Artificial liver support as a bridge to orthotopic liver transplantation in a case of acute liver dysfunction on Non-Alcoholic SteatoHepatitis (NASH)

Introduction

Despite recent advances in the care of critically ill patients, the prognosis of severe liver failure (SLF) remains extremely poor and orthotopic liver transplantation (OLT) represents the only definitive treatment for SLF [1] [2] [3] [4]. However a world-wide shortage of organs significantly limits a rapid and easy access to this procedure and has prompted the development of extracorporeal liver support systems as a bridge to OLT. Recently a non-cell based extracorporeal hepatic support device, namely Molecular Adsorbent Recycling System (MARS), has been employed in the clinical practice [5] [6] [7]. The MARS using hemodiafiltration with albumin and an activated charcoal adsorption column, removes both the albumin-bound toxins and the water-soluble substances (conjugated bilirubin, aromatic amino acids, free phenols, bile acids, ammonia) that rapidly accumulate in SLF. This device lacks of the side effects and the risks that may occur with cell-based Bioreactors [8] [9] [10] [11]. We report the successful use of the MARS treatment as a bridge to OLT in a patient with acute liver dysfunction on non-alcoholic steatohepatitis (NASH) [12].

Case report

A 28 year-old caucasian woman was admitted to the hospital in June 1999 presenting with nausea, vomiting and acute jaundice. Tests for anti-nuclear, anti-mithocondrial and smooth muscular antibodies were negative. A liver biopsy performed at that time was described as NASH. After two weeks of medical therapy her laboratory evaluation was normal and she was discharged. In May 2000 she clinically deteriorated and presented to a primary care hospital, where a progressive hepatic failure was diagnosed (total bilirubin levels 63.6 mg/dl, conjugated bilirubin levels 43.3 mg/dl, aspartate transaminase [AST] 90 IU/l, alanine aminotransferase [ALT] 9 IU/l, alkaline phosphatases 34 IU/l, serum ammonia 172 g/dl and bile acid 43.9 mg/dl). Futhermore, a coagulatory impairment with hypofibrinogenemia (168 mg/dl), decreased prothrombin activity (36.8 %), increased D-dimer (400 ng/dl) and antithrombin III (ATIII) activity reduction (66.4 %) was also documented. The patient had a normochromic-normocytic anemia (Hb = 7 mg/dl), but no acantocytes were observed on blood smear. Folate and B12 vitamin were within normal range. LDH was strongly elevated (1,340 IU/l). The direct and indirect Coombs’ tests were negative. The hepatitis markers serum and urine toxicology screens (drugs, mushrooms, oral contraceptives, alcohol, other hepatotoxic agents) were negative. No oesophageal varices were demonstrated by endoscopy. Intracranial hypertension and hemorrhages were excluded by cerebral CT scan. Doppler sonography showed signs of portal hypertension, moderate ascites and hepato-splenomegaly, excluding posthepatic cholestasis. A normal pulsatility index of the mesenteric and the renal arteries was demonstrated by sonography. Despite standard care, the patient clinically deteriorated and was therefore transferred to our ICU. On arrival, she was in hepatic encephalopathy (HE) grade III, according to Conn and Leevy [13], and fullfilled the criteria of status 2 A in the United Network for Organ Sharing (UNOS) classification [14]. The SAPS II score was 23, the hemodynamic, respiratory, ventilatory and renal parameters were monitored and resulted stable. The next day her neurologic, metabolic, biochemical parameters further deteriorated and we decided to start the MARS treatment, as described by Stange and coll. We used a standard system for Continuos Renal Replacement Therapy (CRRT) (BAXTER System BM11-BM14 Monitor) and a closed-loop albumin circuit (MARS Monitor, Teraklin, Rostock, Germany). A double-lumen catheter was placed in the superficial femoral vein for the MARS treatment. The blood circuit is driven by the CRRT Monitor pump with a blood flow rate of 150 ml/min. The blood passes through a non-albumin permeable high flux dialysis membrane (MARS FLUX 1S, Teraklin, Rostock, Germany). A closed-loop dialysate circuit, containing 1.5 l of a buffered 20 % Human Serum Albumin (HSA), is driven by the MARS Monitor pump with a mean flow rate of 150 ml/min. The dialysate HSA passes through the dialysate compartment of the blood dialyzer and subsequently is filtered through a low flux dialyzer (Dia FLUX 1S, Teraklin, Rostock, Germany), an uncoated charcoal column (Dia MARS AC 25, Teraklin, Rostock, Germany) and at least an anion exchanger column (Dia MARS IE 250, Teraklin, Rostock, Germany). Intravenous heparin was used for the maintenance of the extracorporeal circuit and the dosage was adjusted to maintain an activated clotting time between 150-200 seconds. Standard care included digestive decontamination, enteral and parenteral nutritional support, diuretics, vitamins, fresh frozen plasma (FFP) and blood transfusions (BT) during the treatment period. The patient gave informed consent to the MARS procedure. We performed 4 MARS treatments, lasting 6 hours each, until a donor organ became available.

During the MARS treatment no hemodynamic abnormalities, technical problems (i. e., embolization, thrombosis, bleeding) or significant adverse reactions occured. The effect of the MARS on liver function tests, serum electrolytes, hematologic and coagulatory parameters are listed in Table [1]. During each procedure we observed a decrease in both total and conjugated bilirubin and in bile acid and ammonia concentrations. After the first treatment, the increased level of responsiveness was documented. Moreover, the improvement in neurologic status, confirmed by the writing specimen (Fig. [1] A-B) and the reduction in the HE grade (grade III versus grade I), was maintained until OLT was successfully performed.

Table 1 Effect of the MARS treatment on biochemical and hematologic parameters Parameters I treatment II treatment III treatment IV treatment pre post pre post pre post pre post Total bilirubin (0.3-1.2 mg/dL) 77.5 46.4 66.4 40.3 41.8 29.6 42.3 28 Conjugated bilirubin (0.1-0.3 mg/dL) 47.3 34 44 27.7 28.9 19.6 29.8 18.8 Bile acid (< 6.0 µmol/dL) 43.9 19.7 46.1 23 62.2 47.8 112.5 100.2 Ammonia (20-80 γ/dL) 177 160 205 170 142 38 193 49 Platelets (140-450* 109 /L) 141 135 122 118 82 77.1 49 47.8 INR (0.80-1.20) 2.06 2.16 3.46 2.99 2.84 2.79 4.15 3.33 ATIII (70-120 %) 66.4 57.9 49.9 52.3 50.0 43.5 40 50.7 Sodium (135-145 mmol/L) 145 139 138 138 129 134 126 133 Potassium (3.5-5 mmol/L) 3.1 3.5 3.1 3.4 4.2 3.6 4.8 4.2 Osmolarity (mmOsm/Kg) 290 283 281 282 262 270 260 269 Lactic acid (0.7-2.5 mmol/L) 4 3.8 3.5 5.3 3.5 3.4 4 4.1 Hemoglobin (12-16 g/dL) 7.4 6.0 8.5 8.27 7.6 7.35 6.4 6.78 Fig. 1 A, B A: Writing specimen before the first MARS treatment. B: Writing specimen after the third MARS treatment.

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