1Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India

Abstract
High‑volume plasma exchange (PLEX) to treat acute liver failure is now categorized as a Category I indication (i.e., first‑line treatment as
a stand‑alone treatment or with other treatment modalities) by the American Society for Apheresis after a randomized controlled trial of
183 patients demonstrated survival benefit by this treatment. In this review, we provide an introduction to PLEX to treat acute liver failure
syndromes for hepatologists and gastroenterologists. From our recent experience of treating 188 patients with acute liver failure syndromes
with low‑volume PLEX and low‑dose steroid, we present five illustrative case histories of patients who benefitted from this management
protocol. We discuss some postulated mechanisms how PLEX benefits patients with acute liver failure syndromes. PLEX appears to provide
survival benefit in patients with acute liver failure syndromes (severe acute liver injury, acute liver failure, and acute‑on chronic liver failure)
and may be a nontransplant treatment option for some of these patients, especially in resource‑constrained settings.

Keywords: Acute liver failure, nontransplant therapy, plasma exchange

Introduction
Therapeutic plasma exchange  (PLEX) is used to treat a
variety of disorders: neurological diseases (such as Guillain–
Barre syndrome), renal diseases  (Good Pasture’s syndrome
and hemolytic uremic syndrome), and hematological
diseases  (thrombotic thrombocytopenic purpura) for many
decades. Different abbreviations for therapeutic PLEX in
use include TPE, PEX, or PLEX. The published literature
supports the use of therapeutic apheresis to treat 84 diseases
for 157 indications.[1] Recently, there is increasing evidence
supporting the use of PLEX to treat patients with acute liver
failure. For the purpose of this review, we have considered
severe acute liver injury, acute liver failure (hyperacute liver
failure, acute liver failure, and subacute hepatic failure), and
acute‑on chronic liver failure (ACLF) under the broad heading
of acute liver failure syndromes.
Introduction to Plasma Exchange and Some
Technical Aspects
When anticoagulated blood is centrifuged, it separates out
into plasma and blood cells. The 5 L of blood volume in an
adult broadly comprises of hematocrit (packed cell volume)
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of 45% and plasma volume of 55%. PLEX has two steps:
plasmapheresis (i.e., removal of plasma from the body) and
replacement with fluids such as isotonic  (5%) albumin or
fresh frozen plasma. A combination of 5% albumin (70% of
the replaced volume) and normal saline can also be used as a
replacement fluid; however, there remains an increased risk
of hypotension during PLEX.[2]
In coagulopathic patients, like patients with acute liver failure,
fresh frozen plasma is the preferred replacement fluid. In addition
to supplementation of a balance of both pro‑ and anti‑coagulant
factors, we believe that the use of fresh frozen plasma as the
replacement fluid in patients with liver failure helps to prevent
sepsis. Patients with acute liver failure syndromes are prone to
bacterial sepsis. It is possible that removal of plasma during the
Address for correspondence: Dr. C. E. Eapen,
Department of Hepatology, Christian Medical College, Vellore,
Tamil Nadu, India.
E‑mail: eapen@cmcvellore.ac.in
Submitted: 16-Aug-2020 Revised: 25-Aug-2020
Accepted: 26-Aug-2020 Published: 23-Mar-2021
This is an open access journal, and articles are distributed under the terms of the Creative
Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to
remix, tweak, and build upon the work non‑commercially, as long as appropriate credit
is given and the new creations are licensed under the identical terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com

DOI: How to cite this article: Zachariah U, Kumar SE, Alexander V, Patel L,
10.4103/ghep.ghep_18_20 Goel A, Eapen CE. Low-volume plasma exchange and low-dose steroid to
treat severe liver injury. Gastroenterol Hepatol Endosc Pract 2021;1:47-54.

© 2021 Gastroenterology, Hepatology and Endoscopy Practice | Published by Wolters Kluwer - Medknow 47
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Zachariah, et al.: Low‑volume plasma exchange and steroid to treat acute liver failure
plasmapheresis arm of PLEX will remove some of the humoral
defenses against bacteria such as antibodies or immunoglobulins
and predispose the patient to sepsis. By replacing fresh frozen
plasma at 1:1 exchange for the volume of plasma removed, the
patient receives the humoral defenses present in the plasma of
the healthy blood donor. This should avoid any increased risk
of sepsis due to PLEX in acute liver failure.
The blood taken out of the patient is separated out into cells
and plasma by two methods: centrifugation or filtering through
a membrane. Studies comparing the two methods over the
last decade favor centrifugal PLEX due to greater plasma
removal efficiency; shorter duration of PLEX; more flexible
vascular access options; lower flow rates (reduced volume and
pressure fluxes); and fewer, milder adverse events.[3‑5] While
an anticoagulant is used in both procedures, blood clotting
and development of a secondary membrane on the filter
lead to circuit failure more often during membrane filtration
for PLEX. In contrast, circuit failure attributable to clotting
has not been reported during centrifugal PLEX. In the acute
inflammatory milieu of acute liver failure, the blood cells are
already activated and filtering these cells through a membrane
may activate them further. Hence, we feel that the centrifugal
method of plasma separation is the preferred option when
PLEX is used to treat acute inflammatory syndromes such as
acute liver failure or ACLF.
Liver is the site of production of most coagulation factors;
hence, deranged coagulation parameters are universal in
patients with acute liver failure or acute liver injury. Bleed at
the site of central venous access insertion to perform PLEX
could be a concern in these patients. Should we choose the
femoral vein or internal jugular vein for central venous access
to perform PLEX in acute liver failure? Local bleed at the site
of femoral venous access insertion can be easily controlled
by local compression. However, the chance of line‑related
sepsis may be higher in the groin (femoral venous access) as
compared to internal jugular venous access. After analyzing
these complications with femoral versus internal jugular
venous access for PLEX in our initial 45 patients with acute
liver failure/ACLF, we have moved to using femoral site as the
preferred site of port insertion for PLEX in these patients.[6]
The complications of PLEX, if any, are mostly mild.
Anticoagulant (citrate/heparin) is needed to prevent clotting
of the blood taken out of the patient into the extracorporeal
circuit during PLEX. Citrate works as an anticoagulant by
chelating ionized calcium. Citrate toxicity is the most common
complication of PLEX (manifesting as hypocalcemia) and to
prevent this, calcium is supplemented during PLEX. The other
complications include local bleeds at the site of central venous
line insertion, line‑related sepsis, depletion of coagulation
factors, fluid overload or depletion, vasovagal episodes,
allergic or anaphylactic reaction to plasma transfusion, and
removal of medications during PLEX. As far as possible, the
timing is adjusted such that medications are administered after
the PLEX session.
48 Gastroenterology, Hepatology and Endoscopy Practice  ¦  Volume 1  ¦  Issue 2  ¦  April-June 2021
The American Society for Apheresis  (ASFA) has classified
indications for therapeutic apheresis into Category I (published
evidence supports the use of apheresis as first‑line treatment,
with or without other therapies), Category II  (published
evidence supports use of apheresis as second‑line treatment,
with or without other therapies), Category III (apheresis not
yet considered as established therapy, treatment decisions
need to be individualized), and Category IV  (published
evidence suggests that apheresis is not effective or may be
detrimental).[1] The indications for PLEX can also be classified
as emergent (PLEX to be performed within 4 h), urgent (PLEX
to be performed within 24 h), and routine.
Plasma Exchange to Treat Acute Liver Failure
Syndromes
In patients with acute liver failure, treatment with high‑volume
PLEX is considered a Category I indication with Grade 1A
recommendation (i.e., strong recommendation, with high‑quality
evidence) and treatment with PLEX is considered as Category
III indication with Grade 2B recommendation  (i.e., weak
recommendation, with moderate‑quality evidence) by the
ASFA (2019 guidelines).[1] We consider acute liver failure as an
emergent indication for PLEX, to be performed in an intensive
care unit, and PLEX for severe acute liver injury, an urgent
indication for PLEX, to be performed in a high‑dependency unit.
A randomized controlled trial conducted in Denmark, Finland,
and UK studied the effect of high‑volume PLEX on survival
in 182 patients with acute liver failure.[7] In this study, ninety
patients were randomized to standard medical treatment
and 92  patients to high‑volume PLEX  (8–12 L of plasma
exchanged with fresh frozen plasma) daily for 3  days. The
authors reported 10% increase in survival in patients treated
with PLEX (overall in‑hospital survival was 58.7% in patients
treated with high‑volume PLEX and 47.8% in patients on
standard medical treatment; P = 0.0083). The survival benefit
was more pronounced in patients who did not undergo
emergency liver transplantation. The authors concluded that
high‑volume PLEX improved liver transplant‑free survival in
these patients, probably by attenuating innate immune response
and reducing multiorgan dysfunction.
Our Experience of Low‑Volume PLEX and
Low‑Dose Steroid to Treat Acute Liver Failure
Syndromes
We have now performed PLEX in 188  patients with acute
liver failure syndromes in our department  [Figure  1]. In
contrast to the study by Larsen et al.,[7] our departmental
management protocol uses low‑volume PLEX (50% of plasma
volume (~1–1.2 L) exchanged with fresh frozen plasma daily
for 3 days) along with low‑dose steroid.[8] We target PLEX
once daily for 3 days. The need to perform PLEX is reviewed
each day based on patient’s clinical progress and how well the
patient is tolerating the procedure.
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Zachariah, et al.: Low‑volume plasma exchange and steroid to treat acute liver failure
70
64
59
60
51
50
40
30
20
13
10
1
0
2016 2017 2018 2019 2020
Figure 1: Year‑wise break up of patients who underwent PLEX to treat
acute liver failure syndromes in our department till August 2020, n = 188
We have considered the following as relative contraindications
to PLEX in patients with acute liver failure syndromes: recent
major bleeds (e.g., gastrointestinal or intracranial bleed), active
sepsis  (bacteremia), or hemodynamic instability. In select
patients with the latter two relative contraindications, we have
performed PLEX using 25% plasma volume exchange.
In our first 100 patients who underwent low‑volume PLEX
to treat liver failure, 51 patients had acute liver injury/failure
and 38 patients had ACLF.[9] The most common syndromes
of liver disease in these 100  patients were severe alcoholic
hepatitis (24 patients), rodenticidal hepatotoxicity (18 patients),
and idiosyncratic drug‑induced liver injury  (16  patients).
These 100  patients were treated in the high‑dependency
unit (72 patients) and in the intensive care unit (28 patients)
and underwent a median (with range), 3 (2–5), PLEX sessions
with 1.5 (0.5–2) L of plasma exchanged with equal volume of
fresh frozen plasma at each session.
Of 21 patients with very severe alcoholic hepatitis with Model
for End‑Stage Liver Disease (MELD) score of 32 (28–42) and
discriminant function (DF) score of 91.8 (70.7–159.6) treated
by low‑volume PLEX and low‑dose steroid, 13 patients (62%)
survived the hospital stay, without liver transplantation.[10]
Similarly, of 13 idiosyncratic drug‑induced liver injury
patients who met the criteria for liver transplantation treated by
low‑volume PLEX and low‑dose steroid, 6 patients survived
the hospital stay without liver transplantation.[11]
Of ten patients with rodenticidal hepatotoxicity who met
the listing criteria for liver transplantation  (MELD score
39  [36–40]) treated by this protocol, five patients  (50%)
survived without liver transplantation.[12]
Treatment with low‑volume PLEX improves survival in ACLF
patients, especially at milder grades of disease severity.[13]
In a study on rodenticidal hepatotoxicity conducted across
Tamil Nadu in 2019 by Tamil Nadu Chapter of Indian Society
of Gastroenterology, only one of 450 patients underwent liver
transplantation.[14] Thus, in resource‑constrained settings, liver
Gastroenterology, Hepatology and Endoscopy Practice  ¦  Volume 1  ¦  Issue 2  ¦  April-June 2021
transplantation does not appear to be a realistic treatment option
for most patients at present. Low‑volume PLEX (in contrast to
high‑volume PLEX) is more likely to be feasible in these settings.
Illustrative Cases Treated with Low‑Volume
Plasma Exchange and Low‑Dose Steroid in our
Department
We present below five illustrative case histories of patients with
acute liver failure syndromes treated with low‑volume PLEX
and low‑dose steroid, wherein the patient/patient’s family opted
not to have liver transplantation. All patients improved with
low‑volume PLEX and low‑dose steroid treatment, suggesting
that this nontransplant treatment option may benefit more
patients with these indications.
Patient 1: Severe acute hepatitis A with multiorgan
dysfunction
A 14‑year‑old boy presented with jaundice and irritability for
2  days. There was no history of neighborhood outbreak of
jaundice. There was no major past illness. Moreover, there
was no family history of liver disease. On examination, icterus
was present. He was alert and conscious. Small abscess was
noted in the left gluteal region (site of intramuscular injection
administered at hometown).
His laboratory parameters are summarized in Table  1. IgM
HAV antibody was positive, and other hepatitis B, C, and E
serology were negative as were tests for Wilson’s disease and
autoimmune hepatitis.
Ultrasound abdomen revealed an enlarged liver, ascites,
borderline enlarged spleen (12 cm), bilateral pleural effusion,
and bilateral Grade 1 renal parenchymal changes.
A diagnosis of severe acute hepatitis A, acute pancreatitis, acute
kidney injury, and gluteal abscess was made. He was treated
with low‑volume PLEX and low‑dose steroid and antibiotics.
He improved remarkably with this treatment.
Patient 2: Subacute hepatic failure induced or aggravated
by herbal medicine
A 57‑year‑old female presented with jaundice for 6
months (from July 2019) and swelling of the abdomen for 2
months. She took herbal medicines to treat jaundice as oral
medications and parenterally for 2 weeks in August 2020.
Tests at her hometown
viral hepatitis serology: negative, ANA: 1+. Computed
tomography abdomen: parenchymal liver disease. At her
hometown, noting high iron indices (ferritin: 2525, transferrin
saturation: 96.5%, HFE gene mutation  [H63D, C282Y]:
negative), she was thought to have hemochromatosis and had
venesection done once on November 1, 2019. However, her
clinical condition worsened. There was no major past illness but
for hypothyroidism. There was no family history of liver disease.
On examination, she was icteric and looking unwell  (was
brought in a wheelchair). Abdomen: No ascites or organomegaly.
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Zachariah, et al.: Low‑volume plasma exchange and steroid to treat acute liver failure

Table 1: Serial laboratory parameters in a 14‑year‑old boy with severe acute hepatitis A and multiorgan dysfunction
treated with low‑volume plasma exchange and low‑dose steroid
Date
2019 January
27, 2020
November November November November November November November December
8 9 10 11 12 14 18 2
Bilirubin (mg/dL)
Total 48.1 44.6 29.4 19.9 7.8 5.2 4.4 2.1 0.3
Direct 37 35 26.6 16.9 7.4 5 4.1 1.9 0.2
Albumin (g/dL) 3.1 3.1 3.1 3 3.1 3.5 4.3 5.3 5.2
SGOT (U/L) 569 272 83 60 36 45 39 74 26
SGPT (U/L) 588 420 222 151 126 99 79 133 30
INR 1.1 1.11 1.1 1.1 1 1
Creatinine (mg/dL) 2.7 2.6 2.3 1.9 1.5 1.1 0.8 0.9
MELD 31 29 20 14 12
Ferritin (ng/mL) 5463 2096 981 801 572 50
VWF (%) 292 159 160 160 140 154 108
Amylase (U/L) 1123 102
PLEX, 2 sessions, 1 L each done on November 9 and 10, 2019. Tablet prednisolone 10 mg once daily given from November 8 to 17, 2019. Normal
plasma VWF antigen level: 50%–150%. VWF: Von Willebrand factor, MELD: Model for End‑Stage Liver Disease, INR: International normalized ratio,
SGPT: Serum glutamic pyruvic transaminase, SGOT: Serum glutamic‑oxaloacetic transaminase, PLEX: Plasma exchange

was negative. Her laboratory parameters are summarized in

Table 2: Serial laboratory parameters in a 57‑year‑old
Table 2.
female with herbal medicine‑induced subacute hepatic
failure treated with low‑volume plasma exchange and Ultrasound abdomen
low‑dose steroid An irregular liver with altered texture, omental collaterals,
Date mild ascites; spleen: normal sized.
2019 2020 We considered a differential diagnosis of herbal medicine-
December December February March induced subacute hepatic failure (OR) herbal medicine‑induced
06 12 06 04 acute liver insult superimposed on autoimmune hepatitis
Bilirubin (i.e., ACLF). The raised ferritin levels were probably due to
Total 8.5 4.9 3.7 3.3 macrophage activation. She was treated with low‑volume
Direct 5.4 3.3 2.7 2.3 PLEX and low‑dose steroid. Her clinical condition improved
Albumin 2.4 3 2.2 2.3 with this treatment. Her tiredness improved and overall felt
SGOT 225 142 119 135 better (was on wheelchair at admission here, now is ambulant
SGPT 129 83 77 72 and does all her activities independently at the last follow‑up
INR 2.5 1.9 2.1 1.8 here in March 2020).
Creatinine 0.7 0.6 0.78 0.6
MELD 25 20 20 18 Patient 3: Seronegative/idiosyncratic drug‑induced
VWF 964 612 522 subacute hepatic failure, unresponsive to high‑dose
Ferritin 1931 1268 109 89 steroid
PLEX, 1 session,  (600 mL) done on December 10, 2019. The plasma
pheresed from the patient had VWF antigen (672%). Tablet prednisolone
A 34‑year‑old female had nausea and malaise for 2  days
10 mg once daily from December 9, 2019, tapered to 5 mg once daily after 2 followed by jaundice for 2 months, and swelling of the abdomen
months, then 5 mg on alternate days after 3 months. VWF: Von Willebrand and feet for 7 days. After evaluation at her hometown, she was
factor, MELD: Model for End‑Stage Liver Disease, INR: International started on tab. prednisolone 40 mg once daily for 12 days, and
normalized ratio, SGPT: Serum glutamic pyruvic transaminase,
SGOT: Serum glutamic‑oxaloacetic transaminase, PLEX: Plasma then 30 mg once daily for 8 days. Four days ago, she also took
exchange, oral alternative medications to treat jaundice for 2 days. Two
days before presenting to out hospital, she had confusion for
Viral serology 1 day (not able to operate her mobile phone correctly).
hepatitis A–E was negative. IgG: 4182 mg%  (normal: She was treated for psoriasis 2  years ago with alternative
800%–1700% mg), IgA: 786 mg%  (normal: 140%–420% medicine for 1 month. She was planned for urgent live related
mg), IgM: 135 mg% (normal: 50%–190% mg), antinuclear liver transplantation at her hometown and had come for a
antibody: 1:80 (3+), and rest of the autoimmune hepatitis panel second opinion.

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Zachariah, et al.: Low‑volume plasma exchange and steroid to treat acute liver failure

Table 3: A 34‑year‑old female with seronegative/idiosyncratic drug‑induced subacute hepatic liver failure, unresponsive
to high‑dose steroid treated with low‑volume plasma exchange and low‑dose steroid
Date
2020
January January February February March March March March March April April
20 29 11 24 11 12 13 14 18 10 23
Bilirubin Worse
Total 4.5 6.9 9.4 11.2 clinically** 6.3 3.2 2.8 3.8 4 2.1 1.8
Direct 3.8 4.9 5 5.8 6.1 3.2 2.6 3.4 3.4 1.5 0.8
Albumin 3 2.8 2.2 2.2 2.6 2.7 2.6 2.7 3 3 2.8
SGOT 398 701 205 189 89 62 62 50 64 60 85
SGPT 130 439 144 230 70 46 46 37 37 49 56
INR 1.8 1.6
Creatinine 0.7 0.7 0.6
MELD 20 17
VWF 313 350 286 251 262
Ferritin 21 30
Steroid dose (mg)* Nil 40 30 30 10 10 10 10 10 5 5
PLEX, 3 sessions, 1.2 L each done on March 12–14, 2020. *At another center, tablet prednisolone 40 mg once daily from January 29, 2020; this was reduced
to 30 mg once daily on February 11, 2020. At our center, tablet prednisolone 10 mg once daily was given from March 11, 2020, reduced to 5 mg once daily
from April 10, 2020 (continued to date). **Ascites and pedal edema since March 04, 2020, confusion for 1 day on March 07, 2020. VWF: Von Willebrand
factor, MELD: Model for End‑Stage Liver Disease, INR: International normalized ratio, SGPT: Serum glutamic pyruvic transaminase, SGOT: Serum
glutamic‑oxaloacetic transaminase, PLEX: Plasma exchange

On examination, she was conscious, alert. Icterus was present.
Abdomen: mild ascites + Doppler and ultrasound abdomen:
Liver: normal sized, coarse, and irregular. Portal vein: normal
size (12 mm), normal color flow. Spleen: normal size. Moderate
ascites was present. There were patent hepatic veins.
Her laboratory parameters are summarized in Table 3. Review
of outside liver biopsy showed features suggestive of acute
to subacute hepatic injury, possibly due to drug/toxin. The
underlying viral/autoimmune hepatitis needed to be excluded.
We considered a diagnosis of seronegative/viral hepatitis
aggravated by alternative drug‑induced liver injury causing
subacute hepatic failure. She was treated with low‑volume PLEX
and low‑dose steroid. Her clinical condition improved with this
treatment, and there was no further episode of confusion and
remains well at her last correspondence in July 2020.
Patient 4: Rodenticidal acute liver failure
A 15‑year‑old girl was brought to our hospital with a history of
alleged ingestion of rodenticide with suicidal intent, jaundice
for 2 days, and altered sensorium for 1 day. There was no major
past illness. Along with her, other family members had also
consumed rodenticide, and her sister developed jaundice and
died at another center. On examination, the patient was agitated.
Glasgow Coma Scale score: 10/15 (Grade 3 encephalopathy),
and she was icteric. Her laboratory parameters are summarized
in Table 4.
We made a diagnosis of rodenticide‑induced acute liver failure.
She was treated with low‑volume PLEX and low‑dose steroid.
She was treated with anticerebral edema (mannitol infusions)
measures as well. She improved with the above treatment
measures and remains well at 3‑month follow‑up.
Patient 5: Very severe alcoholic hepatitis/alcohol‑related
acute‑on chronic liver failure
Patients with “very severe” alcoholic hepatitis as defined by
DF >60 or MELD score >30 have poorer survival.[15]
A 40‑year‑old male presented with jaundice for 1 month,
swelling of the abdomen, and reduced urine output for 15 days.
He had a history of significant alcohol intake daily, till 20 days
prior to presentation to our hospital. He had no major past illness.
On examination, he had icterus, pedal edema, and ascites.
His laboratory parameters are summarized in Table 5. His DF
score was 75 and MELD score was 42 on June 15, 2018. He was
diagnosed to have very severe alcoholic hepatitis/alcohol‑related
ACLF. He needed repeated therapeutic paracentesis while in
the hospital here. He was treated with low‑volume PLEX and
low‑dose steroid. He was hospitalized with pneumonia (? viral)
on July 25, 2018. He showed steady improvement after this.
He did not need further therapeutic paracentesis after PLEX
treatment. He developed diabetes mellitus in August 2019 (on
dietary restrictions and oral hypoglycemic agents). He was
quite well otherwise at his last follow‑up visit.
Is Plasma Exchange to Be Done as Rescue
Therapy for Acute Liver Failure or Earlier in
the Illness?
We had initially started PLEX to treat acute liver failure, in
patients/their families not opting for urgent liver transplantation.
Over time, we have moved to treating severe acute liver
injury with PLEX. For example, in patients with rodenticidal
hepatotoxicity and worsening coagulopathy (i.e., severe acute

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Zachariah, et al.: Low‑volume plasma exchange and steroid to treat acute liver failure

Table 4: A 15‑year‑old girl with rodenticide‑induced acute liver failure treated with low‑volume plasma exchange and
low‑dose steroid
Date
2020
June June June June June June July August
01 02 03 04 07 18 02 03
Bilirubin
Total 12.3 11.1 13.6 13.1 10.7 11.3 3.7 0.7
Direct 8.7 8.7 10.2 10.7 9.6 7.1 3.5 0.5
Albumin 3.4 3.4 2.8 2.9 2.8 4.6 4.2 4.8
SGOT 415 415 148 111 67 154 68 29
SGPT 658 658 299 214 169 114 68 25
INR 6.6 >10 1.6 1.5 1.4 0.9
Creatinine 0.8 0.5 0.4 0.4 0.3 0.4 0.5 0.5
MELD 37 24 22 21 19
VWF 546 336 323 445 216 103
Ferritin 782 391 397
PLEX 3 sessions, 800 mL each, June 02–04, 2020. Tablet prednisolone 10 mg once daily given from June 02 to 30, 2020. VWF: Von Willebrand factor,
MELD: Model for End‑Stage Liver Disease, INR: International normalized ratio, SGPT: Serum glutamic pyruvic transaminase, SGOT: Serum
glutamic‑oxaloacetic transaminase, PLEX: Plasma exchange

Table 5: A 40‑year‑old gentleman with very severe alcoholic hepatitis treated with low‑volume plasma exchange and
low‑dose steroid
Date
2018 2019 2020
June June June June June June July August October January November January
15 19 20 22 25 29 09 18 25 16 04 30
Bilirubin
Total 29 39.7 28.7 21.6 21 18.6 23.8 2.8 0.8 1.1 0.3 0.5
Direct 27 28.6 26.9 20.6 19.9 16.2 21.1 2.6 0.3 0.5 0.2 0.2
Albumin 2.3 2.7 2.5 2.6 2.4 2.5 3.4 4.5 4.4 4.6 4.5
SGOT 76 78 105 65 68 58 57 30 40 70 18 24
SGPT 41 37 37 22 24 18 26 16 29 38 16 25
INR 2.1 1.9 1.8 1.3 1.3 1.0 1.0 1.0 1.1
Creatinine 4.5 3.1 3.2 2.2 1.9 1.5 1.5 1 1.1 1.2 1.4
MELD 42 35 34 26 17 7 8 9 10
VWF 1048 808 766 681 230 348 284 270 206 212
Ferritin 3041 3184 1884 1436 1113 1383 398 286 176 287
PLEX,7 sessions from June 20–30, 2018 (1.4–1.5 L each). Tablet prednisolone 10 mg once daily dose given from June 19, 2018, reduced to 5 mg once daily
on July 09, 2018, stopped on July 14, 2018. VWF: Von Willebrand factor, MELD: Model for End‑Stage Liver Disease, INR: International normalized ratio,
SGPT: Serum glutamic pyruvic transaminase, SGOT: Serum glutamic‑oxaloacetic transaminase, PLEX: Plasma exchange

liver injury), we initiate PLEX, in addition to other supportive
treatment.
How Does Treatment with Low‑Dose Plasma
Exchange and Low‑Volume Steroid Improve
Survival in Acute Liver Failure Syndromes?
PLEX is thought to work by the removal of macromolecules – the
latter maybe different in the different disease conditions
treated by PLEX. For example, removal of antiglomerular
basement membrane antibodies by PLEX may benefit patients
with Good Pasture’s syndrome. Removal of ultra‑large Von
Willebrand factor  (VWF) multimers during plasmapheresis
as well as supplementation of VWF cleaving enzyme (called
ADAMTS13) by fresh frozen plasma transfusions is the
mechanistic basis of using PLEX to treat patients with
thrombotic thrombocytopenic purpura.
It has been suggested that PLEX improves survival in acute
liver failure patients by dampening the innate immune
activation and ameliorating multiorgan dysfunction.[7] At
present, we do not fully understand the mechanistic basis of
how PLEX is beneficial in patients with acute liver failure
syndromes. As hemodialysis has not been shown to improve
survival in acute liver failure syndromes, the survival benefit

52 Gastroenterology, Hepatology and Endoscopy Practice  ¦  Volume 1  ¦  Issue 2  ¦  April-June 2021

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Zachariah, et al.: Low‑volume plasma exchange and steroid to treat acute liver failure
conferred by PLEX in these patients may be due to the removal
of deleterious substances in the patient’s plasma which are too
large to be dialyzed.
VWF is one such candidate molecule which may be removed
at PLEX to treat acute liver failure syndromes. VWF is a
blood clotting protein, and the deficiency of VWF (termed von
Willebrand disease) is the most common inherited bleeding
disorder. However, in acute and chronic liver diseases, raised
plasma VWF levels are seen. In patients with cirrhosis, plasma
VWF levels are 2–3 fold raised and these levels predict
mortality over 24–33 months.[16] In contrast, in patients with
rat killer‑induced severe acute liver injury or acute liver
failure, plasma VWF levels are 4–4.5 fold raised and predict
death over the next 7 days.[17] In patients with ACLF, plasma
VWF levels are 7 fold raised and predict death over the next
8  days.[18] Markedly raised plasma VWF levels correlate
with organ failure and predict in‑hospital survival in patients
with severe alcoholic hepatitis, and also with “very severe”
alcoholic hepatitis.[19]
VWF is a glycoprotein which is released from endothelium
or platelets into the blood stream. VWF moieties in
circulation may be dimers, high‑molecular‑weight or ultra-
large multimers; these are large molecules. For example, the
high‑molecular‑weight VWF multimers are up to 10,000 kDa in
size.[20] It is possible that raised levels of large‑sized molecules
such as VWF in blood stream may clog up microcirculation in
vital organs such as the liver, impair perfusion of that organ,
and cause organ failure.[21]
We have demonstrated the collagen binding activity of VWF in
the plasma removed from patients with acute liver failure and
ACLF during PLEX.[22] The collagen binding activity of VWF
is thought to reflect high‑molecular‑weight VWF multimers. It
is possible that VWF‑pheresis may be one mechanism which
demonstrates how PLEX works in patients with ALF or ACLF.
Macrophage activation markers such as CD163 and CD206
correlate disease severity and predict mortality in patients
with ACLF.[23] Raised ferritin levels in patients with acute
liver failure syndromes suggest macrophage activation. We
have postulated that our management protocol with low‑dose
steroid and low‑volume PLEX helps ameliorate the endothelial
and macrophage activation in patients with acute liver failure
syndromes, which improves microcirculatory perfusion and
reduces multiorgan failure and death.[8]
Does Plasma Exchange Promote Liver
Regeneration in Patients with Acute Liver
Failure Syndromes?
We have hypothesized that acute liver failure is caused by
impaired microcirculatory perfusion due to clogging of the
microcirculation due to cell debris and large molecules such
as VWF and influx of inflammatory cells.[8] The imbalance
of high VWF and low ADAMTS13 is now better recognized
Gastroenterology, Hepatology and Endoscopy Practice  ¦  Volume 1  ¦  Issue 2  ¦  April-June 2021
in acute liver failure patients.[24] It is possible that treatment
to improve microcirculation in the liver may promote liver
regeneration and improve organ failure.
Is Plasma Exchange a Bridge to Liver Transplant
or is it Curative in Acute Liver Failure
Syndromes?
The worldwide experience with PLEX to treat liver diseases
is preliminary.[25] While PLEX has been described as a bridge
to stabilize the patient till liver transplantation, it is also likely
that many patients may survive without liver transplantation.
Plasma Exchange to Treat Acute Liver Failure:
The Future
It has been suggested that acute liver failure may be curable
without liver transplantation by 2024. [26] The need for
nontransplant therapies to treat acute liver failure and ACLF
is urgent. PLEX appears a promising nontransplant option to
treat acute liver failure syndromes.[27] PLEX to treat acute liver
failure syndrome can be done in any hospital which has renal
dialysis and blood bank facilities as well as high‑dependency
unit or intensive care unit to monitor the patient during the
procedure. While PLEX has now been shown to improve
survival in patients with acute liver failure, studies on its role
to treat ACLF patients are ongoing.[28] Our experience suggests
that low‑volume PLEX and low‑dose steroid protocol may be
beneficial in these patients, especially in resource‑constrained
settings.
Declaration of patient consent
The authors certify that they have obtained all appropriate
patient consent forms. In the form the patient(s) has/have
given his/her/their consent for his/her/their images and other
clinical information to be reported in the journal. The patients
understand that their names and initials will not be published
and due efforts will be made to conceal their identity, but
anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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