Treatment of migraine in the setting of either renal or hepatic disease can be daunting for clinicians. Not only does the method of metabolism have to be considered, but also the method of elimination/excretion of the parent drug and any active or toxic metabolites. Furthermore, it is difficult to think about liver or kidney disease in isolation, as liver disease can sometimes contribute to impaired renal function and renal disease can sometimes impair hepatic metabolism, through the cytochrome P450 system.

A detailed search for terms related to liver disease, renal disease, and migraine management was performed in PubMed, Ovid Medline, Embase, and the Cochrane Library.For each medication, product labels were retrieved and reviewed using the US FDA website, with additional review of IBM Micromedex, LiverTox, and the Renal Drug Handbook.

This manuscript provides an overview of migraine drug metabolism and how it can be affected by liver and renal impairment. It reviews the standard terminology recommended by the US Food and Drug Administration for the different stages of hepatic and renal failure. The available evidence regarding the use of abortive and preventative medicines in the setting of organ failure is discussed in detail, including more recent therapies such as lasmiditan, gepants, and calcitonin gene-related peptide antibodies.

For acute therapy, the use of NSAIDS should be limited, as these carry risk for both severe hepatic and renal disease. Triptans can be selectively used, often with dose guideline adjustments. Ubrogepant may be used in severe hepatic disease with dose adjustment and lasmiditan can be used in end stage renal disease. Though non-medicine strategies may be the most reasonable initial approach, many preventative medications can be used in the setting of hepatic and renal disease, often with dose adjustment. This review provides tables of guidelines, including reduced dosing recommendations, for the use of abortive and preventative migraine medications in hepatic and renal failure.

Despite widespread use of lactulose and rifaximin for the treatment of hepatic encephalopathy, this complication of advanced liver disease remains a major burden on the health care system in the United States and continues to predispose to high morbidity and mortality. Several agents have surfaced over recent years with promise to treat hepatic encephalopathy and mitigate the cognitive impairment associated with this disease process. The purpose of this article is to highlight the leading emerging therapies in hepatic encephalopathy as well as their therapeutic targets.

The Child-Pugh score, the model for end-stage liver disease (MELD) score, and the occurrence of cirrhosis-related complications are independent prognostic predictors used in the assessment of chronic liver diseases.

The objectives of this study were to determine the best prognostic scoring system, and to create a combined method to predict the prognosis of liver cirrhosis more accurately.

We retrospectively reviewed 435 cirrhotic patients from January 2009 to June 2010 and evaluated their short- and medium-term survival. Child-Pugh, MELD and its advanced scoring systems were computed for each patient. The sensitivity and specificity of these scoring systems were analyzed and their validity was assessed using concordance (c)-statistics in predicting the prognosis of cirrhotic patients.

Overall, 107 patients died within 6 months and 150 patients died within 1 year. The clinical and biochemical characteristics, cirrhosis-related complications, and the scores were significantly different among the survivors and patients who died. The largest area under the receiver operating characteristic curve was 0.741 for the integrated MELD (iMELD) at 6 months and 0.713 for iMELD at 12 months, indicating that iMELD was the best scoring system tested. Given this result, we created a new scoring system that combined iMELD and an index of cirrhosis-related complications, called iMELD-C. This novel system had c indexes of 0.758 for the 6-month survival and 0.746 for the 1-year survival.

The iMELD-C score is a better predictor of both short- and medium-term survival in patients with cirrhosis.

The model for end-stage liver disease (MELD) has been used to prioritize cirrhotic patients awaiting liver transplantation. Bleeding esophageal varices, spontaneous bacterial peritonitis and hepatic encephalopathy are major complications of cirrhosis and traditional indications for liver transplantation evaluation. However, these complications are not included in the MELD and it is not clear if these complications correlate with MELD score in terms of outcome prediction. This study aimed to investigate the feasibility of cirrhosis-related complication as a prognostic predictor in 290 cirrhotic patients. The MELD score and outcome were compared between patients with and without cirrhosis-related complications. There was no significant difference of the MELD score between patients with (n = 67) and without (n = 223) complications (11.6 +/- 2.9 vs. 12.2 +/- 3.2, p = 0.184). The area under the receiver operating characteristic curve was 0.687 for MELD vs. 0.604 for complications (p = 0.174) at six months, and the area was 0.641 for MELD vs. 0.611 for complications (p = 0.522) at 12 months. A high MELD score and presence of complications had a similar profile of predictive accuracy and both were significant predictors of mortality at six and 12 months in multivariate logistic regression analysis. Patients with cirrhosis-related complications at presentation had a decreased survival compared with those without complications (p < 0.0001). In conclusion, the occurrence of cirrhosis-related complications is a predictor of poor prognosis. While early transplantation referral is recommended, these patients do not necessarily have a higher MELD score and could be down-staged in the MELD era.

To evaluate the influence of L-carnitine on mental conditions and ammonia effects on patients with hepatic encephalopathy (HE).

One hundred and fifty patients (10 patients with alcoholism, 41 patients with hepatitis virus B infection, 78 patients with hepatitis C virus infection, 21 patients with cryptogenetic cirrhosis) meeting the inclusion criteria were randomized into group A receiving a 90-d treatment with L-carnitine (2 g twice a day) or into group B receiving placebo in double blind.

At the end of the study period, a significant decrease in NH4 fasting serum levels was found in patients with hepatic encephalopathy (P<0.05) after the treatment with levocarnitine (LC). Significant differences were also found between symbol digit modalities test and block design in patients with hepatic encephalopathy (P<0.05).

Results of our study suggest an important protective effect of L-carnitine against ammonia-precipitated encephalopathy in cirrhotic patients.

The model for end-stage liver disease (MELD) is used to prioritize cirrhotic patients awaiting liver transplantation. Many cirrhosis-related complications are indications for transplantation but are not included in MELD. This study investigated the impact of these complications on survival and association with MELD.

The mortality risk of cirrhosis-related complications, including bleeding esophageal varices, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome and hepatic decompensation, was analyzed using a time-dependent Cox regression model in 227 cirrhotic patients.

A total of 281 episodes of complications occurred in 142 (63%) patients. Patients who died had a significantly higher baseline MELD score compared with those who survived (14.5 +/- 4.5 vs 12.8 +/- 3.9, P = 0.004). There was no significant difference in the MELD score between patients with and without the occurrence of complications (13.6 +/- 4.3 vs 12.9 +/- 4.0, P = 0.093). Patients with a higher baseline MELD score tended to develop early complications (rho = -0.598, P< 0.001). Using the Cox regression model, the risk ratio of mortality was 4.9 (95% confidence interval: 3.9-6.3, P< 0.0001) for each additional episode of complication.

The mortality risk increases as the number of complication episodes increases. While patients with repeated complications have a poor outcome, they do not necessarily have a higher baseline MELD score and could be down-staged in the MELD era.

Acute liver failure is a rare and life-threatening clinical syndrome following severe hepatic injury. Depending on the rapidity of its development, two distinct complications contribute to a high mortality: in hyperacute liver failure, rapid development of massive hepatic necrosis and apoptosis gives rise to severe hyperammonemia, hepatic encephalopathy and life-threatening cerebral edema. The high risk of cerebral herniation requires early listing for emergency liver transplantation. Patients with hyperacute liver failure surviving the initial episode of cerebral edema have a substantial potential for hepatic recovery. If progressive hepatic failure develops more slowly, astrocytic osmoregulation prevents cerebral herniation in most instances. Unfortunately, these patients have a small potential of hepatic regeneration and transplantation should be performed before renal failure, sepsis or multiorgan failure emerge. Experimental treatment methods including detoxification by artificial or bioartificial liver support or by stimulating hepatic regeneration are currently evaluated. Recognition of ammonia toxicity has stimulated the search for early ammonia-lowering strategies and strongly renewed the interest in dialytic therapies. Anti-apoptotic interventions are among the most promising pharmacological options for the near future.

Headache is regarded by patients as a disturbing (or unpleasant) symptom. It can be produced by either organic diseases or functional head abnormalities. Twenty-five years ago headache was supposed to be a psychosomatic angiospastic algia. Certain unusual forms were thought to be caused by triggers like anger, cough, exertion, and sexual activity. Experimental research explored the role of circulating serotonin, prostaglandin, estrogen levels, and platelet abnormalities. As computed tomography, helical computed tomography, and scanning or magnetic resonance imaging evolved, new data became available. None of the newer reports have demonstrated liver involvement as a cause of headache. This minireview intends to cover the spectrum of brain alteration in liver disease. It describes some of the pathophysiological characteristics of hepatic encephalopathy and, also, the relationship among migraine, constipation, and liver disease.

Brain oedema leading to intracranial hypertension occurs in a significant proportion of patients with acute liver failure in whom it is a leading cause of death. Although precise pathogenic mechanisms associated to this severe complication remain incompletely understood, increasing evidence points to gut-derived neurotoxins including ammonia as key mediators in cerebral osmotic and perfusion disturbances. The management of brain oedema and intracranial hypertension requires a multidisciplinar approach in a center where liver transplantation is available, as this option is the only treatment modality that provides improvement in outcome. This article reviews the most common causes of acute liver failure and the standard of supportive care management, and describes future potential therapeutic aspects of brain oedema and intracranial hypertension.

In cirrhotic patients, plasma amino acid levels are severely deranged. A decreased ratio of branched-chain to aromatic amino acids (Fischer ratio) has been implicated in the pathogenesis of hepatic encephalopathy. In this prospective study, we investigated the effects of extracorporeal detoxification on amino acid levels using a sorbent suspension dialysis system. Twenty patients with documented cirrhosis and hepatic encephalopathy grade II-III not responding to standard treatment were randomized to receive either six hours of sorbent dialysis and standardized conventional medical treatment or ongoing medical treatment alone. In contrast to previous uncontrolled studies, no significant effect on amino acid levels, Fischer ratio or clinical grade of hepatic encephalopathy was detected in either treatment group. In conclusion, a 6-hour treatment with sorbent dialysis did not significantly influence plasma levels of amino acids and did not ameliorate the clinical grade of hepatic encephalopathy.

Fulminant hepatic failure is a life-threatening clinical syndrome following severe hepatic injury leading to cerebral edema and brainstem herniation. Excessive mortality can be currently reduced only by timely orthotopic liver transplantation. Due to the shortage of donor organs, a considerable proportion of patients develop irreversible neurological damage, multiorgan failure or death while waiting for transplantation. Consequently, alternatives to orthotopic liver transplantation and methods of stabilizing patients on the waiting list including extracorporeal detoxification treatment are currently investigated. Recent advances in the pathophysiology of cerebral edema have challenged some of the traditional assumptions on which many blood detoxification systems are based. This article aims to integrate pathophysiology of hepatic encephalopathy and cerebral edema into a proposed future concept of liver support.

Chronic alcoholism, viral hepatitis or hepatotoxic drug overdose result in liver dysfunction which may lead to a neuropsychiatric disorder termed hepatic encephalopathy (HE). Although, the exact molecular mechanisms underlying the pathophysiology of HE are not known, excitatory/inhibitory neurotransmitter imbalance leading to dysfunction of the glutamate-nitric oxide (NO) system is thought to play a major role. Activation of the NMDA subtype of glutamate receptors leads to increase in intracellular calcium, which initiates several calcium-dependent processes including NO formation. NO is a gaseous, highly reactive, freely diffusible molecule with a short half-life. Recent studies demonstrate increased expression of the neuronal isoform of NO synthase (NOS) and the uptake of L-arginine (the obligate precursor of NO) in both chronic and acute HE. Hyperammonemia associated with liver dysfunction results in increased NO, which may lead to learning and memory impairments and cerebral edema commonly seen, particularly in acute hyperammonemia.

Paracetamol is frequently involved in intended self-poisoning, and concomitant overdosing of other drugs is commonly reported. The purpose of the study was to investigate further concomitant drug overdose in patients with paracetamol poisoning and to evaluate its effects on the outcome of the paracetamol intoxication.

Six hundred and seventy-one consecutive patients admitted with paracetamol poisoning were studied and concomitant drug intake was recorded. The relative risk of hepatic encephalopathy, death or liver transplantation, hepatic dysfunction, liver cell damage, and renal dysfunction associated with concomitant overdosing of other drugs was evaluated by multivariate analysis.

Concomitant drug overdose was found in 207 patients (31%, 95% confidence interval [CI] 27, 34%). Concomitant overdosing of benzodiazepines (99 cases), opioid analgesics (38 cases), acetylsalicylic acid (33 cases), and NSAID (32 cases) predominated. Concomitant benzodiazepine overdose was an independent risk factor in the development of hepatic encephalopathy (odds ratio [OR] 1.91; CI 1.00, 3.65) and renal dysfunction (OR 1.81; CI 1.00, 3.22). Concomitant overdosing of opioid analgesics was a protective factor in the development of hepatic encephalopathy (OR 0.26; CI 0.07, 0.96). Concomitant acetylsalicylic acid overdose was a risk factor in the development of hepatic encephalopathy (OR 4.87; CI 1.52, 15.7) and death or liver transplantation (OR 6.04; CI 1.69, 21.6). A tendency towards a more favourable outcome was observed in patients with concomitant NSAID overdose.

Concomitant overdosing of benzodiazepines or analgesics is frequent in patients admitted with paracetamol poisoning. Concomitant benzodiazepine or acetylsalicylic acid overdose was associated with more severe toxicity, whereas concomitant overdosing of opioid analgesics was associated with less toxicity.

We aimed to test the hypothesis that subclinical cognitive brain dysfunction in cirrhotic patients would deteriorate after a transjugular intrahepatic portosystemic shunt (TIPS) in the absence of clinically detectable hepatic encephalopathy.

Out of 49 consecutive cirrhotic patients receiving elective TIPS for recurrent variceal hemorrhage, we identified 22 patients who were not encephalopathic and had not undergone liver transplantation at 6-month follow-up and confirmed TIPS patency by Doppler ultrasound. Patients were tested before and 6 months after TIPS implantation using event-related (P300) cognitive evoked potentials, late somatosensory median nerve (N70) potentials, and standard psychometric tests (Mini-Mental State and trailmaking test A). Twenty-two age-matched healthy subjects served as controls.

Relative to controls, patients showed significantly impaired P300 and N70 latencies and abnormal psychometric test results at baseline. Six months after the TIPS, a further impairment of P300 latency was observed (p = 0.005), whereas no relevant changes in N70 latency and psychometric test results occurred.

In cirrhotic patients with portal hypertension, neurophysiological signs of cognitive brain dysfunction are detectable in the absence of hepatic encephalopathy. A further subclinical deterioration of cognitive processing was observed 6 months after the TIPS. These findings demonstrate an aggravation of subclinical hepatic encephalopathy after a TIPS.

Perioperative care involves many disciplines, each of which contributes in important ways. Changes in liver-transplantation care during the last 40 years can be attributed to the accumulation of improvements, discoveries, and technologic improvements across different disciplines. Here we review some of the articles that were published during the last year that relate to these advances.

To investigate the role of extracorporeal detoxification in cirrhotic patients with advanced hepatic encephalopathy not responding to medical treatment, 20 patients were randomized to receive six hours of additional sorbent dialysis or ongoing standardized medical treatment. Following treatment, the clinical stage of encephalopathy remained unchanged in both groups. Abnormal sensory evoked potentials improved following sorbent dialysis (N70 latency, 128 ms before versus 110 ms after treatment, P<0,05; cervico-cranial transmission, 7.7 ms versus 6.8 ms, P<0.01) indicating improvement in important aspects of cerebral function. In contrast, brain function remained unchanged following medical treatment (N70 latency, 114 ms versus 113 ms; cervico-cranial transmission, 7.7 ms versus 7.2 ms, P=NS, respectively). Serum benzodiazepine levels decreased significantly after sorbent dialysis but not after medical treatment. Biocompatibility of sorbent dialysis was limited and clinical complications occurred in a proportion of patients. In conclusion, a six-hour treatment with sorbent suspension dialysis did not ameliorate the clinical stage of HE but improved neurophysiologic function in cirrhotic patients who had not responded to conventional medical treatment.

Liver failure, notwithstanding advances in medical management, remains a cause of considerable morbidity and mortality in the developed world. Although bioartificial liver (BAL) support systems offer the potential of significant therapeutic benefit for such patients, many issues relating to their use are still to be resolved. In this review, these issues are examined in terms of the functions required, the cells of choice in such a system, and the most appropriate environment to optimize the function of such cells. The major functions identified to date for a BAL are ammonia detoxification and biotransformation of toxic compounds, although this somewhat belies the complexity of the functions required. Two practical choices for cell type within such a system are xenogenic hepatocytes and immortalized human hepatocyte lines. Both these choices have drawbacks, such as the transmission of zoonoses and malignant infiltration, respectively. Finally, improvements in culture conditions, such as supplemented media, biodegradable scaffolds, and coculture, offer the possibility of prolonging the differentiated function of hepatocytes in a BAL.

Hepatic encephalopathy arises from the combination of hepatocellular dysfunction and portal-systemic shunting. Encephalopathy is more prominent in advanced stages of liver cirrhosis and signals the presence of fulminant hepatic failure in patients with acute liver injury. As important as the extent of shunting is the presence of large spontaneous collaterals. Ammonia continues to be a leading toxin influencing brain function. Endogenous benzodiazepines and cytokines may contribute to one of ammonia's key effects in the brain: astrocyte swelling. The diagnosis of hepatic encephalopathy is a diagnosis of exclusion; the search for a precipitating factor should be started immediately in all cases of encephalopathy. The treatment of hepatic encephalopathy has three aims: decrease the nitrogenous load from the gut, improve the extra-intestinal elimination of ammonia and counteract central abnormalities of neurotransmission. The mainstay of treatment is directed at the colon. Newer approaches targeting the brain, such as flumazenil, have become available.