Acute intermittent porphyria.
INSERM U409, Faculte de Medecine Xavier Bichat, Paris, France.
Acute intermittent porphyria (AIP) is transmitted as an autosomal dominant disorder with incomplete penetrance. Recent population studies suggest that the prevalence of asymptomatic heterozygotes for a mutant AIP gene may be in the range of 1 in 2,000. Clinical manifestations include abdominal pain and neurological dysfunctions. These symptoms occur during acute attacks, which are often precipitated by drugs, alcohol, low caloric intake, or infections. Biochemical abnormalities are thought to result from primary defects of porphobilinogen deaminase (PBGD; also called hydroxymethyl bilane synthase), the third enzyme of the heme synthesis pathway, and consecutive hepatic overexpression of the first enzyme of the pathway, 5-aminolevulinate synthase. As a result of these enzymatic disturbances, heme precursors are synthesized in excess in the liver, and massive amounts of compounds upstream of the enzymatic block are excreted in urine. Although the pathophysiology of the disease has not yet been fully elucidated, a specific treatment of acute attacks with heme has improved the prognosis. The cDNAs and the gene encoding PBGD have been isolated, permitting identification of mutations that account for the corresponding enzymatic deficiencies. Consequently, DNA analysis improves the accuracy of detection of presymptomatic heterozygotes in AIP families, permitting better counseling.
Department of Biochemistry, University of Texas Health Science Center, San Antonio 78284-7760, USA.
Hereditary coproporphyria (HC) is a rare acute hepatic porphyria. Attacks may be precipitated by certain drugs, alcohol, infections, or low caloric intake. HC is caused by defects in the enzyme coproporphyrinogen III oxidase (copro-ox) which converts coproporphyrinogen III (coprogen) to protoporphyrinogen IX (protogen). Coprogen is made mainly in the liver and is excreted predominantly in the feces. The dramatic increase in coproporphyrin III (copro) excretion (10-200 times compared with the control value) with intensive red fluorescence under UV light is a specific and easily detectable marker for diagnosis of acute attacks of HC. HC is inherited as an autosomally dominant genetic defect. The cDNA and gene encoding copro-ox have been isolated recently and mutations have been identified, providing critical information concerning molecular heterogeneity and the potential for molecular diagnosis. In this review, we describe 10 mutations in the copro-ox gene which are spread along six exons. It is postulated that DNA analysis of gene carriers and the use of heme arginate for specific treatment will improve the care of HC patients dramatically.
Kirsch RE. Meissner PN. Hift RJ.
Lennox Eales Porphyria Laboratories, MRC/UCT Liver Research Centre, Department of Medicine, University of Cape Town, South Africa.
Variegate porphyria is an autosomal dominant inherited trait resulting in decreased activity of protoporphyrinogen oxidase. It is characterized clinically by photosensitive skin disease and a propensity to acute neurovisceral crises. The disease is found worldwide but has an exceptionally high frequency in South Africa. The gene for human protoporphyrinogen oxidase has been identified and sequenced, and several mutations in the protoporphyrinogen oxidase gene sequence have been identified. In South Africa, fewer patients now present with acute attacks, leaving a greater proportion with skin disease or asymptomatic disease. Acute attacks of variegate porphyria appear to be less easily provoked and to be milder than those associated with acute intermittent porphyria.
Acute porphyrias: pathogenesis of neurological manifestations.
Meyer UA. Schuurmans MM. Lindberg RL.
University of Basel, Dept. Pharmacology, Switzerland.
Four types of hepatic porphyria (acute intermittent porphyria; hereditary coprophorphyria; variegate porphyria; delta-aminolevulinate dehydratase deficiency porphyria) present clinically with an identical neurological syndrome. Symptoms include severe abdominal pain, vomiting, constipation, hypertension, tachycardia, and bladder dysfunction. These symptoms have been ascribed to autonomic neuropathy. Other symptoms are motor weakness and sensory involvement, which correlate with peripheral axonal neuropathy, and mental symptoms occurring without clear morphological findings in the cerebrum. The pathogenetic mechanisms which lead to the neurological dysfunction have remained poorly understood, partly due to the lack of a suitable animal model of these rare disorders. Two hypotheses, the possible neurotoxicity of delta-aminolevulinate (ALA) and heme deficiency in nervous tissue are discussed and corresponding data from porphobilinogen-deaminase deficient mice are presented. The present evidence suggests that multiple mechanisms interact in causing the varied symptoms, including ALA interaction with GABA receptors, altered tryptophan metabolism, and possibly heme depletion in nerve cells.
Acute porphyria: treatment with heme.
Tenhunen R. Mustajoki P.
Dept. of Clinical Chemistry, Helsinki University Central Hospital, Finland.
The characterization of porphyrias as disorders of heme biosynthesis leading to hepatic heme deficiency and raised formation and secretion of heme precursors laid the basis for heme treatment. Although mild attacks sometimes respond to glucose administration, severe attacks or symptoms that are likely to progress should be treated with heme. The heme compounds used in treatment are hematin and heme arginate. In our opinion, heme arginate is preferable to hematin in the treatment of acute porphyrias because of its better stability, fewer side effects, and better documentation of its benefits.
Porphyria cutanea tarda.
Department of Medical Biochemistry, University of Wales College of Medicine, Cardiff, UK.
Porphyria cutanea tarda (PCT) is a skin disease that results from decreased activity of uroporphyrinogen decarboxylase (UROD). About 80% of patients have the sporadic (type I) form in which UROD deficiency is restricted to the liver. Others have familial (type II) PCT in which mutations in the UROD gene are inherited in an autosomal dominant pattern with low clinical penetrance. PCT may also follow exposure to porphyrogenic chemicals. Clinically overt PCT (types I and II) is provoked by liver cell injury, particularly when associated with alcohol abuse, hepatitis C infection, or estrogens. Hepatic iron overload is common, depletion of iron stores produces remission, and their replenishment leads to relapse. In PCT, hepatic UROD is inactivated by a process targeted at its catalytic site, which is iron-dependent, requires a heme precursor, and may be accelerated by induction of cytochrome P450s. Susceptibility to develop PCT in response to common causes of liver injury may be determined by co-inheritance of genes that regulate components of this inactivation process.
Cox TM. Alexander GJ. Sarkany RP.
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.
Human protoporphyria results from mutations in the ferrochelatase gene. Heritable deficiency of ferrochelatase causes overproduction of protoporphyrin IX, principally in the erythron. Photosensitivity is a universal feature of protoporphyria but hepatic clearance of the hydrophobic protoporphyrin molecule with excretion in bile may lead to precipitation within biliary pathways. Thus cholestatic injury and protoporphyrin gallstones occur. Minor hepatic abnormalities are frequent, but at least 30 patients have been reported with a progressive liver disease that requires transplantation. Fulminant hepatic disease appears to be recessively inherited in some pedigrees. Hazards of liver transplantation include tissue photolysis, hemolysis, and an unexplained neurological syndrome, but most of the 15 patients reported after transplantation have survived for several months to > 6 years. Aspects of protoporphyria, its pathogenesis and contemporary therapeutic strategies are considered, with emphasis on hepatic sequelae.
Dysregulation of apoptosis as a mechanism of liver disease: an overview.
Patel T. Roberts LR. Jones BA. Gores GJ.
Mayo Medical School, Clinic, and Foundation, Rochester, Minnesota 55905, USA.
Apoptosis is a morphologically distinct form of cell death which occurs in a wide variety of liver diseases. In this overview chapter, we review: (1) the current definitions of apoptosis; (2) the biochemical pathways effecting apoptosis; and (3) the intracellular pathways regulating apoptosis. We also describe how apoptosis is identified in the liver and review the ligand/receptor interactions which trigger hepatobiliary apoptosis. Finally, we speculate on potential therapeutic applications for modulating apoptosis in human liver diseases. This information is meant to provide a foundation for the following chapters each focused on a specific role of apoptosis in liver diseases.
Dysregulation of apoptosis in hepatocellular carcinoma.
Thorgeirsson SS. Teramoto T. Factor VM.
Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
The tightly controlled homeostatic mechanisms between cell growth and apoptosis that exist in normal liver tissue are disrupted during hepatocarcinogenesis. The TGF (transforming growth factor)-beta signaling system is a central component of the mechanisms by which cell growth and apoptosis are controlled in the liver. The recent delineation of the TGF-beta signaling pathway has provided a unique framework for analysis of the impact that disruption of individual components of this signaling pathway can have on apoptosis during hepatocarcinogenesis. Here we review recent data on involvement of the TGF-beta signaling pathway in the dysregulation of apoptosis frequently observed in hepatocellular carcinomas. The data indicate that disruption of the TGF-beta pathway at the pre-receptor, receptor, and post-receptor levels occurs in hepatocellular carcinomas and can cause dysregulation of apoptosis. Also, substantial evidence now exists that phosphatidylinositol-3-kinase (PI3K) may function as an important negative regulator of the TGF-beta 1-induced apoptosis in hepatocellular carcinomas. Taken together, the available evidence indicates that disruption of the TGF-beta 1-induced apoptosis as well as growth inhibition is an important and integral part of the multistage process of liver carcinogenesis.
CD95-induced apoptosis in human liver disease.
Galle PR. Krammer PH.
University Hospital, Department of Internal Medicine, Heidelberg, Germany.
The CD95 receptor is a death receptor capable of transducing apoptotic cell death upon ligation with the CD95 ligand (CD95L). The CD95/CD95L system plays a physiological role in apoptosis of lymphocytes and liver cells. In addition, the striking finding of acute hepatic failure in mice upon CD95 triggering has stimulated general interest in the involvement of CD95 mediated apoptosis in human liver disease. The currently available data point to a deregulated CD95 system in viral hepatitis, alcoholic hepatitis, acute hepatic failure of different etiology, diseases of the bile ducts, and hepatocellular carcinoma. Animal experiments suggest a causative relationship between CD95 activation and liver cell death, which, however, still has to be proven for liver disease in man. This review summarizes our present knowledge on CD95 mediated human liver disease.
Apoptosis and viral hepatitis.
Lau JY. Xie X. Lai MM. Wu PC.
Department of Medicine, University of Florida, Gainesville, USA.
Viral hepatitis is a diffuse inflammatory reaction of the liver caused by hepatotropic viruses. Pathomorphologic studies have shown acidophilic bodies and hepatocyte dropout, features that are compatible with apoptosis. Using in situ terminal transferase labeling, the number of hepatocytes showing features of apoptosis in patients with chronic hepatitis B and C was found to be small but higher than healthy subjects, indicating that apoptosis is involved in the pathogenesis of these diseases. There is evidence that the immune (cytotoxic T lymphocyte)-mediated pathways of apoptosis are activated, suggesting that the apoptosis of liver cells may at least in part be related to the host immune defense. Whether other cytokine-mediated and cellular constitutive apoptotic pathways are involved or not remains to be studied. There are recent data suggesting that hepatitis B and C viral proteins may modulate apoptosis. The exact role of these observations in relation to pathogenesis remains to be established.
Dysregulation of apoptosis in the cholangiopathies and cholangiocarcinoma.
Celli A. Que FG.
Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
The importance of cholangiocytes, the epithelial cells lining bile ducts, in the biology and pathobiology of biliary epithelia is rapidly growing due to the advent of suitable experimental models and techniques to study these cells. However, the role of cholangiocytes as a major cellular target in a variety of severe hepatobiliary diseases or cholangiopathies remains unanswered. As the biology of cholangiocyte death evolves, apoptosis has emerged as a key player in the development of ductopenia in these cholangiopathies. Cholangiocytes are continuously exposed to a variety of genotoxic insults, such as chronic inflammation and hydrophobic bile acids. This chronic exposure may predispose cholangiocytes to oncogenic mutations and the further progression to malignancy (or cholangiocarcinoma [CC]), due, in part, to failure to activate apoptosis and delete cells with genetic damage.
Apoptosis and alcoholic liver disease.
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Apoptosis occurs in both clinical and experimental alcoholic liver disease. The mechanisms involved in alcohol-induced apoptosis of liver cells are not completely understood. Induction of cytochrome P450 2E1, the alcohol-inducible cytochrome P450, is one of the proposed mechanisms. Exposure of Hep G2 cells expressing cytochrome P450 2E1 to arachidonic acid leads to increased lipid peroxidation and apoptosis. Increased levels of iron in the liver also promote lipid peroxidation and are associated with increased numbers of apoptotic hepatocytes. Tumor necrosis factor (TNF) acting through its receptors can induce apoptosis in hepatocytes. Increased levels of tumor necrosis factor and its receptors have been described in alcoholic liver disease. The liver is also CD95 receptor positive and in liver tissue from patients with alcoholic hepatitis, the CD95 ligand is expressed at high levels in hepatocytes. Cytotoxic T lymphocytes could, through the CD95 receptor-ligand interaction, promote apoptosis.