Mild Liver Disease Research Articles

Comorbidity and repeat admission to hospital for adverse drug reactions in older adults: retrospective cohort study

Objectives To identify factors that predict repeat admission to hospital for adverse drug reactions (ADRs) in older adults.Design Population based retrospective cohort study.Setting All public and private hospitals in Western...

HFE C282Y homozygotes have reduced low-density lipoprotein cholesterol: the Atherosclerosis Risk in Communities (ARIC) Study

Recent studies have raised questions about the long-term health risks for individuals with mutations in the <i>HFE</i> gene, although previous studies may have been plagued by selection bias or lack of population-based comparison groups. We examined cardiovascular disease risk factors and iron and liver biomarkers, as well as morbidity and mortality associated with the C282Y and H63D variants of <i>HFE</i> in the Atherosclerosis Risk in Communities (ARIC) study, which is a population-based cohort of nearly 16,000 U.S. white and black men and women who were 45–64 years old at baseline. Subjects were followed for an average of 15 years for death, incident coronary heart disease, stroke, and heart failure, and an average of 8 years for incident diabetes. The prevalence of C282Y homozygosity was 0.42% (45/10,800) in whites, which is similar to other North American population-based studies. C282Y homozygotes had significantly lower mean low-density lipoprotein (LDL) cholesterol and fibrinogen as well as higher mean levels of iron (ferritin, transferrin saturation) and liver biomarkers (alanine aminotransferase, Hepascore) compared with <i>HFE</i> wild-type subjects. Rates of all-cause mortality, cardiovascular disease, and diabetes were similar across <i>HFE</i> genotypes. These prospective, population-based data indicate higher serum iron indices and possible mild liver dysfunction or disease in some C282Y homozygotes, but they provide little evidence that <i>HFE</i> C282Y or H63D mutations are related to all-cause mortality, cardiovascular disease, or diabetes. Reduced LDL in C282Y homozygotes may be because of effects of excess iron on cholesterol metabolism and lipoprotein formation in the liver.

Diagnosis and Quantitation of Fibrosis

Hepatic fibrosis is the final common pathway for many different liver insults. Originally considered to be irreversible, hepatic fibrosis is now known to be a dynamic process with a significant potential for resolution. The diagnosis and quantitation of fibrosis have traditionally relied on liver biopsy. However, there are a number of drawbacks including the invasive nature of the procedure, sampling error, and interobserver variability. This article reviews the current role of liver biopsy in the assessment of hepatic fibrosis and discusses the role of the newer noninvasive methods including serum markers and radiologic tests.

Relevance of endotoxin receptor CD14 and TLR4 gene variants in chronic liver disease

Objective. The lipopolysaccharide (LPS)-triggered release of inflammatory cytokines from Kupffer cells is mediated via the CD14/TLR4 receptor complex. This inflammatory pathway can be influenced by alterations in genes encoding for LPS receptor components. Thus, a -260 C>T transition in the CD14 promoter is thought to result in enhanced CD14 expression thereby increasing the LPS responsiveness in chronic liver diseases, whereas a D299G exchange in the TLR4 gene has the opposite effect. Our objective was to analyze these two variations. Material and methods. The study comprised 1712 patients with chronic liver diseases of different etiologies and 385 healthy controls. Genotyping was carried out by melting curve analysis with fluorescence resonance energy transfer (FRET) probes in the LightCycler. Results. Genotype frequencies of CD14 -260C>T and TLR4 D299G did not significantly differ between patients and controls (CD14 TT 21.6% versus 21.8%; TLR4 DG or GG 9.7% versus 10.4%). We found no significant correlation of these alterations with disease course either in the groups of patients with alcoholic liver disease or hepatitis C virus (HCV) infection or among patients requiring liver transplantation. A significantly higher frequency of the CD14 -260TT genotype was observed (36.6% versus 21.8% in healthy controls, p=0.036) only in a small subgroup of patients (n=41) with mild cryptogenic chronic liver disease. Conclusions. Variants within these LPS receptor genes were equally distributed among patients with chronic liver diseases of different etiologies and obviously do not confer an increased risk for the severity of these chronic liver processes.

Correction of copper metabolism is not sustained long term in Wilson’s disease mice post bone marrow transplantation

Alternative cell sources have been sought for the treatment of liver diseases, since liver cells are in short supply for cell transplantation. Although bone marrow-derived cells have been investigated as an alternative cell source, few studies have demonstrated long-term disease correction. Here we examined bone marrow stem cell transplantation into the toxic milk (tx) mouse model for Wilson's disease, a mild liver disease characterized by hepatic copper accumulation. The aim of this study was to determine whether bone marrow cells engrafted in the liver could sustain correction of abnormal copper metabolism in the tx mouse. Bone marrow cells were isolated from congenic normal mice, transduced to express enhanced green fluorescent protein, sorted for stem cell (Sca-1) and lineage cell (Lin) surface markers, and then transplanted into sub-lethally irradiated normal or tx mice. Analysis for donor cell activity and distribution was undertaken 5 and 9 months post-transplant to allow for sufficient time to repopulate the liver and demonstrate disease correction. Donor bone marrow cells engrafted in both normal and tx mouse liver within 5 months. Significantly reduced liver copper was found in tx mice with donor cell liver engraftment at 5 months post-transplant compared to controls, demonstrating partial correction of abnormal copper metabolism in the short term. However, disease correction was not maintained 9 months post-transplantation. Lin(-)Sca-1(+) cells were more likely to partially correct disease than Lin(+)Sca-1(-) cells in the short term. These results demonstrate that bone marrow transplants cannot maintain disease correction in a mouse model of mild hepatic damage, although initial copper metabolism correction was observed.

Pravastatin Appears Safe in Patients with Mild Chronic Liver Disease

According to official prescribing information, statins are contraindicated in patients “with active liver disease or unexplained persistent elevations

Long-Term Outcome in Children with Chronic Hepatitis B: A 24-Year Observation Period

Chronic hepatitis B seems to manifest as mild disease in children and young adults. However, data regarding the long-term course of hepatitis B in untreated and interferon-treated children are still scarce. This study investigates the long-term outcome of disease in a large series of untreated and treated children with hepatitis B virus (HBV) infection. Clinical, biochemical, virological, and histological features were evaluated in children (age range, 2-18 years) with chronic HBV infection who did not have concomitant chronic systemic diseases other than HBV infection and who were admitted to the liver unit in the Department of Pediatrics at University "Frederico II" (Naples, Italy) during the period 1981-2005. One hundred eight consecutive patients observed for up to 24 years were studied. During the observation period, 67 children remained untreated, and 41 were treated with interferon-alpha. After a median period of observation of 12.1 years (range, 5-23 years), hepatitis B early antigen loss and serum HBV DNA clearance occurred in 43 untreated patients (69.3%) who were hepatitis B early antigen positive at study entry and in 33 treated children (80%; the P value is not statistically significant). In addition, 6 untreated patients (9.7%) and 4 treated patients (9.7%) became anti-HBs [corrected] positive at the end of the follow-up period. Histological assessment, evaluated for 57 children, showed mild-to-moderate disease in 91.2% of cases of HBV infection. No patient developed end-stage liver disease or hepatocellular carcinoma. Children with chronic HBV infection are symptom free, with morphologically mild liver disease. Considering that the overall long-term outcomes did not differ between treated and untreated patients, the real impact of therapy on the long-term course of HBV infection remains to be established. Additional studies are needed to confirm our conclusions.

Liver Failure in Mitochondrial DNA Depletion Syndrome: The Importance of Serial Neuroimaging in Liver Transplantation Evaluation

Liver Failure in Mitochondrial DNA Depletion Syndrome: The Importance of Serial Neuroimaging in Liver Transplantation Evaluation

Depletion of High‐density Lipoprotein and Appearance of Triglyceride‐rich Low‐density Lipoprotein in a Japanese Patient With FIC1 Deficiency Manifesting Benign Recurrent Intrahepatic Cholestasis

Lipoprotein metabolism in FIC1 deficiency due to ATP8B1 mutations has never been studied sufficiently. This study was performed to investigate the detailed lipoprotein metabolism in benign recurrent intrahepatic cholestasis (BRIC) caused by FIC1 deficiency. Lipoprotein profile and major lipoprotein regulators such as lecithin:cholesterol acyltransferase (LCAT), hepatic triglyceride lipase (HTGL), lipoprotein lipase, and cholesteryl ester transfer protein in a Japanese patient with BRIC were serially examined during a bout of cholestasis. Liver expression of farnesoid X receptor (FXR), which suppresses high-density lipoprotein (HDL) generation, was also examined. Hypercholesterolemia and lipoprotein X accumulation were never observed throughout this study. When the cholestasis was severe, triglyceride-rich low-density lipoprotein (LDL) accounted for most of the plasma lipoproteins whereas HDL was hardly detectable. Concurrently, activities of all regulators were decreased, together with decreases of the serum parameter for liver protein synthesis. In particular, suppressions of LCAT and HTGL activities were severe and greatly contributed to the appearance of triglyceride-rich LDL. As the cholestasis improved, this LDL gradually transformed into normal LDL with the recoveries of LCAT and HTGL activities. The activities of all regulators for the last 1 to 2 months were normal but HDL remained depleted. His liver showed low FXR expression compared with control livers. The present study showed an appearance of triglyceride-rich LDL due to suppressions of LCAT and HTGL activities and a depletion of HDL that is not able to be explained by lipoprotein regulators or FXR in our patient.

Disease progression in Chinese chronic hepatitis C patients with persistently normal alanine aminotransaminase levels

Although chronic hepatitis C virus-infected patients with persistently normal alanine aminotransaminase levels usually have mild liver disease, disease progression can still occur. However, it is uncertain which group of patients is at risk of disease progression. To examine the severity of liver disease on liver biopsy in Chinese patients with persistently normal alanine aminotransaminase levels, and their disease progression over time. Eighty-two patients with persistently normal alanine aminotransaminase levels were followed up longitudinally. The median time of follow-up was 8.1 years. Forty-seven of the 82 patients (57.3%) had a second liver biopsy. At the time of analysis, six of the 82 patients (7.3%) developed decompensated liver cirrhosis. Patients with an initial fibrosis stage F2 or F3 [6/23 (26.1%) vs. 0/59 (0%), P < 0.0001] or inflammatory grade A2 or A3 [5/40 (12.5%) vs. 1/42 (2.4%), P = 0.04] were more likely to develop decompensated liver cirrhosis. On multivariate analysis, initial fibrosis stage F2 or F3 was independently associated with progression to decompensated liver cirrhosis (relative risk 2.3, 95% confidence interval 0.03-2.5, P = 0.02). Chinese chronic hepatitis C virus patients with persistently normal alanine aminotransaminase levels with moderate to severe fibrosis at initial evaluation are more likely to develop decompensated liver cirrhosis.

“Silent” Tyrosinemia Presenting as Hepatocellular Carcinoma in a 10‐year‐old Girl

“Silent” Tyrosinemia Presenting as Hepatocellular Carcinoma in a 10‐year‐old Girl

Late-Onset Wilson’s Disease

The clinical symptoms and age at onset of Wilson's disease (WD) are highly variable. This study investigated patients who became symptomatic at >40 years of age. Clinical features, laboratory data, and mutation analysis were evaluated in 46 (3.8%) of 1223 patients who were investigated in a multinational study on genotype-phenotype correlations (1053 index patients, 170 siblings) who were >40 years of age at onset of symptoms and, in 2 asymptomatic siblings, diagnosed at >40 years of age. Thirty-one patients presented with neurologic symptoms (mean age, 44.5 years; range, 40-52; male/female, 14/17), 15 presented with liver disease (mean age, 47.1 years; range, 40-58; male/female, 6/9), and 2 were asymptomatic siblings. Hepatic copper content was measured in 17 patients and was above 250 microg/g dry weight in 13. One patient with hepatic presentation had "fulminant" WD, the remaining 14 abnormal liver function tests and/or hepatomegaly. Liver biopsy specimens were available in 13 patients presenting with liver disease (cirrhosis, 10; chronic hepatitis, 2; steatosis, 1; no abnormalities, 1) and in 14 neurologic patients (cirrhosis, 9; advanced fibrosis, 1; chronic hepatitis, 2; no abnormalities, 2). Twenty-seven of the 46 index cases had mutations on both chromosomes (including 13 H1069Q/H1069Q), 13 on just 1 chromosome. Late-onset WD is a frequently overlooked condition. The diagnostic features and the frequency of late-onset WD gene mutations were not different than in patients with an earlier onset of disease. Factors other than ATP7B mutations may modify the phenotypic presentation of WD.

Hyperammonemic Coma—Barking Up the Wrong Tree

Hepatic encephalopathy and myxedema coma share clinical features: coma, ascites, anemia, impaired liver functions, and a “metabolic” electroencephalogram (EEG). Hyperammonemia, a hallmark of hepatic encephalopathy, has also been described in hypothyroidism. Differentiation between the 2 conditions, recognition of their possible coexistence, and the consequent therapeutic implications are of utmost importance. We describe a case of an 82-year-old woman with a history of mild chronic liver disease who presented with hyperammonemic coma unresponsive to conventional therapy. Further investigation disclosed severe hypothyroidism. Thyroid hormone replacement resulted in gain of consciousness and normalization of hyperammonemia. In patients with an elevated ammonia level, altered mental status, and liver disease, who do not have a clear inciting event for liver disease decompensation, overwhelming evidence of hepatic decompensation, or who do not respond to appropriate therapy for hepatic encephalopathy, hypothyroidism should be considered and evaluated.

PATHOLOGY TEACH AND TELL: FIBRINOGEN STORAGE DISEASE IN A CHILD WITH HYPOFIBRINOGENEMIA AND DECREASED CERULOPLASMIN

The authors present a clinical case of a patient with mild liver disease and coagulopathy. The diagnosis was reached through careful histologic examination of liver biopsy. Electron microscopy played an important role in confirming the diagnosis.

Hepatic Histologic Response (HR) to Combination Therapy among HCV/HIV-Coinfected Individuals: Interferon Induces HR Independent of Sustained Virologic Response (SVR)

Most HIV/HCV-coinfected patients fail to achieve a sustained virologic response (SVR) to peginterferon-ribavirin therapy. We examined the hepatic histologic response (HR), defined as an improvement in hepatic inflammation scores of two points or more, to combination therapy among HIV/HCV-coinfected subjects. An open label prospective trial treated 32 HIV/HCV-coinfected patients with peginterferon alpha-2b and ribavirin for 48 weeks. Liver biopsies, scored by a single pathologist using the Histology Activity Index (HAI, range 0-18) and Ishak fibrosis scores (range 0-6), were performed before and after treatment. Gene expression profiles of PBMCs were performed using Affymetrix U133A gene chips. A total of 87% of SVR subjects and 88% of nonresponders (NR) had an HR, but no significant change in the liver fibrosis scores was observed (p > 0.05). For genotype 1 patients, a baseline fibrosis score </=2 was related to a higher likelihood of SVR than those with a score >2 (p = 0.012). Combination therapy for HCV among HIV-coinfected subjects resulted in a modest SVR rate. Persons with mild liver disease had a better SVR rate, suggesting early treatment may be beneficial. Combination therapy resulted in an HR for most of the patients, however, further follow-up of these patients will determine the durability of such an HR.

Liver disease selectively modulates cytochrome P450–mediated metabolism

The liver plays a significant role in drug metabolism; thus it would be expected that liver disease may have a detrimental effect on the activity of cytochrome P450 (CYP) enzymes. The extent to which the presence and severity of liver disease affect the activity of different individual drug-metabolizing enzymes is still not well characterized. The purpose of this study was to assess the effect of liver disease on multiple CYP enzymes by use of a validated cocktail approach. The participants in this investigation were 20 patients with different etiologies and severity of liver disease and 20 age-, sex-, and weight-matched healthy volunteers. Liver disease severity was categorized by use of the Child-Pugh score. All participants received a cocktail of 4 oral drugs simultaneously, caffeine, mephenytoin, debrisoquin (INN, debrisoquine), and chlorzoxazone, as in vivo probes of the drug-metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, and CYP2E1, respectively. The primary end points were measurements of specific CYP metabolism indexes for each enzyme. Mephenytoin metabolism was significantly decreased in both patients with mild liver disease (Child-Pugh score of 5/6) (-63% [95% confidence interval (CI), -86% to -40%]; P = .0003) and patients with moderate to severe liver disease (Child-Pugh score >6) (-80% [95% CI, -95% to -64%]; P = .0003). In comparison with control subjects, the caffeine metabolic ratio was 69% lower (95% CI, -85% to -54%; median, 0.14 versus 0.62; P = .0003), the debrisoquin recovery ratio was 71% lower (95% CI, -96% to -47%; median, 0.10 versus 0.65; P = .012), and the chlorzoxazone metabolic ratio was 60% lower (95% CI, -91% to -29%; median, 0.21 versus 0.83; P = .0111) in patients with moderate to severe liver disease. All 4 drugs showed significant negative relationships with the Child-Pugh score. CYP enzyme activity is differentially affected by the presence of liver disease. We propose that the data can be explained by the "sequential progressive model of hepatic dysfunction," whereby liver disease severity has a differential effect on the metabolic activity of specific CYP enzymes.

Late Onset Wilson Disease Frequently Overlooked

Wilson disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism and is characterized by excessive deposition of copper in the liver, brain, and other tissues. It’s frequency worldwide ranges from 1 case per 30,000 population in Japan to 1 case per 100,000 population in Australia. The increased frequency in certain countries is due to high rates of consanguinity. The genetic defect, localized to chromosome arm 13q, has been shown to affect the copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver. The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. Patients with WD usually present with liver disease during the first decade of life or with neuropsychiatric illness during the third decade. In a study presented in Los Angeles, May 21 at Digestive Disease Week 2006, collaborators from Austria, Hungary, Germany, Turkey, and Poland point out that some people with WD may present much later in life and even may be in their seventies. The researchers state that late onset WD is “a frequently overlooked condition.” Of 1034 patients in this ongoing, multinational study on genotype-phenotype correlations, 85 (8.25) were age 35 years or older at onset of symptoms. Forty-six presented with neurologic symptoms (mean age, 40.8; range, 35–52; male/female, 21/25), 36 with liver disease (41.3 range, 35–58; male/female, 16/20). Three were asymptomatic siblings. Diagnosis was made at presentation only in 38 (45%), and in the remaining patients, there was delay in diagnosis of up to 15 years. The study found that Kayser-Fleischer (KF)-rings were present in 12 with hepatic presentation (33.3%) and in 34 (74%) patients with neurologic disease. Eleven patients had normal serum ceruloplasmin (13%). Hepatic copper content was measured in 31 patients and was above 250 μg in 24. Among the patients with hepatic presentation, 3 had fulminant hepatic failure and underwent liver transplantation, one had hemolytic anemia, 23 compensated or decompensated cirrhosis, and 7 just abnormal LFTs (liver biopsy showed chronic hepatitis in 2, steatosis in 3, and no abnormalities in 2). Liver biopsy was performed in 24 patients with neurologic presentation: 16 had cirrhosis, 3 advanced fibrosis, 2 chronic hepatitis, 1 mild steatosis, and 2 were without abnormalities. The study thus far found no significant phenotypic-genotypic correlations for late onset WD. “Surprisingly one third of the patients had only mild liver disease,” the researchers state, adding that the frequency of the observed WD gene mutations was not different than that of patients with an earlier onset of disease. “Apparently, factors other than ATP7B mutations may modify the phenotypic presentation of WD.”

A Glycine N-methyltransferase Knockout Mouse Model for Humans with Deficiency of this Enzyme

Three human cases having mutations in the glycine N-methyltransferase (GNMT) gene have been reported. This enzyme transfers a methyl group from S-adenosylmethionine (SAM) to glycine to form S-adenosylhomocysteine (SAH) and N-methylglycine (sarcosine) and is believed to be involved in the regulation of methylation. All three cases have mild liver disease but they seem otherwise unaffected. To study this further, gnmt deficient mice were generated for the first time. This resulted in the complete absence of GNMT protein and its activity in livers of homozygous mice. Compared to WT animals the absence of GNMT resulted in up to a 7-fold increase of free methionine and up to a 35-fold increase of SAM. The amount of SAH was significantly decreased (3 fold) in the homozygotes compared to WT. The ratio of SAM/SAH increased from 3 in WT to 300 in livers of homozygous transgenic mice. This suggests a possible significant change in methylation in the liver and other organs where GNMT is expressed.

Association between vitamin D receptor, CCR5, TNF-α and TNF-β gene polymorphisms and HBV infection and severity of liver disease

1,25-dihydroxyvitamin-D is involved in immunomodulation. Expression of vitamin-D receptors in hepatocytes suggests its role in hepatocellular injury. We studied the association of single nucleotide polymorphisms in genes involved in immunoregulatory functions of vitamin-D with susceptibility, severity and persistence of HBV infection. Five polymorphisms in VDR, CCR5, TNF-alpha and TNF-beta were studied in 214 chronic hepatitis B patients and 408 controls. Clinical parameters were compared between mild or severe liver disease patients. The frequency of heterozygosity of CCR5Delta32 was higher in chronic hepatitis B patients than controls (4.2 vs 0.73%, P=0.005). Frequency of VDR Apa1 a/a and TNF-beta A/A was higher in severe compared with mild liver disease based on HAI (19.3 vs 5.4%, P=0.003 and 18.1 vs 3.8%, P=0.001, respectively) and fibrosis score (23.7 vs 3.6%, P<0.001 and 18.1 vs 4.4%, P=0.002, respectively). The frequency of VDR a/a allele was also higher in patients with higher HBV DNA (11 vs 2.6%, P=0.002). Apa1 and Taq1 markers in VDR are in linkage-disequilibrium and 'at'haplotype is associated with severe liver disease. CCR5Delta32 heterozygosity was associated with susceptibility and VDR a/a, TNF-beta A/A with severity of HBV-related liver disease and VDR a/a allele with higher viral load. These results affirm an important role of immunogenetic factors in the outcome of chronic HBV infection.

CCR5Δ32 mutation does not influence the susceptibility to HCV infection, severity of liver disease and response to therapy in patients with chronic hepatitis C

To study whether CCR5Delta32 mutation was associated with viral infection and severity of liver disease. Two hundred and fifty two histologically proven, chronic HCV patients (mean age: 41 +/- 14 years; M/F: 164/88) were genotyped. PCR based genotyping of 32 bp deletion at the CCR5 locus was done. Four-hundred and eight matched healthy controls were studied to assess susceptibility to HCV infection. To assess correlation of immune gene polymorphism with severity of HCV related liver disease, patients with chronic HCV infection were divided into those with a fibrosis score of <= 2 (mild) or > 2 (severe) and histological activity index (HAI) of <= 5 or > 5. For correlation between CCR5Delta32 mutations and response to therapy, 129 patients who completed therapy were evaluated. The majority (89.4%) of the patients were infected with genotype 3. The frequency of homozygous CCR5Delta32 mutants was comparable to HCV patients as compared to the healthy controls (0.7% vs 0%, P = 0.1). Further more, the frequency of CCR5Delta32 mutation was comparable in patients with mild or severe liver disease. (P = NS). There was also no association observed with response to therapy and CCR5Delta32 mutation. CCR5Delta32 mutation does not have a role in disease susceptibility, severity or response to therapy in patients with chronic hepatitis C infection.