Rajiv R. Varma

Minimal hepatic encephalopathy is associated with motor vehicle crashes: the reality beyond the driving test.

Patients with minimal hepatic encephalopathy (MHE) have impaired driving skills, but association of MHE with motor vehicle crashes is unclear. Standard psychometric tests (SPT) or inhibitory control test (ICT) can be used to diagnose MHE. The aim was to determine the association of MHE with crashes and traffic violations over the preceding year and on 1‐year follow‐up. Patients with cirrhosis were diagnosed with MHE by ICT (MHEICT) and SPT (MHESPT). Self and department‐of‐transportation (DOT)‐reports were used to determine crashes and violations over the preceding year. Agreement between self and DOT‐reports was analyzed. Patients then underwent 1‐year follow‐up for crash/violation occurrence. Crashes in those with/without MHEICT and MHESPT were compared. 167 patients with cirrhosis had DOT‐reports, of which 120 also had self‐reports. A significantly higher proportion of MHEICT patients with cirrhosis experienced crashes in the preceding year compared to those without MHE by self‐report (17% vs 0.0%, P = 0.0004) and DOT‐reports (17% vs 3%, P = 0.004, relative risk: 5.77). SPT did not differentiate between those with/without crashes. A significantly higher proportion of patients with crashes had MHEICT compared to MHESPT, both self‐reported (100% vs 50%, P = 0.03) and DOT‐reported (89% vs 44%, P = 0.01). There was excellent agreement between self and DOT‐reports for crashes and violations (Kappa 0.90 and 0.80). 109 patients were followed prospectively. MHEICT patients had a significantly higher future crashes/violations compared to those without (22% vs 7%, P = 0.03) but MHESPT did not. MHEICT (Odds ratio: 4.51) and prior year crash/violation (Odds ratio: 2.96) were significantly associated with future crash/violation occurrence. Conclusion: Patients with cirrhosis and MHEICT have a significantly higher crash rate over the preceding year and on prospective follow‐up compared to patients without MHE. ICT, but not SPT performance is significantly associated with prior and future crashes and violations. There was an excellent agreement between self‐ and DOT‐reports. (HEPATOLOGY 2009.)

Probiotic Yogurt for the Treatment of Minimal Hepatic Encephalopathy

OBJECTIVES:Minimal hepatic encephalopathy (MHE), the preclinical stage of overt hepatic encephalopathy (OHE), is a significant condition affecting up to 60% of cirrhotics. All MHE therapies modify gut microflora, but consensus regarding MHE treatment and long-term adherence studies is lacking. The aim was to determine the effect of probiotic supplementation in the form of a food item, probiotic yogurt, on MHE reversal and adherence.METHODS:Nonalcoholic MHE cirrhotics (defined by a standard psychometric battery) were randomized with unblinded allocation to receive probiotic yogurt (with proven culture stability) or no treatment (no Rx) for 60 days in a 2:1 ratio. Quality of life (short form [SF]-36), adherence, venous ammonia, model of end-stage liver disease (MELD) scores, and inflammatory markers (tumor necrosis factor [TNF]-α, interleukin [IL]-6) were also measured. Outcomes were MHE reversal using blinded scoring, OHE development, and adherence.RESULTS:Twenty-five patients (17 yogurt, 8 no Rx; 84% Child class A) were enrolled. A significantly higher percentage of yogurt patients reversed MHE compared to no Rx patients (71% vs 0%, P= 0.003, intention-to-treat). Yogurt patients demonstrated a significant improvement in number connection test-A (NCT-A), block design test (BDT), and digit symbol test (DST) compared to baseline/no Rx group. Twenty-five percent of no Rx versus 0% of yogurt patients developed OHE during the trial. Eighty-eight percent of yogurt patients were adherent. No adverse effects or change in covariates were observed. All patients who completed the yogurt arm were agreeable to continue yogurt for 6 months if needed.CONCLUSIONS:This trial demonstrated a significant rate of MHE reversal and excellent adherence in cirrhotics after probiotic yogurt supplementation with potential for long-term adherence.

Inhibitory Control Test for the Diagnosis of Minimal Hepatic Encephalopathy

BACKGROUND & AIMS Minimal hepatic encephalopathy (MHE) is difficult to diagnose. The Inhibitory Control Test (ICT) measures response inhibition and has diagnosed MHE with 90% sensitivity and specificity in a selected population; high lure and low target rates indicated poor ICT performance. We studied the reliability and validity of ICT for MHE diagnosis. METHODS ICT was compared with a psychometric battery (standard psychometric tests [SPT]) for MHE diagnosis and overt hepatic encephalopathy (OHE) prediction. ICT was administered twice for test-retest reliability, before/after transvenous intrahepatic portosystemic shunting (TIPS), and before/after yogurt treatment. The time taken by 2 medical assistants (MA) to administer ICT was recorded and compared with that of a psychologist for cost analysis. RESULTS One hundred thirty-six cirrhotic patients and 116 age/education-matched controls were studied. ICT (>5 lures) had 88% sensitivity for MHE diagnosis with 0.902 area under the curve for receiver operating characteristic. MHE-positive patients had significantly higher ICT lures (11 vs 4, respectively, P = .0001) and lower targets (92% vs 97%, respectively, P = .0001) compared with MHE-negative patients. The test/retest reliability for ICT lures (n = 50, r = 0.90, P = .0001) was high. ICT and SPT were equivalent in predicting OHE (21%). ICT lures significantly worsened after TIPS (n = 10; 5 vs 9, respectively; P = .02) and improved after yogurt supplementation (n = 18, 10 vs 5, respectively; P = .002). The MAs were successfully trained to administer ICT; the time required for test administration and the associated costs were smaller for ICT than for SPT. CONCLUSIONS ICT is a sensitive, reliable, and valid test for MHE diagnosis that can be administered inexpensively by MAs.

Navigation skill impairment: Another dimension of the driving difficulties in minimal hepatic encephalopathy

Patients with minimal hepatic encephalopathy (MHE) have attention, response inhibition, and working memory difficulties that are associated with driving impairment and high motor vehicle accident risk. Navigation is a complex system needed for safe driving that requires functioning working memory and other domains adversely affected by MHE. The aim of this study was to determine the effect of MHE on navigation skills and correlate them with psychometric impairment. Forty‐nine nonalcoholic patients with cirrhosis (34 MHE+, 15 MHE−; divided on the basis of a battery of block design, digit symbol, and number connection test A) and 48 age/education‐matched controls were included. All patients underwent the psychometric battery and inhibitory control test (ICT) (a test of response inhibition) and driving simulation. Driving simulation consisted of 4 parts: (1) training; (2) driving (outcome being accidents); (3) divided attention (outcome being missed tasks); and (4) navigation, driving along a marked path on a map in a “virtual city” (outcome being illegal turns). Illegal turns were significantly higher in MHE+ (median 1; P = 0.007) compared with MHE−/controls (median 0). Patients who were MHE+ missed more divided attention tasks compared with others (median MHE+ 1, MHE−/controls 0; P = 0.001). Similarly, accidents were higher in patients who were MHE+ (median 2.5; P = 0.004) compared with MHE− (median 1) or controls (median 2). Accidents and illegal turns were significantly correlated (P = 0.001, r = 0.51). ICT impairment was the test most correlated with illegal turns (r = 0.6) and accidents (r = 0.44), although impairment on the other tests were also correlated with illegal turns. Conclusion: Patients positive for MHE have impaired navigation skills on a driving simulator, which is correlated with impairment in response inhibition (ICT) and attention. This navigation difficulty may pose additional driving problems, compounding the pre‐existing deleterious effect of attention deficits. (HEPATOLOGY 2008.)

Inhibitory Control Test Is a Simple Method to Diagnose Minimal Hepatic Encephalopathy and Predict Development of Overt Hepatic Encephalopathy

OBJECTIVES:To compare inhibitory control test (ICT), a simple/rapid test of attention, to a standard psychometric battery (SPT) to diagnose minimal hepatic encephalopathy (MHE) and predict development of overt hepatic encephalopathy (OHE) in cirrhotic patients.METHODS:Fifty nonalcoholic cirrhotics and 50 age/educational-status-matched controls were given ICT and SPT in the same sitting. Performance impaired beyond two standard deviations of controls was considered MHE in cirrhotics. ICT results (lure/target response and lures/person) were compared between controls and cirrhotics and within cirrhotics with/without MHE. Receiver-operating characteristic analysis was used to study ICT for MHE diagnosis. Twenty subjects were administered SPT and ICT twice to assess test–retest reliability. All cirrhotics were followed routinely for the development of OHE.RESULTS:Cirrhotics performed worse than controls on SPT and ICT. Using SPT, 39 cirrhotics had MHE. ICT was administered faster than SPT (15 vs 37 min). Cirrhotics with MHE had significantly higher lure (28% vs 3%) and lower target response (91% vs 96%) compared with those without MHE. Lure/person >5 had 90% sensitivity/specificity for MHE diagnosis. AUC for receiver-operating characteristic for lures alone was 95.8%. Lure and target responses were highly correlated (r = 0.9) between sessions showing high test–retest reliability. Five (10%) patients developed OHE on f/u of 26 ± 10 months; all five had been diagnosed with MHE using ICT and SPT. None of the five patients with discordant results on SPT and ICT developed OHE.CONCLUSIONS:ICT has good sensitivity/specificity for MHE diagnosis, is reliable and is equivalent to SPT for predicting OHE development.

High-dose vitamin E supplementation does not diminish ribavirin-associated haemolysis in hepatitis C treatment with combination standard alpha-interferon and ribavirin

Background : Ribavirin is associated with haemolytic anaemia. Antioxidants have been reported to decrease severity of this anaemia.

On the Nature and Excretion of the Hepatic Pigment in the Dubin-Johnson Syndrome

A dark hepatic pigment occurs in the Dubin-Johnson Syndrome (DJS) and it has been suggested but not proved that it is melanin. if acute viral hepatitis (AVH) complicates DJS, the pigment disappears from the liver and reappears after recovery. The unusually dark urine seen in a DJS patient with AVH suggested urine as the possible site of pigment excretion. We have used a sensitive new method for detecting melanin to investigate these problems. The method is based on the fact that melanin is an unusually stable free radical whose electron spin resonance (ESR) spectrum is characteristically altered by visible light, pH changes, zinc(II) and paramagnetic trace elements. Liver and urine specimens were examined in (a) a DJS patient during and after AVH, (b) patients with uncomplicated DJS, (c) patients with AVH without DJS, (d) patients with other types of hepatitis, and (e) patients with apparently normal livers. The ESR spectra indicated the absence of melanin in all specimens. A stable free radical with unusual properties was found in the liver of patients with uncomplicated DJS. This was absent from the liver of a DJS patient studied during acute hepatitis but was present in his urine. It disappeared from his urine during and after recovery from hepatitis. We conclude that the hepatic pigment in DJS is: (a) not melanin; (b) excreted in the urine during acute hepatitis; (c) a stable free radical; and (d) not present in the liver or urine in any of the other diseases that were studied.

Clomiphene citrate therapy in a patient with Laennec's cirrhosis.

Clomiphene citrate therapy was initiated in a male with Laennecs cirrhosis complicated by gynecomastia, testicular atrophy, impotence, and loss of libido. The patient had abstained from alcohol and had stable hepatic function tests for 1 year before starting therapy. Luteinizing hormone and endogenous testosterone levels were maximally elevated with low dose therapy (50 mg per day). Follicle-stimulating hormone was maximally elevated with a dose of 100 mg per day and the elevation of total estrogen levels was not affected by increasing the dose. During treatment increase in testicular size was noted with resolution of impotence and improvement of libido which continued for 6 months after cessation of therapy. Gynecomastia remained unchanged despite the increased serum testosterone. Serum prolactin was normal before and after the clomiphene citrate. Semen initially unobtainable was analyzed after completion of therapy. The patient relapsed 8 months after the course of clomiphene citrate therapy.

Exchange transfusion in hepatic coma: Factors affecting results, with long-term follow-up data☆☆☆

1. Exchange transfusion in our experience has produced a response in 42 per cent of the patients. 2. Complicating factors, primarily sepsis, have been responsible for a 50 per cent mortality in those patients who initially respond, yielding a survival rate of 21 per cent. 3. In a select group of patients with infectious hepatitis under the age of twenty-five years, the survival rate was 37.5 per cent. 4. Excess bilirubin and ammonia rebound after exchange transfusions indicates a grave prognosis. 5. All survivors have normal results on liver function studies.

Percutaneous liver biopsy in difficult cases simplified by CT or ultrasonic localization

Repeat liver biopsy guided by CT and ultrasound was performed in ten prospectively selected patients with chronic liver disease, small liver size, and a previous unsuccessful biopsy. Biopsy sites selected by both radiographic techniques were essentially similar and within 1 cm of each other. The bulk of the liver was located more posteriorly and superiorly than expected, explaining the failure of the previous unsuccessful biopsies. Adequate cores of liver 1–2.5 cm in length were easily obtained with radiologic guidance. This technique is especially useful in patients with chronic active hepatitis complicated by cirrhosis.