Marcia G. Villanova

Are Haemochromatosis Mutations Related to the Severity of Liver Disease in Hepatitis C Virus Infection

It has been proposed that iron overload may adversely affect liver disease outcome. The recent identification of 2 mutations in the HFE gene related to hereditary haemochromatosis (Cys282Tyr and His63Asp) provided an opportunity to test whether they are associated with hepatic iron accumulation and the activity and severity of liver disease in hepatitis C virus (HCV) infection. We investigated the prevalence of HFE mutations in 135 male patients with chronic HCV hepatitis, and correlated genotype distribution with different parameters of iron status and the activity and severity of liver disease. Of these 135 patients, 6 (4.4%) carried Cys282Tyr and 32 (23.7%) carried His63Asp, frequencies which were similar to those observed in healthy controls. Serum iron levels and transferrin saturation (but not ferritin levels or liver iron content) were significantly higher in carriers than in non-carriers of HFE mutations. No difference was observed in serum ALT, AST and GGT levels between carriers and non-carriers. Finally, scores for necroinflammatory activity and fibrosis in the liver were significantly higher in HFE carriers than in non-carriers. Patients with chronic HCV infection carrying HFE mutations tend to present more evident body iron accumulation and a higher degree of necroinflammatory activity and fibrosis in the liver. HFE gene mutations might be an additional factor to be considered among those implicated in the determination of a worse prognosis of the liver disease in chronic HCV infection.

Esophageal dysfunction does not always worsen in systemic sclerosis.

Using the manometric method, we studied the progression of esophageal involvement in 17 women with a diagnosis of systemic sclerosis (SSc) and compared the results with those obtained for 14 healthy women. The manometric examination of SSc patients was performed twice, with an interval of 9 to 111 months (median, 40 months). All patients had peristaltic contractions in the proximal esophagus. Eight had peristaltic contractions, and 9 had no contraction in the middle and distal esophagus. The lower esophageal sphincter pressure and the amplitude of contractions in the esophageal body were lower in SSc patients than in controls. The duration of contractions was the same in SSc patients and controls. The velocity of peristaltic contractions did not differ between patients and controls in the distal esophagus, but was higher in SSc patients in the proximal esophagus. In 16 patients, no difference in lower esophageal sphincter (LES) pressure, esophageal contraction amplitude, duration, and velocity was observed between the first and second evaluation. In one patient, the distal esophageal contractions changed from peristaltic to completely absent, and the lower esophageal sphincter pressure changed from 20.2 mm Hg to 5.1 mm Hg. The results suggest that the esophageal involvement of SSc patients was not progressive in all cases.

Abnormal uroporphyrin levels in chronic hepatitis C virus infection.

A strong association between hepatitis C virus (HCV) infection and porphyria cutanea tarda (PCT) has been observed, but the implications of the viral infection in the metabolism of porphyrins in patients without clinical manifestations of PCT are not known. The levels of porphyrin in plasma and uroporphyrin (URO) and coproporphyrin (COPRO) in 24-hour urine were measured in 156 patients with chronic HCV infection showing no clinical evidence of PCT. Levels of URO higher than the upper limit were observed in 35 of 156 patients (22.4%). The range and the mean values +/- standard deviation were 26-1,196 microg/24 hours and 82 +/- 204 microg/24 hours. Increased levels of COPRO and plasma porphyrin were observed in 12 of 156 patients (7.7%) and 2 of 156 patients (1.3%) respectively. There were no differences between patients with increased URO levels and patients with normal URO levels in terms of gender, age, risk factors for HCV infection, alcohol abuse, or hepatitis B viral infection. Transferrin saturation (p = 0.040), gamma glutamyl transpeptidase (p < 0.0001), aspartate aminotransferase (p = 0.006), and alanine aminotransferase (p = 0.040) were significantly higher in patients with abnormal URO than in patients with normal URO. The frequency of cirrhosis was higher, but not significantly different, in patients with increased URO (16.7%) compared with patients with normal URO (3.8%). The authors demonstrated that even without a clinical manifestation of PCT it is possible to detect abnormalities in the metabolism of porphyrins in patients with chronic HCV infection. The implications of these findings deserve additional investigation.

The H63D genetic variant of the HFE gene is independently associated with the virological response to interferon and ribavirin therapy in chronic hepatitis C.

Background Conflicting results have been reported in studies evaluating the relationship between serum markers of iron overload, liver iron deposits, and HFE mutations (C282Y and H63D) in chronic hepatitis C patients, and also their impact on the response to therapy in these patients. Aim To evaluate the role of HFE mutations in the severity of liver disease and in the response to therapy in chronic hepatitis C. Methods Two hundred and sixty-four hepatitis C patients treated with standard interferon and ribavirin were divided into two groups according to type of antiviral response: sustained virological response (SVR) and nonresponse or relapse. We evaluated the relationship between HFE mutation and the type of antiviral response, clinical data, biochemical tests, liver histopathology, virological data, and HFE mutations. Results Of the 264 patients, 88 (32.1%) had SVR whereas 67.9% had nonresponse or relapse. Liver iron deposits were observed in 49.2% of the patients. The factors associated with SVR were hepatitis C virus genotype 2 or 3, transferrin saturation value of 45% or less, and detection of the H63D mutation. HFE mutation was more frequent in patients with iron deposits, but without association with serum iron biochemistry or severity of liver disease. Steatosis was more frequent in patients with liver iron deposits. Conclusion The H63D mutation was an independent factor associated with SVR in chronic hepatitis C patients, as also were hepatitis C virus genotype 2 or 3 and transferrin saturation value of 45% or less. Moreover, the H63D mutation was associated with liver iron deposits.