|Year : 2021 | Volume
| Issue : 2 | Page : 47-54
Low-volume plasma exchange and low-dose steroid to treat severe liver injury
Uday Zachariah1, Santhosh E Kumar1, Vijay Alexander1, Lalji Patel2, Ashish Goel1, CE Eapen1
1 Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||16-Aug-2020|
|Date of Decision||25-Aug-2020|
|Date of Acceptance||26-Aug-2020|
|Date of Web Publication||23-Mar-2021|
C E Eapen
Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
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
|How to cite this article:|
Zachariah U, Kumar SE, Alexander V, Patel L, Goel A, Eapen C E. Low-volume plasma exchange and low-dose steroid to treat severe liver injury. Gastroenterol Hepatol Endosc Pract 2021;1:47-54
|How to cite this URL:|
Zachariah U, Kumar SE, Alexander V, Patel L, Goel A, Eapen C E. Low-volume plasma exchange and low-dose steroid to treat severe liver injury. Gastroenterol Hepatol Endosc Pract [serial online] 2021 [cited 2022 May 27];1:47-54. Available from: http://www.ghepjournal.com/text.asp?2021/1/2/47/311732
| 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. 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) 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.
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 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.,, 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.
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.
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). 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). 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. 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., 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. 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.
|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|
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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. 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.
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.
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.
Treatment with low-volume PLEX improves survival in ACLF patients, especially at milder grades of disease severity.
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. Thus, in resource-constrained settings, liver 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.
|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|
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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.
hepatitis A–E was negative. IgG: 4182 mg% (normal: 800%–1700% mg), IgA: 786 mg% (normal: 140%–420% mg), IgM: 135 mg% (normal: 50%–190% mg), antinuclear antibody: 1:80 (3+), and rest of the autoimmune hepatitis panel was negative. Her laboratory parameters are summarized in [Table 2].
|Table 2: Serial laboratory parameters in a 57-year-old female with herbal medicine-induced subacute hepatic failure treated with low-volume plasma exchange and low-dose steroid|
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An irregular liver with altered texture, omental collaterals, mild ascites; spleen: normal sized.
We considered a differential diagnosis of herbal medicine-induced subacute hepatic failure (OR) herbal medicine-induced acute liver insult superimposed on autoimmune hepatitis (i.e., ACLF). The raised ferritin levels were probably due to macrophage activation. She was treated with low-volume PLEX and low-dose steroid. Her clinical condition improved with this treatment. Her tiredness improved and overall felt better (was on wheelchair at admission here, now is ambulant and does all her activities independently at the last follow-up here in March 2020).
Patient 3: Seronegative/idiosyncratic drug-induced subacute hepatic failure, unresponsive to high-dose steroid
A 34-year-old female had nausea and malaise for 2 days followed by jaundice for 2 months, and swelling of the abdomen and feet for 7 days. After evaluation at her hometown, she was started on tab. prednisolone 40 mg once daily for 12 days, and then 30 mg once daily for 8 days. Four days ago, she also took oral alternative medications to treat jaundice for 2 days. Two days before presenting to out hospital, she had confusion for 1 day (not able to operate her mobile phone correctly).
She was treated for psoriasis 2 years ago with alternative medicine for 1 month. She was planned for urgent live related liver transplantation at her hometown and had come for a second opinion.
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.
|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|
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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].
|Table 4: A 15-year-old girl with rodenticide-induced acute liver failure treated with low-volume plasma exchange and low-dose steroid|
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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.
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.
|Table 5: A 40-year-old gentleman with very severe alcoholic hepatitis treated with low-volume plasma exchange and low-dose steroid|
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| 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 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. 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 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. 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. In patients with ACLF, plasma VWF levels are 7 fold raised and predict death over the next 8 days. 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.
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. 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.
We have demonstrated the collagen binding activity of VWF in the plasma removed from patients with acute liver failure and ACLF during PLEX. 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. 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.
| 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. The imbalance of high VWF and low ADAMTS13 is now better recognized in acute liver failure patients. 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. 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. 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. 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. 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
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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