Publisher Summary The classification of cell death can be based on morphological or biochemical criteria or on the circumstances of its occurrence. Currently, irreversible structural alteration provides the only unequivocal evidence of death; biochemical indicators of cell death that are universally applicable have to be precisely defined and studies of cell function or of reproductive capacity do not necessarily differentiate between death and dormant states from which recovery may be possible. It has also proved feasible to categorize most if not all dying cells into one or the other of two discrete and distinctive patterns of morphological change, which have, generally, been found to occur under disparate but individually characteristic circumstances. One of these patterns is the swelling proceeding to rupture of plasma and organelle membranes and dissolution of organized structure—termed “coagulative necrosis.” It results from injury by agents, such as toxins and ischemia, affects cells in groups rather than singly, and evokes exudative inflammation when it develops in vivo. The other morphological pattern is characterized by condensation of the cell with maintenance of organelle integrity and the formation of surface protuberances that separate as membrane-bounded globules; in tissues, these are phagocytosed and digested by resident cells, there being no associated inflammation.

Cell death : the significance of apoptosis

Nonalcoholic fatty liver disease (NAFLD) is present in up to one third of the general population and in the majority of patients with metabolic risk factors such as obesity and diabetes. Insulin resistance is a key pathogenic factor resulting in hepatic fat accumulation. Recent evidence demonstrates NAFLD in turn, exacerbates hepatic insulin resistance and often precedes glucose intolerance. Once hepatic steatosis is established, other factors including oxidative stress, mitochondrial dysfunction, gut-derived lipopolysaccharide and adipocytokines, may promote hepatocellular damage, inflammation and progressive liver disease. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies, however staging the disease requires a liver biopsy. NAFLD is associated with an increased risk of all-cause death, probably because of complications of insulin resistance such as vascular disease, as well as due to cirrhosis and hepatocellular carcinoma, which occurs in a minority of patients. NAFLD is also now recognized to account for a substantial proportion of patients previously diagnosed with 'cryptogenic cirrhosis'. Diabetes, obesity and the necroinflammatory form of NAFLD known as non-alcoholic steatohepatitis, are risk factors for progressive liver disease. Current treatment relies on weight loss and exercise, although various insulin-sensitizing medications appear promising. Further research is needed to identify which patients will achieve the most benefit from therapy.

Nonalcoholic fatty liver disease.

Steatohepatitis: a tale of two "hits"?

https://www.aspe.vb.it/it/downloads/Brunt%20classificazione%20NASH.pdf

Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions

Hereditary haemochromatosis (HH), which affects some 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals of Northern European descent, results in multi-organ dysfunction caused by increased iron deposition, and is treatable if detected early. Using linkage-disequilibrium and full haplotype analysis, we have identified a 250-kilobase region more than 3 megabases telomeric of the major histocompatibility complex (MHC) that is identical-by-descent in 85% of patient chromosomes. Within this region, we have identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations. One of these is predicted to inactivate this class of proteins and was found homozygous in 83% of 178 patients. A role of this gene in haemochromatosis is supported by the frequency and nature of the major mutation and prior studies implicating MHC class I-like proteins in iron metabolism.

A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis

https://www.gastrojournal.org/article/S0016-5085(98)70482-2/pdf

Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis

Hemochromatosis is a common disorder characterized by excess iron absorption and accumulation of iron in tissues. Usually hemochromatosis is inherited in an autosomal recessive pattern and is caused by mutations In the HFE gene. Less common non-HFE-related forms of hemochromatosis have been reported and are caused by mutations in the transferrin receptor 2 gene and in a gene localized to chromosome 1q. Autosomal dominant forms of hemochromatosis have also been described. Recently, 2 mutations in the ferroportin1 gene, which encodes the iron transport protein ferroportin1, have been implicated in families with autosomal dominant hemochromatosis from the Netherlands and Italy. We report the finding of a novel mutation (V162del) in ferroportinl in an Australian family with autosomal dominant hemochromatosis. We propose that this mutation disrupts the function of the ferroportin1 protein, leading to impaired iron homeostasis and iron overload.

Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis

The effect of cigarette smoking on salivary antipyrine disappearance rate, and as an index of hepatic drug metabolism, was studied in 42 healthy subjects. Antipyrine half life was significantly shorter in smokers compared with non-smokers. To determine whether this difference was due solely to tobacco consumption eight subjects were restudied two months after they stopped smoking. The mean antipyrine disappearance rate in this group increased by 23% in contrast to that of a control group, which did not alter. Cigarette smoking contributes to the considerable variation in interindividual rates of drug metabolism.

Enhanced drug metabolism in cigarette smokers.

The concentration of cytochrome P-450 and activities of the microsomal enzymes aryl hydrocarbon hydroxylase and ethylmorphine demethylase were measured in hepatic tissue obtained at biopsy from 69 patients Antipyrine half-life (AP t1/2) was measured simultaneously as an in vivo marker of drug metabolism Values for each index of the drug-metabolizing system varied greatly, but the mean values in groups of patients with mild hepatitis or inactive cirrhosis did not differ significantly from those of controls Hepatic cytochrome P-450 content and aryl hydrocarbon hydroxylase activity were lower in patients with severe hepatitis or active cirrhosis than in controls, but ethylmorphine demethylase activity was unchanged in the patients Drug ingestion was associated with enhancement of drug-metabolizing enzymes in all patients but those with severe liver disease; ethylmorphine demethylase activity was enhanced proportionately more than aryl hydrocarbon hydroxylase activity or cytochrome P-450 concentration The observation that aryl hydrocarbon hydroxylase and ethylmorphine demethylase activities are influenced to a different extent by liver disease and also by drug ingestion indicates functional heterogeneity of the hepatic microsomal drug-metabolizing system in man Correlations between t1/2 and hepatic drug oxidases were weak, even when allowance was made for variation in liver size Thus, the rate of drug metabolism in vivo assessed by measuring AP t1/2 does not appear to be closely related to the activity of some hepatic drug-metabolizing enzymes

Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes.

The conversion of prednisone to the biologically active corticosteroid prednisolone and the degree of plasma protein binding of prednisolone were studied in 22 patients with acute or chronic liver disease and in eight control subjects. In patients whose disease was active at the time of study, as judged by elevated serum levels of bilirubin and transaminase, significantly higher levels of plasma prednisolone were obtained after prednisolone administration than after equivalent doses of prednisone. In addition, the amount of unbound drug in the plasma was higher in patients with active disease. There was a significant correlation between the extent of plasma protein binding of prednisolone and the serum albumin concentration. Azathioprine did not affect the plasma binding of prednisolone in vitro. The plasma half-life of prednisolone was prolonged in two of three patients with chronic liver disease studied. These results suggest that in patients with acute hepatitis or active chronic liver disease there is impairment of reduction of the 11-oxo group of prednisone, and also impaired ring A reduction of prednisolone. Thus, incomplete conversion of prednisone to prednisolone occurs, which is a necessary step for biological activity; on the other hand there is also impairment of prednisolone degradation. These, together with low serum albumin concentrations which are associated with higher levels of circulating unbound prednisolone, result in quite different levels of biologically active corticosteroids compared with equivalent doses of prednisone or prednisolone in subjects without liver disease. The findings have important practical implications for the use of corticosteroids in patients with active liver disease.

https://gut.bmj.com/content/gutjnl/13/9/690.full.pdf

L. W. Powell

Papers

Increased hepatic iron concentration in nonalcoholic steatohepatitis is associated with increased fibrosis

Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis

Enhanced drug metabolism in cigarette smokers.

Drug metabolism in liver disease: activity of hepatic microsomal metabolizing enzymes.

Corticosteroids in liver disease: Studies on the biological conversion of prednisone to prednisolone and plasma protein binding