Petra Steindl

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.

The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C

BACKGROUND & AIMS Elevated hepatic iron concentration may affect the response to antiviral therapy in chronic hepatitis C. This study explored the contribution of genetic hemochromatosis to iron accumulation in chronic hepatitis C. METHODS HFE mutations (C282Y and H63D) were assessed in 184 patients with chronic hepatitis C virus and 487 controls. Liver biopsy specimens were available in 149 patients. Hepatic iron content was measured in 114 patients by atom-absorption spectrophotometry. RESULTS The C282Y and H63D allele frequencies were 7.06 and 11.6 in patients and 4.83 and 11.09 in controls, respectively. Eight patients were homozygotes (5 C282Y [2.7%] and 3 H63D [1.6%]), 2 compound heterozygotes (1%), and 49 heterozygotes (14 C282Y [7.6%] and 35 H63D [19%]). Biochemical evidence of iron overload was more common in patients with HFE mutations (28 of 47) than in those without (34 of 102; P = 0.0045). Histological iron grading and hepatic iron content overlapped among patients with or without mutations. A hepatic iron index of >1.9 was observed only in 1 of the 4 C282Y homozygotes and 1 of the 3 H63D homozygotes. CONCLUSIONS HFE mutations contribute to but do not fully explain hepatic iron accumulation in chronic hepatitis C. Furthermore, C282Y or H63D homozygosity in chronic hepatitis C is not necessarily associated with a high hepatic iron content.

Current concepts in the pathophysiology of hepatic encephalopathy

The mechanisms causing brain dysfunction in liver failure are still unknown. None of the various hypotheses of the pathogenesis of hepatic encephalopathy (HE) are generally accepted. Since brains of patients with HE cannot be studied with appropriate neurochemica1 or neurophysiological methods, data on cerebral function in HE are usually derived from animal studies. It is beyond the scope of this article to discuss each of the animal models in detail. However, it should be emphasized that these models reflect human disease only in certain aspects. Studies in humans concentrate on biochemical changes in body fluids, mostly in the blood. As the liver has a central role in metabolism it is not surprising that many changes will occur in liver failure. Concentrations of substances produced by the liver will decrease and those catabolised by the liver will increase. It is unknown whether such biochemical abnormalities reflect only decreased hepatic function or are also related to the development of HE. The following mechanisms may impair brain function in liver failure:

Diagnosis of Wilson's disease in an asymptomatic sibling by DNA linkage analysis

The molecular genetic diagnosis of Wilsons disease in the 5-year-old sister of a patient with Wilsons disease is reported. The girl was clinically free of disease and had no conventional biochemical markers of Wilsons disease (i.e., normal ceruloplasmin, normal copper in the serum, normal 24-hour urinary copper excretion). Diagnosis with restriction fragment length polymorphisms and a nonradioactive polymerase chain reaction-based analysis with microsatellite markers showed her to be homozygous for the disease-associated markers. A liver biopsy was performed, and a 20-fold increased liver copper content confirmed the diagnosis. The child was treated with chelation therapy with D-penicillamine. The report of this study clearly shows the advantage of DNA linkage analysis (especially polymerase chain reaction) over conventional laboratory methods for presymptomatic diagnosis of Wilsons disease before irreparable liver and neurological damage occurs. The only limitation of this DNA-based diagnosis is the fact that it is only applicable in siblings of an index patient whose diagnosis was made by phenotypic criteria.

Role of tryptophan in the elevated serotonin-turnover in hepatic encephalopathy

Summary. The increase of the brain levels of 5-hydroxyindoleacetic acid (5-HIAA) in hepatic encephalopathy (HE) suggests an increased turnover of serotonin (5-HT). To study the role of tryptophan on the increased brain 5-HT metabolism in HE, we attempted to monitor brain levels of tryptophan in rats with thioacetamide-induced acute liver failure by intravenous infu-sion of branched-chain amino acids (BCAA). The effect of this treatment on 5-HT synthesis and metabolism was investigated in five brain areas. BCAA-infusions (1 and 2 gm/kg/24 h) increased the ratio BCAA/aromatic amino acids in plasma two- and fourfold, respectively, and lowered both plasma and brain levels of tryptophan. At the higher BCAA-dose all parameters suggesting an altered brain 5-HT metabolism (increased brain levels of 5-HT and 5-HIAA, increased 5-HIAA/5-HT ratio) were almost completely normalized. These results provide further evidence for the role of tryptophan in the elevation of brain 5-HT metabolism and for a potential role of BCAA in the treatment of HE.

M3/M21 serum levels in women with adnexal masses and inflammatory diseases

The aim of the present study was to evaluate the clinical usefulness of the cytokeratin tumor marker M3/M21 as a screening marker for ovarian cancer, as a predictive marker in patients with adnexal masses and as a prognostic factor in women with ovarian cancer. To determine the specificity of the M3/M21 test, we investigated M3/M21 serum levels in several benign conditions. This retrospective study comprises 37 patients with ovarian cancer FIGO stages Ia to III. Sera of patients with benign cysts, endometriosis, pelvic inflammatory disease, inflammatory bowel disease and liver cirrhosis were evaluated in 90, 10, 38, 10 and 20 cases, respectively. With a sensitivity of 57% and a specificity of 95%, M3/M21 is not suitable as a screening marker for ovarian cancer. Although M3/M21 is able to discriminate between ovarian cancer and benign adnexal tumors (univariate logistic regression, p = 0.0003), M3/M21 does not provide information additional to CA 125. M3/M21 serum levels are elevated in several benign conditions such as liver cirrhosis and inflammatory bowel disease. In ovarian cancer patients, elevated M3/M21 serum levels prior to therapy were associated with poor overall and disease‐free survival (log‐rank test, p = 0.03; log‐rank test, p = 0.01, respectively). M3/M21, while obviously not suitable for screening or differential diagnosis of adnexal masses, could be useful as an additional prognostic factor in ovarian cancer patients. Int. J. Cancer (Pred. Oncol.) 79:434–438, 1998.

Neuropharmacologic Modulation of Hepatic Encephalopathy: Experimental and Clinical Data

Various neurochemical studies in hepatic encephalopathy (HE) (for review: 1) indicate that alterations of several neurotransmitter systems including the GABAA-benzodiazepine-ergic, glutamatergic, dopaminergic, serotoninergic, noradrenergic and opiatergic neurotransmitter systems may contribute to the pathogenesis of this syndrome, but the precise role of each of these changes remains controversial. Using specific agonists and antagonists of these neurotransmitters the importance of altered neurotransmission in HE can be examined in vivo. Such experiments may improve our understanding of the pathophysiology of HE and can ultimately help to develop better treatments. In this paper the current status of neurobehavioural studies in experimental and in human HE will be reviewed.

CLINICAL ISSUES IN THE MANAGEMENT OF ALCOHOLIC LIVER DISEASE

The syndrome of alcoholic liver disease (ALD) includes a huge variety of clinical manifestations that are the result of three factors—hepatocellular insufficiency, portal hypertension, and extrahepatic damage by alcohol. Overt hepatic disease (hepatomegaly, jaundice, ascites, and portal hypertension) may be accompanied by digestive, endocrine, hematologic, muscular, neural, and other extrahepatic manifestations. In this article, some of the more important issues in clinical routine are addressed, as are some of the controversies concerning establishment of the diagnosis.