Georg Grimm

Wilson's disease in patients presenting with liver disease: A diagnostic challenge

BACKGROUND & AIMS In patients with Wilsons disease presenting with liver involvement, the correct diagnosis is often missed or delayed. The aim of this study was to find an algorithm for diagnosis of this difficult patient group. METHODS Clinical and laboratory findings of 55 patients with Wilsons disease were evaluated at diagnosis before treatment. Presenting symptom was chronic liver disease in 17 patients, fulminant hepatic failure in 5 patients, hemolysis in 3 patients, and neurological disease in 20 patients, and 10 patients were detected by family screening (siblings). Evaluation included neurological and ophthalmologic examination, routine laboratory tests, and parameters of copper metabolism including liver copper content in 43 liver biopsy specimens. RESULTS In the whole group, serum ceruloplasmin level was <20 mg/dL in 73%, urinary copper excretion was increased in 88%, and liver copper content was elevated in 91% at diagnosis. Kayser-Fleischer rings were detected in 55%. In contrast to patients with neurological disease (90% Kayser-Fleischer rings, 85% low ceruloplasmin), only 65% of patients presenting with liver disease were diagnosed by these typical findings. Ceruloplasmin levels were lower in patients with Kayser-Fleischer rings or with neurological disturbances than in patients without these symptoms. CONCLUSIONS The commonly used clinical and laboratory parameters are not sufficient to exclude the diagnosis of Wilsons disease in patients with liver disease of unknown origin.

Early prediction of individual outcome after cardiopulmonary resuscitation

Prediction of individual outcome after cardiopulmonary resuscitation is of major medical, ethical, and socioeconomic interest but uncertain. We studied the early predictive potency of evoked potential recording after cardiac arrest in 66 resuscitated patients who returned to spontaneous circulation but were unconscious and mechanically ventilated. Detailed long-latency and short-latency sensory evoked potentials were recorded and neurological evaluations were done 4-48 h after admission to intensive care. In all 17 patients with favourable outcome (cerebral performance categories 1 and 2) the cortical evoked potential N70 peak, a reliable measure of cortical function, was detected between 74 and 116 ms. In 49 patients with bad outcome (categories 4 and 5) the N70 peak was absent in 35 or found with a delay between 121 and 171 ms in 14 (p < 0.05 vs favourable outcome). Thus the predictive ability was 100% with cutoff of 118 ms. To confirm reproducibility and validity, repeated tracings, and linked-earlobe referenced techniques were done and gave similar results. Early recording of long-latency evoked potentials after cardiopulmonary resuscitation is highly predictive of outcome.

Improvement of hepatic encephalopathy treated with flumazenil.

The effects of the benzodiazepine antagonist flumazenil were studied in 20 episodes of hepatic encephalopathy (HE) in 17 patients with acute (n = 9) or chronic (n = 8) liver failure who had not responded to conventional therapy. Patients with a history of benzodiazepine intake were excluded. Changes in HE stage, in Glasgow coma scale, and in somatosensory evoked potentials were measured. In 12 of 20 episodes HE stage improved. The response to treatment occurred rapidly (within 3-60 min). In 8 of these 12 episodes HE worsened 0.5-4 h after treatment. In 5 of the 8 episodes that did not respond to flumazenil patients had clinical evidence of brain oedema. Flumazenil may be valuable in the treatment of HE in acute and chronic liver failure.

Successful long-term treatment of portal-systemic encephalopathy by the benzodiazepine antagonist flumazenil

A patient with portal-systemic encephalopathy refractory to standard therapy (40-g protein diet, oral neomycin and lactulose, supplementation of diet with branched chain amino acids) following extensive liver resection and construction of a portacaval shunt was treated with 25 mg of flumazenil twice daily by mouth. Before treatment with flumazenil she was encephalopathic and experienced 12 attacks of coma within 2 yr. When treated with flumazenil all signs of encephalopathy abated in spite of an unrestricted dietary intake of protein. Two days after discontinuation of flumazenil treatment she became comatose again. She remained chronically encephalopathic and had four further episodes of coma during the subsequent 3 mo. Since reinstitution of flumazenil treatment she has been well for 14 mo during follow-up without any signs of encephalopathy while on an unrestricted protein diet. Furthermore, flumazenil therapy reversed abnormalities of recordings of multimodality evoked potentials that were associated with hepatic encephalopathy. The striking remission of encephalopathy by treatment with flumazenil suggests that this benzodiazepine antagonist may be valuable in the long-term management of portal-systemic encephalopathy.

Neurological and neuropsychiatric spectrum of Wilson's disease: a prospective study of 45 cases

SummaryForty-five patients with Wilsons disease (WD) were prospectively studied: 27 had neurological deficits, 12 hepatic signs, and 6 were asymptomatic. Kayser-Fleischer rings occurred in 23 of the neurological patients and in only 4 of the hepatic patients. Neurological features were extremely variable with respect to frequency and severity. Most frequent were dysdiadochokinesis (25 patients), dysarthria (23), bradykinesia (17), and posture tremor (14). Fifteen, mainly long-term treated patients, presented with rather discrete neurological abnormalities which predominantly consisted of dysarthria and various forms of tremor. Eight patients had a parkinsonian type of neurological WD associated with signs of an organic mood syndrome. Three patients were predominantly hyperkinetic, presenting with dystonic and choreatic movements. In 1 patient, ataxia was the predominant neurological feature. There was a clear-cut correlation between the severity of neurological impairment and the restriction in functional capacity. Nine patients were not able to engage in salaried employment or were retired. Psychiatric symptoms and behavioural disorders were common, varying from mild personality and psychological disturbances to severe psychiatric illness resembling psychotic disorders and major depressive syndromes. Significant mental deterioration was not found in the patients. Disturbances of mood were observed in 12 patients, all of whom had neurological abnormalities. There was a history of an attempted suicide in 7 patients, and a history of an organic delusional syndrome in 3.

Energy Metabolism in Acute Hepatic Failure

BACKGROUND Conflicting data are available concerning energy metabolism in liver disease. Changes should be most pronounced in acute hepatic failure in which loss of 85% of liver cell mass is reported. Metabolic rate could be decreased due to impairment in liver mass but may also be increased as a result of systemic-mediator actions. To clarify this issue we studied energy metabolism in acute hepatic failure. METHODS Energy metabolism was evaluated by indirect calorimetry in 12 patients with acute liver failure and 22 sex-, age-, and body size-matched healthy individuals. In controls and 5 patients, studies were performed in the postabsorptive state; the remaining 7 patients received glucose at a rate of 8 mumol/kg body weight.min to prevent hypoglycemia. RESULTS Resting energy expenditure was increased in acute liver failure compared with healthy controls (5.1 +/- 0.14 kJ.min-1 x 1.73 m-2 vs. 3.97 +/- 0.08 kJ.min-1 x 1.73 m-2; mean +/- SEM; P < 0.001). Respiratory quotient and oxidation rates for major fuels were not different between the total patient-group and controls. In patients without glucose supply, energy derived from fat was higher and from carbohydrate lower than in healthy controls and patients with glucose supply. CONCLUSIONS Energy expenditure is increased in acute liver failure. Altered substrate oxidation can be normalized by glucose supply.

Prevention of upper gastrointestinal bleeding in long-term ventilated patients: Sucralfate versus ranitidine

Thirty-two long-term ventilated patients were randomly selected for a study of the efficacy of sucralfate (1 g six times per day via gastric tube) versus ranitidine (six 50-mg to six 100-mg doses per day intravenously) for the prevention of upper gastrointestinal bleeding. The patients of the two treatment groups (each 16) were comparable with respect to diseases precipitating acute respiratory failure and risk factors of bleeding, e.g., renal failure, thrombopenia, coagulopathy, and anticoagulant treatment. Mean duration of mechanical ventilation was 7.4 in sucralfate- and 7.7 days in ranitidine-treated patients. During mechanical ventilation, macroscopically visible bleeding developed in three of the sucralfate-treated (18.7 percent) and seven of the ranitidine-treated (43.7 percent) patients. Until the end of the study, only three of the sucralfate-treated but nine of the ranitidine-treated (56.2 percent) patients bled; the difference between the two treatment groups was at all times significant (p less than 0.05). Packed red blood cells had to be administered to the three bleeding patients in the sucralfate group and to seven bleeding in the ranitidine group. Therefore it seems that sucralfate prevented mostly minor bleeding. The high bleeding rate during ranitidine treatment was presumably due to the high number of pH-nonresponders, as almost 30 percent of the gastric aspirates of this group had a pH less than 5. During treatment no difference was found in positive blood culture specimens and bronchial secretions between the two groups. However, nosocomial pneumonia developed in two ranitidine-treated patients, whereas that complication developed in none of the sucralfate-treated patients. In long-term ventilated patients, sucralfate prevented minor upper gastrointestinal bleeding significantly better than ranitidine. However, this does not imply that major upper gastrointestinal bleeding can be prevented by either sucralfate or ranitidine in these patients.

Evoked potentials in assessment and follow-up of patients with Wilson's disease

Treatment of 9 patients with Wilsons disease was prospectively studied with evoked potentials and magnetic resonance imaging (MRI). Oral penicillamine therapy led to a decrease in auditory brainstem (ABP) and somatosensory (SEP) conduction times in 6 and 4 neurologically symptomatic patients, respectively. ABP and SEP were normal in 3 other symptom-free patients. MRI showed cerebral lesions in 4 of 7 patients. Quantified indices of brain atrophy were unaffected by treatment. ABP and SEP may reveal a reversible component of the disease that cannot be detected by MRI, and may be a more sensitive measure of treatment efficacy.

Detailed evaluation of evoked potentials in Wilson's disease ☆

Detailed evoked potentials (EPs) were studied in 52 patients (28.7 +/- 11.9 years) with Wilsons disease (WD). Various peak latencies, interpeak latencies and amplitudes of somatosensory, auditory brain-stem and visual EPs were significantly abnormal in the group of 28 neurologically symptomatic patients as compared to controls. Interhemisphere latency and amplitude differences tended to be increased without reaching significance, indicating a symmetrical rather than focal subclinical brain involvement. Selected conduction times of at least 1 EP modality were prolonged in all 4 patients with severe, in 16 of 18 with moderate, in 4 of 6 with mild, and in 4 of 24 patients without neurological symptoms. Auditory brain-stem and somatosensory EPs were more frequently prolonged than visual EPs (more abnormalities with check sizes of 13 than 54 min of arc). Cortical somatosensory EPs correlated well (P much less than 0.01) with either Fz or earlobe reference.

Pancreatitis in acute hemolysis

SummaryForty cases of hemolysis (drop of hematocrit > 12%/12 h) were retrospectively analyzed for hyperamylasemia and pancreatic complications. In 15 subjects the serum amylase level was > 360 U/l, i.e., three times the normal range, in ten the amylase level exceeded 900 U/l. Excluding patients in circulatory shock and/or hepatic coma, acute pancreatitis as defined by an elevation of serum amylase and clinical signs (epigastric pain) was present in four, with additional ultrasound findings (pancreatic swelling) and/or laparatomy/postmortem findings in a further six subjects (total ten patients = 25%) with various causes of hemolysis: autoimmune hemolysis 2, microangiopathic hemolytic anemia 2, toxicemia, G-6-PDH deficiency, septic abortion, malaria, Wilsons disease, and hypophosphatemia, one case each. In all subjects acute renal failure and in seven an activation of intravascular coagulation was seen. Three patients died (33% vs 47% of all hyperamylasemic patients and 46% of the whole group), but none of the deaths was attributed to pancreatitis. Pancreatic postmortem findings were diffuse edema and patchy parenchymal necrosis in two cases and petechial bleeding in one case. We conclude that acute pancreatitis is a complication of massive hemolysis, occurring at a prevalence of above 20%. It may progress from diffuse edema and inflammation to focal necrosis, rarely if ever to gross hemorrhage, and does not contribute to the high mortality of massive hemolysis. Back pain in hemolysis might originate from the pancreas rather than from the kidneys.