The clinical course of alcoholic cirrhosis, a condition with a high mortality, has not been well described. We examined prevalence, risk, chronology, and mortality associated with three complications of cirrhosis: ascites, variceal bleeding, and hepatic encephalopathy. We followed a population-based cohort of 466 Danish patients diagnosed with alcoholic cirrhosis in 1993-2005, starting from the date of hospital diagnosis and ending in August 2006. Data were extracted from medical charts during the follow-up period. Risk and mortality associated with complications were calculated using competing-risks methods. At diagnosis of alcoholic cirrhosis, 24% of patients had no complications, 55% had ascites alone, 6% had variceal bleeding alone, 4% had ascites and variceal bleeding, and 11% had hepatic encephalopathy. One-year mortality was 17% among patients with no initial complications, 20% following variceal bleeding alone, 29% following ascites alone, 49% following ascites and variceal bleeding (from the onset of the later of the two complications), and 64% following hepatic encephalopathy. Five-year mortality ranged from 58% to 85%. The risk of complications was about 25% after 1 year and 50% after 5 years for all patients without hepatic encephalopathy. The complications under study did not develop in any predictable sequence. Although patients initially without complications usually developed ascites first (12% within 1 year), many developed either variceal bleeding first (6% within 1 year) or hepatic encephalopathy first (4% within 1 year). Subsequent complications occurred in an unpredictable order among patients with ascites or variceal bleeding. Conclusion: Patients with alcoholic cirrhosis had a high prevalence of complications at the time of cirrhosis diagnosis. The presence and type of complications at diagnosis were predictors of mortality, but not of the risk of subsequent complications. (HEPATOLOGY 2010;51:1675-1682

Cerebral edema leading to cerebral herniation (CH) is a common cause of death in acute liver failure (ALF). Animal studies have related ammonia with this complication. During liver failure, hepatic ammonia removal can be expected to determine the arterial ammonia level. In patients with ALF, we examined the hypotheses that high arterial ammonia is related to later death by CH, and that impaired removal in the hepatic circulation is related to high arterial ammonia. Twenty-two patients with ALF were studied retrospectively. In addition, prospective studies with liver vein catheterization were performed after development of hepatic encephalopathy (HE) in 22 patients with ALF and 9 with acute on chronic liver disease (AOCLD). Cerebral arterial-venous ammonia difference was studied in 13 patients with ALF. In all patients with ALF (n ‫؍‬ 44), those who developed CH (n ‫؍‬ 14) had higher arterial plasma ammonia than the non-CH (n ‫؍‬ 30) patients (230 ؎ 58 vs. 118 ؎ 48 mol/L; P F .001). In contrast, galactose elimination capacity, bilirubin, creatinine, and prothrombin time were not different (NS). Cerebral arterial-venous differences increased with increasing arterial ammonia (P F .001). Arterial plasma ammonia was lower than hepatic venous in ALF (148 ؎ 73 vs. 203 ؎ 108 mol/L; P F .001). In contrast, arterial plasma ammonia was higher than hepatic venous in patients with AOCLD (91 ؎ 26 vs. 66 ؎ 18 mol/L; P F .05). Net ammonia release from the hepatic-splanchnic region was 6.5 ؎ 6.4 mmol/h in ALF, and arterial ammonia increased with increasing release. In contrast, there was a net hepatic-splanchnic removal of ammonia (2.8 ؎ 3.3 mmol/h) in patients with AOCLD. We interpret these data that in ALF in humans, vast amounts of ammonia escape hepatic metabolism, leading to high arterial ammonia concentrations, which in turn is associated with increased cerebral ammonia uptake and CH. (HEPATOL-OGY 1999;29:648-653.)

, PS BBB , was 0.21 mL blood/min/mL tissue in patients with HE, 0.31 in patients without HE, and 0.34 in healthy controls; similar differences were seen in basal ganglia and cerebellum. Metabolic trapping of blood 13 N-ammonia in the brain showed neither regional, nor patient group differences. Mean net metabolic flux of ammonia from blood into intracellular glutamine in the cortex was 13.4 mol/min/L tissue in patients with cirrhosis with HE, 7.4 in patients without HE, and 2.6 in healthy controls, significantly correlated to blood ammonia. In conclusion, increased cerebral trapping of ammonia in patients with cirrhosis with acute HE was primarily attributable to increased blood ammonia and to a minor extent to changed ammonia kinetics in the brain. (HEPATOLOGY 2006;43:42-50.) T he role of ammonia in the pathogenesis of hepatic encephalopathy (HE) and possible deleterious effects on brain energy metabolism and neurotransmission has been extensively studied. [1][2][3][4] The effects of experimental porta-caval anastomosis with or without pharmacological manipulations of ammonia metabolism have been examined in rat brain, 5-13 and the effects of excess ammonia have been tested in astrocyte cell cultures. 14 Human studies of cerebral uptake and metabolism of ammonia included postmortem examinations of brain tissue from patients dying of HE 15 and biochemical analysis of jugular vein blood samples. [16][17][18] More recently, ammonia metabolism has been tested in positron emission tomography (PET) studies of monkeys, 19 healthy humans, [19][20][21][22] and patients with cirrhosis and minimal HE. [20][21][22][23] The 13 N-ammonia PET technique can, in conjunction with proper compartmental analysis, give quantitative estimates of kinetic parameters in awake subjects.Results of early PET studies by Phelps et al. 19 indicated the presence of regional variations in cerebral 13 N-ammonia uptake in normal human subjects. Lockwood et al. 20 subsequently emphasized that the metabolism of ammonia to glutamine in brain influences cerebral ammonia uptake and later calculated a global rate of cerebral 13 Nammonia metabolism in patients with cirrhosis with minimal HE and healthy controls. 21,22 Recently, Ahl et al., 23 using dynamic PET studies, found no significant difference of the permeability-surface area product of the trans-

Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction.