Joanna K. Dowman

Pathogenesis of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The prevalence of NAFLD has risen rapidly in parallel with the dramatic rise in obesity and diabetes,1,2 and is rapidly becoming the most common cause of liver disease in Western countries.3 Indeed, NAFLD is now recognized to be the aetiology in many cases previously labelled as cryptogenic cirrhosis.4 In Western populations, estimates of NAFLD prevalence vary between 20 and 30%,5,6 rising up to 90% in morbidly obese individuals.7 The more severe, and clinically significant form of NAFLD, non-alcoholic steatohepatitis (NASH) is less common, affecting an estimated 2–3% of the general population,8 and up to 37% of the morbidly obese.7 Of particular concern, and with significant implications for future disease burden, is the increasing prevalence of NAFLD in children and young adults. Studies have reported a 3% prevalence of NAFLD in the general paediatric population, rising to 53% in obese children.9,10 NAFLD has a strong association with type 2 diabetes, with steatosis present in 70% of type 2 diabetics screened with ultrasound,11 and thus it is now recognized to represent the hepatic manifestation of the metabolic syndrome. NAFLD occurs in all ethnic groups although it appears to have a lower prevalence in African-Americans compared with Hispanic and European Americans. This difference remains even after controlling for obesity and insulin resistance (IR)5,12 and may be related to ethnic differences in lipid homeostasis.5 There are no laboratory, imaging or histological findings which can accurately distinguish between NAFLD and alcohol-induced steatosis or steatohepatitis, and the diagnosis can therefore only be made in the absence of a history of significant alcohol intake. Other specific causes … Address correspondence to J. K. Dowman, Centre for Liver Research, Institute of Biomedical Research, University of Birmingham, Wolfson Drive, B15 2TT, Birmingham, UK. email: j.k.dowman{at}bham.ac.uk

Systematic review: the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

Aliment Pharmacol Ther 2011; 33: 525–540

Systematic Review: Diagnosis and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD)/Non-Alcoholic Steatohepatitis (NASH)?

Aliment Pharmacol Ther 2011; 33: 525–540

Current therapeutic strategies in non-alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease ranging from simple steatosis through steatohepatitis (NASH) to increasing fibrosis and eventual cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome and has now become the most common cause of liver disease in Western countries, with the more advanced stages of disease being associated with an increased risk of liver‐related morbidity and mortality. The optimal management of patients with NAFLD remains a clinical challenge. The aim of this study is to describe established and emerging strategies for the treatment of NAFLD. Relevant research and review articles were identified by searching PubMed. Selected articles referenced in these publications were also examined. Good quality randomized controlled studies have demonstrated the need for multifaceted lifestyle interventions in patients with NAFLD including the need for diet, exercise and behavioural counselling. Despite several trials of pharmacological agents, no highly effective treatment yet exists, with surgery representing the mainstay for advanced disease. A multidisciplinary approach, with a major focus on lifestyle change, represents best treatment pending the development of new therapeutic options.

Liver Transplantation for Acute Intermittent Porphyria is Complicated by a High Rate of Hepatic Artery Thrombosis

Acute intermittent porphyria (AIP) is an autosomal‐dominant condition resulting from a partial deficiency of the ubiquitously expressed enzyme porphobilinogen deaminase. Although its clinical expression is highly variable, a minority of patients suffer recurrent life‐threatening neurovisceral attacks despite optimal medical therapy. Because the liver is the major source of excess precursor production, liver transplantation (LT) represents a potentially effective treatment for severely affected patients. Using data from the UK Transplant Registry, we analyzed all transplants performed for AIP in the United Kingdom and Ireland. Between 2002 and 2010, 10 patients underwent LT for AIP. In all cases, the indication for transplantation was recurrent, biochemically proven, medically nonresponsive acute attacks of porphyria resulting in significantly impaired quality of life. Five patients had developed significant neurological morbidities such as paraplegia before transplantation. The median follow‐up time was 23.4 months, and there were 2 deaths from multiorgan failure at 98 days and 26 months. Eight recipients were alive for 3.2 to 109 months after transplantation. Complete biochemical and symptomatic resolution was observed in all patients after transplantation. However, there was a high rate of hepatic artery thrombosis (HAT; 4/10), with 1 patient requiring regrafting. The effects of previous neuronal damage such as joint contractures were not improved by transplantation. Thus, impaired quality of life in the surviving patients was usually a result of preoperative complications. Refractory AIP is an excellent indication for LT, and long‐term outcomes for carefully selected patients are good. There is, however, an increased incidence of HAT in these patients, and we recommend routine antiplatelet therapy after transplantation. Liver Transpl 18:195–200, 2012.

Development of Hepatocellular Carcinoma in a Murine Model of Nonalcoholic Steatohepatitis Induced by Use of a High-Fat/Fructose Diet and Sedentary Lifestyle

Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice.

Loss of 5α-Reductase Type 1 Accelerates the Development of Hepatic Steatosis but Protects Against Hepatocellular Carcinoma in Male Mice

Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability. Human liver samples from patients with NAFLD and normal donor tissue were used for gene expression and immunohistochemical analysis. NAFLD samples were scored using the Kleiner classification. In addition, 5αR1−/−, 5αR2−/−, and wild-type (WT) mice were fed normal chow or American lifestyle-induced obesity syndrome (ALIOS) diet for 6 or 12 months. Liver histology was graded and staged. Hepatic and circulating free fatty acid and triglyceride levels were quantified, and gene and protein expression was measured by real-time PCR and immunohistochemistry. 5αR1 and -2 were highly expressed in human liver, and 5αR1 protein expression increased with severity of NAFLD. 5αR1−/− (but not 5αR2−/−) mice fed an ALIOS diet developed greater hepatic steatosis than WT mice, and hepatic mRNA expression of genes involved in insulin signaling was decreased. Furthermore, 60% of WT mice developed focal hepatocellular lesions consistent with hepatocellular carcinoma after 12 months of the ALIOS diet, compared with 20% of 5αR2−/− and 0% of 5αR1−/− mice (P < .05). 5αR1 deletion accelerates the development of hepatic steatosis but may protect against the development of NAFLD-related hepatocellular neoplasia and therefore has potential as a therapeutic target.

Recurrent acute hepatic dysfunction in severe anorexia nervosa

Anorexia nervosa (AN) is an eating disorder predominantly affecting young women. Abnormal liver function tests (LFTs) resulting from AN is well-described but to date few cases of dramatic rises in liver enzymes have been described. We report a 32-year-old women with severe anorexia having dramatic rise in LFTs with liver failure during extremely poor nutritional status. Acute rise in liver enzymes observed on several occasions in this patient resulted from ischaemic hepatitis secondary to liver hypoperfusion. Clinicians caring for patients with severe AN should monitor haemodynamic parameters with the knowledge that acute liver failure can be a consequence of sudden liver hypoperfusion. Therapeutic intervention comprising volume support with gradual nutritional support results in normalization of LFTs.

Liver Transplantation From Donors With Acute Intermittent Porphyria

Background: Acute intermittent porphyria (AIP) results from partial deficiency of the enzyme porphobilinogen deaminase (1). The clinical disease includes life-threatening neurovisceral attacks from neuronal damage. The cause of these attacks has not been established but involves the heme precursor δ-aminolevulinic acid (ALA) (2). The liver is the major source of excess ALA production, and transplanting a normal liver into a patient with AIP effectively resolves this disease (3). Because clinical expression of AIP is more common in premenopausal women, we hypothesized that a liver removed from a premenopausal woman who is receiving a normal liver allograft could safely be …

Long-Term Impact of Liver Transplantation on Respiratory Function and Nutritional Status in Children and Adults With Cystic Fibrosis

Early liver transplant (LT) has been advocated for patients with cystic fibrosis liver disease (CFLD) and evidence of deterioration in nutritional state and respiratory function to prevent further decline. However, the impact of single LT on long‐term respiratory function and nutritional status has not been adequately addressed. We performed a retrospective analysis of the outcomes of 40 (21 adult/19 pediatric) patients with CFLD transplanted between 1987 and 2009 with median follow‐up of 47.8 months (range 4–180). One and five‐year actuarial survival rates were 85%/64% for adult and 90%/85% for pediatric LT cohorts, respectively. Lung function remained stable until 4 years (FEV1% predicted; pretransplant 48.4% vs. 45.9%, 4 years posttransplant) but declined by 5 years (42.4%). Up to 4 years posttransplant mean annual decline in FEV1% was lower (0.74%; p = 0.04) compared with the predicted 3% annual decline in CF patients with comorbidity including diabetes. Number of courses of intravenous antibiotics was reduced following LT, from 3.9/year pretransplant to 1.1/year, 5 years posttransplant. Body mass index was preserved posttransplant; 18.0 kg/m2 (range 15–24.3) pretransplant versus 19.6 kg/m2 (range 16.4–22.7) 5 years posttransplant. In conclusion, LT is an effective treatment for selected patients with cirrhosis due to CFLD, stabilizing aspects of long‐term lung function and preserving nutritional status.