Liver transplantation in case of acetaminophen poisoning: importance of assessment of the colon if arterial lactate increases despite appropriate care.

Scarcity of organs justifies efficient transplantation decision making even in toxic acute liver failure (ALF). Modified King’s College Hospital criteria are widely accepted for decision making in emergency liver transplantation (LT) after acetaminophen poisoning: they have good specificity in identifying patients with poor prognosis, but are of low sensitivity in selecting patients who will die of ALF (1). Three of our recent clinical cases illustrate why the LT decision making process should also include careful and early digestive tract assessment. After deliberate acetaminophen poisoning, three young women with no previous medical history were referred for LT in the context of ALF with coma and lactate beyond 14 mmol/L (despite proper 24-hr fluid resuscitation). In these cases, the treatment with N-acetyl cysteine (NAC) had been started beyond 15 hr after acetaminophen intake. In the first patient, the LT proceeded without incident; 48 hr later, clinical worsening and absence of improvement attested in the biological liver tests (i.e., both aspartate aminotransferase and alanine aminotransferase increase and reincrease of arterial lactate) suggested primary liver dysfunction (Table 1). An emergency surgical reintervention disclosed diffuse patches of colon infarction without vascular obstruction, despite the fact that the colon had looked normal at the end of the first LT. Segmental resections were associated to total recovery. While on waiting list for 24 hr, the second patient unexpectedly developed stiffness of the leg with an increase in plasma creatine phosphokinase levels as already reported (2); subsequently, she was withdrawn from the LT list because liver tests no longer worsened. Despite full recovery of her liver tests, the patient developed long-lasting multiple organ failure related to focal colon lesions which resulted in shock requiring multiple segmental colon removal. She ultimately survived without LT. Histological lesions of the colon were similar to those reported previously (3): foci of necrosis and intramucosal hematoma were detected in the right colon. After careful rechecking of the abdominal CT scan taken at admission in connection with long-lasting arterial lactate increase, the presence of signs of mucosa ischemia and of hematoma was confirmed (Fig. 1).TABLE 1: Biological tests on admission, at peak level (approximately 24 hr after admission), and at inscription on the transplantation waiting list (List) for each patientFIGURE 1: Typical injuries detected by CT scan of the colon. Although there were neither clinical complaints or symptoms of abdominal origin, an important edema existed within the mucosa of the colon (1); also, an unexpected lack of enhancement after iodine infusion was seen in relation with focal injuries of the digestive tract. A thin active bleeding of the parietocolonic wall of the cecum (2) was associated to intramucosal air (3) and upstream small bowel distension (4). Finally, intracecal bleeding was also present (5), yet no exteriorization of blood existed when the CT scan was performed. 141×175 mm (96×96 DPI).The third patient died with uncontrollable lactic academia while on waiting list for 4 days despite normal lactate on admission; the autopsy revealed macroscopic ischemic injury of the entire colon without thrombosis of conductance vessels. Our data further indicate that large doses of acetaminophen taken alone (i.e., without additional drugs or alcohol) trigger multiorgan insults after acute liver injury. This potential role of acetaminophen in the pathogenesis of remote organ dysfunction is in relation with many mechanisms, among which the general impairment of mitochondrial respiration and coagulation disturbance involving platelet-derived microparticles as recently reported (4). Experimental data suggest that massive acetaminophen intake induces early lactic acidosis through mitochondrial respiratory chain processes inhibition, sometimes before major hepatocyte injury has occurred: such an acidosis may be cured by early NAC infusion (1). Delayed lactic acidosis may also occur as a consequence of reduced hepatic clearance caused by ALF or as a contribution of peripheral anaerobic respiration (1). In the latter condition, NAC is unlikely to reverse lactic acidosis whose increase should prompt physicians to detect additional causes, such as rhabdomyolysis or necrotic bowel (2). Vascular injuries are not uncommon after acetaminophen poisoning in patients without previous vascular diseases (3), but they are rarely in the foreground. They were believed to be related to the coingestion of nonsteroidal anti-inflammatory drugs given that conductance vessels were of spastic appearance on angiography and thrombosis-free (3). In the absence of large vessel obstruction, it seems reasonable to explain bowel injuries by mechanisms, such as hypercoagulation and transient thrombosis-related ischemia. As previously proposed (5), some constitutive proteins, such as HMGB1, may trigger potent inflammation which is frequently associated with coagulation disturbances in acetaminophen poisoning (4). In addition, after liver necrosis, circulating microparticles contribute to a highly procoagulant state within microvessels with subsequent local foci of ischemia: in the colon, this provides a plausible explanation for secondary bleeding as shown here. In our patients, the clinically relevant acetaminophen-associated injuries occurred later than day 3 after poisoning in relation with defective microvascular irrigation of the mucosa at the colon level which may have proceeded from a combination of several of these mechanisms. Such injuries may affect the outcome even if LT is scheduled. As indicated in Figure 1, injected CT scan of the intestinal tract represents a valuable tool for assessing such injuries—even though clinically silent—when arterial lactate increases despite proper medical procedures. Francis Schneider Antoine Poidevin Sophie Riehm Jean-Etienne Herbrecht Max Guillot Services de réanimation médicale et de radiologie Hôpital de Hautepierre Hôpitaux Universitaires de Strasbourg Fédération de Médecine Translationnelle Faculté de Médecine Université de Strasbourg Strasbourg, France