Oertelt-Prigione et al. Journal of Medical Case Reports 2010, 4:141 http://www.jmedicalcasereports.com/content/4/1/141 Case presentation A 40-year-old Caucasian man with liver cirrhosis and nephrotic syndrome, presented to our Liver Unit in December 2007. His liver disease had been diagnosed when he was 14 years old. Viral and autoimmune etiolo- gies as well as inborn errors of metabolism were then excluded. After the occurrence of an episode of variceal bleeding at the age of 28, a successful prophylaxis of rebleeding with propranolol was started. From histological examinations, he had been diagnosed with hepatoportal sclerosis at age 30 and membranous glomerulonephritis at age 33 requiring the administration of furosemide (125 mg/day). In January 2008, he was admitted as an inpatient to our Unit for a full evaluation for potential liver transplanta- tion. He was asymptomatic and a physical examination revealed a slight hepatomegaly and splenomegaly, with- out asterixis, jaundice or ascites. An ultrasonography of our patient demonstrated evidence of portal hyperten- sion, including an enlarged portal vein diameter and the presence of collateral circles. His proteinuria was 3.7 g/24 hours, despite the administration of losartan 50 mg/day prescribed six weeks previously, with normal creatinine values. Thus, ramipril 2.5 mg/day was added. About 12 hours after the first dose of ramipril, our patient became unconscious. His Glasgow Coma Scale (GCS) was 6 (O1, V1, M4), blood pressure (BP) 130/80 and heart rate (HR) 60 bpm. No substantial changes from baseline were observed in biochemistry and blood gas analysis (Table 1); while his toxicological screening was negative. A cerebral computed tomography (CT) scan revealed no signs of compression or bleeding, while an electroencephalogram (EEG) showed overall slow brain activity compatible with toxic or metabolic alterations. His oral therapy was withdrawn and treatment with lactulose enema and intravenous hydration with branched-chain amino-acids was started, leading to recovery within 30-36 hours. After return to full con- sciousness, angiotensin block was re-introduced and after 48 hours his encephalopathy symptoms relapsed (GCS = 6). His CT scan was again negative and his EEG was simi- lar to the previous one; while his blood ammonia concen- tration was dramatically elevated to 990 μg/dL. Our patient was admitted to the intensive care unit (ICU), where the episode was successfully treated. Angiotensin block was re-introduced for a third time with an addition of maximal lactulose therapy (oral and by enema) and oral rifaximin. By then, our patient was awake and conscious, although imperceptive and detached from his environment. After four days, ACEIs and ARBs were withdrawn, leading to a complete neuro- logical recovery. He was discharged and remained asymptomatic with no further episodes of hepatic Page 2 of 4 encephalopathy with low (normal) ammonia levels at repeated checks for 10 weeks. Discussion and conclusion Targeting the renin-angiotensin system for BP control was introduced in the 1980s by the approval of the two main classes of drugs: ACEIs which are agents that hinder the conversion of angiotensin I (ATI) to the vasoactive angiotensin II (ATII), and ARBs which inhibit the ATI receptor involved in vasoconstriction, aldosterone secre- tion and sodium reabsorption. Both agents demonstrated similar efficacy profiles, leading to recent debates over the selection of initial antihypertensive medications [3]. Several clinical trials on humans were designed to investigate the effects of these agents, alone or in combi- nation, in the control of hypertension [4,5], heart failure [6,7] and proteinuric kidney disease [2]. Most results con- firmed that the ACEI and ARB combination therapy induced a slight improvement in hypertension control [4] and a definite reduction of proteinuria if concomitant renal damage was present [8,9]. However, increased inci- dences of hypotensive episodes [6,7], moderate to severe hyperkalemia [7] and adverse renal outcomes [2], the lat- ter primarily reported in patients without proteinuria; have led to a reconsideration of the balance between the risks (increases of serum creatinine) and benefits (reduc- tions of proteinuria) of the ACEI and ARB combination therapy. Renal side-effects, such as hyperkalemia and excessive reduction of the glomerular filtration rate, as well as potentially worse complications, such as acute renal failure, have to be further and more systematically evaluated. Thus, caution is advisable in the administra- tion of this combination therapy until results from several ongoing trials with specific renal endpoints (Design of combination angiotensin receptor blocker and angio- tensin-converting enzyme inhibitor for treatment of dia- betic nephropathy (VA NEPHRON-D), Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT-PKD studies, and Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) random- ized trial)are available. To the best of our knowledge, this is the first descrip- tion of a serious, life-threatening adverse effect of the ACEI and ARB combination therapy, possibly connected to liver dysfunction in a patient with portal hypertension. We infer that the unfavorable reaction could be directly related to the effect of ATII on the excretion of blood ammonia, although the contribution of co-morbidity and multiple drug therapy cannot be ruled out. As previously described in animal models [10], ATII is essential to the control of ammonia production and excretion by the proximal tubule. Although the effects on