Approach to a child with chronic liver disease

Abstract   Chronic liver disease is suspected on the basis of clinical and laboratory features. The former include a positive past or family history for liver disease, a prolonged duration of what looks like an acute hepatitic illness, presentation with complications of portal hypertension, like bleeding varices or hypersplenism, signs of chronic liver disease on examination, like hard liver, splenomegaly, ascites, and cutaneous stigmata of chronic liver damage. Typical laboratory features are low albumin, prolongation of prothrombin time usually responsive to vitamin K, high gammaglobulins. Differential diagnosis of chronic liver disease requires specific laboratory tests for viral hepatitis, autoimmune liver disease, metabolic disorders and evaluation of the liver histology to confirm the diagnosis or to assess disease severity.     

Chronic liver disease in an ageing population

The prevalence of chronic liver disease is increasing in theelderly population. With a mostly asymptomatic or non-specificpresentation, these diseases may easily go undiagnosed. Abnormalliver function tests of unknown cause are a common reason forreferral to secondary care. Investigating the older person withabnormal liver function is important; even with mild abnormalities,the same vigilance should be applied to an older person as ina young person. Liver biopsy is safe but often overlooked inthis age group and may provide useful information to diagnose,direct therapy and prognosticate. Treatment options are similarfor all age groups, with a few subtle differences, althoughfurther evidence is frequently required for the older population.Morbidity and age-adjusted mortality are often more severe inolder people, and therefore early diagnosis and interventionis important. Presented here are the most common chronic liverdiseases that geriatricians are likely to encounter in clinicalpractise. Their epidemiology, clinical features, investigation,treatment and mortality are described with a particular focuson the elderly population.     

Thrombocytopenia in chronic liver disease

Thrombocytopenia is a common haematological disorder in patients with chronic liver disease. It is multifactorial and severity of liver disease is the most influential factor. As a result of the increased risk of bleeding, thrombocytopenia may impact upon medical procedures, such as surgery or liver biopsy. The pathophysiology of thrombocytopenia in chronic liver disease has long been associated with the hypothesis of hypersplenism, where portal hypertension causes pooling and sequestration of all corpuscular elements of the blood, predominantly thrombocytes, in the enlarged and congested spleen. Other mechanisms of importance include bone marrow suppression by toxic substances, such as alcohol or viral infection, and immunological removal of platelets from the circulation. However, insufficient platelet recovery after relief of portal hypertension by shunt procedures or minor and transient recovery after splenic artery embolization have caused many to question the importance and relative contribution of this mechanism to thrombocytopenia. The discovery of the cytokine thrombopoietin has led to the elucidation of a central mechanism. Thrombopoietin is predominantly produced by the liver and is reduced when liver cell mass is severely damaged. This leads to reduced thrombopoiesis in the bone marrow and consequently to thrombocytopenia in the peripheral blood of patients with advanced‐stage liver disease. Restoration of adequate thrombopoietin production post‐liver transplantation leads to prompt restoration of platelet production. A number of new treatments that substitute thrombopoietin activity are available or in development.     

Hepatocyte senescence in end-stage chronic liver disease: a study of cyclin-dependent kinase inhibitor p21 in liver biopsies as a marker for progression to hepatocellular carcinoma.

BACKGROUND: Histologic markers to predict hepatocellular carcinoma (HCC) include small cell change and dysplastic nodules. Hepatocyte senescence is noted in chronic liver disease and may or may not be important in progression to HCC. AIM: The study was undertaken to compare standard histologic features of chronic liver disease as well as markers of senescence and proliferation in two groups of biopsies from patients followed for at least a year. Methods: Standard histologic evaluation of necroinflammatory activity, fibrosis, steatosis, and iron, internationally accepted criteria of dysplasia, and immunohistochemical markers for proliferation and hepatocyte senescence were compared in 47 liver biopsies from noncholestatic chronic liver disease patients who subsequently either underwent transplant (the Control group, n=19) or had biopsy-proven (HCC group, n=28) over a similar time period of 34.9 months (mean) and 42.5 months (mean) respectively. RESULTS: Both groups were predominantly men; the MELD score was higher, and mean age was less in the Control group (46.9 vs 53.8 years, P=0.01). Small cell change was not significantly different in the biopsies between the two groups; neither were grade, stage (Ishak scores), nor presence or location of iron. Steatosis was more common in the group that subsequently developed HCC (P=0.04). The MIB-1 proliferation index was greater in the biopsies from the Control group. The senescence marker p21, and the ratio of p21:MIB-1 were not statistically different between the two groups. However, a Spearman's rank correlation showed a linear correlation of p21/MIB-1 with a greater amount of dyplasia in the explant livers of Controls. CONCLUSIONS: These findings suggested the Control groups' livers maintained effective removal of cells from the cell cycle by overexpression of p21 and, while not 'protected' from significant involvement by dysplasia, may have been precluded from development of HCC.     

Incidence of hepatitis B virus infection in alcoholic liver disease,HBsAg negative chronic active liver disease and primary liver cell cancer in Britain

ABSTRACT— A study has been undertaken to determine the incidence of serum markers of hepatitis B virus (HBV) infection in British caucasian patients with biopsy-proven alcoholic liver disease (n = 56), HBsAg negative chronic active liver disease (CALD) (n = 47) and primary liver cell cancer (PLCC) (n = 27), compared to a hospital control population without liver disease (n = 112). No increased incidence of any serum marker of HBV infection was found in alcoholic liver disease or in ‘lupoid’ CALD (antinuclear factor positive 1:40 and/or smooth muscle antibody positive > 1:40). In contrast, the incidence of antibody to HB surface and core antigens was significantly increased (p<0.05) in patients with cryptogenic CALD. The incidence of hepatitis B surface antigen and antibodies to HB core and ‘e’ antigens was significantly increased (p<0.005) in PLCC.     

Elevated growth hormone levels in patients with non-alcoholic chronic liver disease

High serum concentrations of growth hormone (GH) were found in five patients with chronic liver diseases, including auto-immune chronic active hepatitis (two cases), Budd-Chiari syndrome, primary biliary cirrhosis and hepatitis B virus associated cirrhosis. Mean levels of GH were 27.8 units (normal up to 5). In three patients elevated prolactin levels were also found (mean 37.3 units for two females, normal up to 20), and 36 units in one male (normal up to 9). No other endocrine disorders were found. Although the association of raised GH levels in patients with alcoholic cirrhosis is well known, its occurrence in patients with non-alcoholic chronic liver disease is not fully established. We describe the effect of the disease course, and steroid treatment on GH levels in one patient with auto-immune chronic active hepatitis, and propose possible mechanisms for this elevation.     

Seroepidemiology of hepatitis A in patients with chronic liver disease

Hepatitis A virus (HAV) rarely causes fulminant hepatic failure in the general population. Yet it is a cause of significant morbidity and mortality in patients with chronic liver disease (CLD), in whom routine HAV vaccination is recommended. However, studies of HAV seroprevalence and exposure predictors in populations with CLD are scarce. We have studied a cohort of 473 patients with various causes of CLD between July 2000 and June 2002. Patients were stratified on the basis of age, gender, ethnicity and aetiology of liver disease. The HAV seroprevalence in patients with CLD was compared with that in the general population. We used a logistic regression analysis to identify independent predictors of HAV exposure. Of the 473 patients studied, HAV seroprevalence was available for 454 individuals. HCV, HBV, alcohol, and HCV and alcohol were the causes of CLD in 337, 72, 37 and eight patients, respectively. The overall HAV seroprevalence was 55% in the studied cohort. The age-stratified HAV prevalence for ages 21-30, 31-40, 41-50, 51-60, 61-70 and greater than 70 years was 44, 51, 44, 63, 65 and 64%, respectively. Hispanic ethnicity, Asian ethnicity, alcohol use and ages of 51-70 years were found to be independent predictive variables of prior exposure to HAV. HAV infection in patients with CLD causes considerable morbidity and mortality. We demonstrated that age-stratified seroprevalence of HAV in patients with CLD of various aetiologies is significantly higher than that of the general population, and identified several independent predictors of HAV prior exposure.     

Malignancies following long-term azathioprine treatment in chronic liver disease

ABSTRACT— One hundred and fifty-four patients with histologically verified nonalcoholic chronic liver disease were randomized to azathioprine or prednisone treatment. After a median of 91 months observation time, the cause of death was assessed retrospectively. Autopsy was performed in 82% of 71 deaths. In the azathioprine group 33% (13/39) died from malignant neoplasia, and in the prednisone group (13%) (4/32) (p = 0.08). Considering a possible fatal outcome as a consequence of treatment, this finding urges caution in the long-term application of azathioprine at the usual dose level.     

Original research: Widespread gaps in the quality of care for primary biliary cholangitis in UK

ObjectivePrimary biliary cholangitis (PBC) is a progressive, autoimmune, cholestatic liver disease affecting approximately 15 000 individuals in the UK. Updated guidelines for the management of PBC were published by The European Association for the Study of the Liver (EASL) in 2017. We report on the first national, pilot audit that assesses the quality of care and adherence to guidelines.DesignData were collected from 11 National Health Service hospitals in England, Wales and Scotland between 2017 and 2020. Data on patient demographics, ursodeoxycholic acid (UDCA) dosing and key guideline recommendations were captured from medical records. Results from each hospital were evaluated for target achievement and underwent χ² analysis for variation in performance between trusts.Results790 patients’ medical records were reviewed. The data demonstrated that the majority of hospitals did not meet all of the recommended EASL standards. Standards with the lowest likelihood of being met were identified as optimal UDCA dosing, assessment of bone density and assessment of clinical symptoms (pruritus and fatigue). Significant variations in meeting these three standards were observed across UK, in addition to assessment of biochemical response to UDCA (all p<0.0001) and assessment of transplant eligibility in high-risk patients (p=0.0297).ConclusionOur findings identify a broad-based deficiency in ‘real-world’ PBC care, suggesting the need for an intervention to improve guideline adherence, ultimately improving patient outcomes. We developed the PBC Review tool and recommend its incorporation into clinical practice. As the first audit of its kind, it will be used to inform a future wide-scale reaudit.     

TRAIL及其受体与HBV相关慢性肝病相关性的研究进展

肿瘤坏死因子相关凋亡诱导配体(TNF-related apoptosis inducing ligand,TRAIL)归属于肿瘤坏死因子超家族,与死亡受体结合后,激活caspase瀑布样级联反应,可诱导肿瘤细胞、转化细胞及病毒感染细胞发生凋亡,而对正常组织及细胞无凋亡诱导作用。TRAIL及其受体通过与HBV、细胞因子等的相互作用,在HBV相关慢性肝病的发病机制中发挥着重要作用。此外,体内TRAIL表达还与慢性乙型病毒性肝炎患者抗病毒治疗存在一定的关联性。本文对TRAIL及其受体与HBV相关慢性肝病的相关性进行综述,为进一步明确两者间的关系提供理论依据。     

Fulminant hepatitis in patients with chronic liver disease

The changing epidemiology of hepatitis A virus (HAV) in the UK has led to a decline in natural immunity against the virus. It is estimated that in the UK, HAV is responsible for 10%-20% of cases of liver failure, and an overall mortality rate of 0.1%. It is clear that certain factors predispose patients to more severe HAV disease and increased mortality, although the reasons for this have yet to be elucidated. The age at which infection occurs clearly influences the outcome, with the risk of severe hepatitis increasing sharply after the age of 40 years. Intravenous drug users, homosexual men, individuals with an excessive alcohol intake or patients with chronic liver disease are also at increased risk of severe disease. An analysis of data from King's College Hospital was performed to determine the factors that influence the outcome or clinical course of HAV infection in at-risk patients. Data compiled from 1991 to 1998 revealed 187 cases with confirmed HAV, 45 of whom developed severe hepatitis. Outcomes were varied, eight (17.7%) patients developed acute liver failure and two (4.4%) died.     

Case report of acute liver injury caused by the eszopiclone in a patient with chronic liver disease

Rationale:Eszopiclone, sold under the brand name Lunesta, is a new type of non-benzodiazepine hypnotic. Eszopiclone is a zopiclone dextrorotation, which is classified as a cyclopyrrolone. It functions by binding gamma-aminobutyric acid (GABA) receptors. Compared with benzodiazepines hypnotics, eszopiclone has higher selectivity for certain subunits of the GABA(A) receptor. So far, there are no reports about the elevation of serum enzymes or severe liver injury caused by eszopiclone. Here, we present a case report of acute liver injury following eszopiclone treatment in a patient with chronic hepatitis B virus (HBV).Patient concerns:The patient was a 53-year-old female with a 36-year history of positive HBV markers. Due to poor sleep, the patient took trazodone hydrochloride orally for 1 year. After hospital admission for positive hepatitis B pathogenic markers, abdominal distension, fatigue, and aggravation, she was treated with eszopiclone under the guidance of the mental health department.Diagnoses:Her transaminase levels increased abnormally after eszopiclone treatment and rapidly decreased after drug withdrawal. This was determined to be an acute liver injury event. liver-protecting treatment was maintained. Considering the patient''s anxiety and depression, the patient''s family members refused a liver biopsy.Outcomes:Transaminase levels decreased rapidly within one week, and the patient continued to take trazodone hydrochloride after discharge. No adverse events occurred in the follow-up period.Lessons:Sleep disorders are more common in patients with chronic diseases, especially patients with chronic liver disease. Recently, it has become common for patients with hepatitis B and C to use antidepressants along with antiviral treatment. Patients with chronic hepatitis B or C may have a threefold risk of liver dysfunction after receiving antituberculosis treatment.^[1,2] A proinflammatory environment induced by actively replicating the hepatitis virus may alter the detoxication process and increase drug toxicity.^[3] At this time, the safety of other drugs should be reevaluated. Although hepatitis and liver injury are listed as rare adverse reactions of eszopiclone, this case is the first to report the eszopiclone-involved acute liver injury.     

Current concepts in the pathogenesis of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized cause of chronic liver disease, representing the leading cause of hepatology referral in some centres. However, its pathophysiology is not completely understood. Insulin resistance is one of the major mechanisms involved in disease prevalence and progression. Owing to the lack of an effective pharmacological therapy, recommendations on treatment are scarce and are based mainly on lifestyle changes, including diet and exercise. A review of the current literature on pathogenesis of NAFLD is presented in this article.     

Hepatitis C in chronic liver disease: an epidemiological study based on 566 consecutive patients undergoing liver biopsy during a 10-year period

We analysed the presence of hepatitis C virus (HCV) antibodies in 566 patients undergoing liver biopsy. While over 20% of the patients were anti-HCV positive according to elisa, only 13.8% had HCV antibodies when tested with a four-antigen recombinant immunoblot assay (RIBA 2). At the time of inclusion in the study, most patients were asymptomatic, irrespective of whether they were HCV-positive. Histological findings in anti-HCV-positive patients were chronic persistent hepatitis, chronic active hepatitis or cirrhosis in > 75% of cases. Only four of the patients who were anti-HCV-positive according to the RIBA 2 had autoimmune chronic active hepatitis. Risk behaviour could be identified in the majority of cases. Community-acquired sporadic cases were rare (12%). Of the 153 patients who died during follow-up, 23 subjects were anti-HCV positive. Although age- and sex-adjusted survival was not shorter in anti-HCV-positive patients than in anti-HCV-negatives, the risk of hepatocellular cancer was higher (P = 0.01). We conclude that HCV infection is associated with chronic liver disease, even when critical evidence of viral aetiology is slight. Truly sporadic cases are rare. Patients infected with HCV are at increased risk of developing hepatocellular cancer.     

Baseline and salt-stimulated paraoxonase and arylesterase activities in patients with chronic liver disease: relation to disease severity

Background: It has been recently reported that serum paraoxonase (PON1) and arylesterase (ARE) activities may be significantly reduced in patients with chronic liver disease. The aim of the study was to investigate the relations between serum PON1 and ARE activities and the degree of liver damage in patients with chronic liver injury.
Methods: We studied a total of 75 patients with chronic liver disease (50 patients with cirrhosis and 25 patients with chronic hepatitis) and 25 healthy comparison subjects. Baseline and salt-stimulated PON1 and ARE activities were determined in all study participants.
Results: Baseline and stimulated PON1 and ARE activities were significantly lower in patients with chronic liver disease than in controls. Cirrhotic patients in Child–Pugh classes B and C subgroups had significantly reduced PON1 and ARE activities compared with Child–Pugh class A patients (both P -values <0.01). Receiver operating characteristic curve analysis showed that serum ARE activity was the most efficient test for identifying the presence and severity of chronic liver injury.
Conclusion: Baseline and stimulated PON1 and ARE activities are reduced in patients with chronic liver disease. Serum ARE activity could be a suitable biomarker for the evaluation of the presence and severity of chronic liver damage.     

Triolein breath test of fat absorption in patients with chronic liver disease

We have compared the [¹⁴C]triolein breath test for fat malabsorption with fecal fat excretion corrected for marker pellet recovery in 23 subjects with chronic liver disease. The breath test identified 15 of the 17 subjects with abnormal fecal fat excretion (sensitivity 88%). However, four of the six subjects with normal fecal fat excretion gave abnormal breath test results (specificity 33%). While three of the four subjects with falsely abnormal breath tests had alcoholic liver disease, the explanation for the low specificity is unclear and may not be confined to patients with alcohol-related disease. We are therefore unable to recommend the breath test as a screen for steatorrhea in patients with chronic liver disease.