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__NOTOC__
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{{CMG}} {{AE}}
  
{{CMG}}; {{AE}}
 
 
==Overview==
 
==Overview==
The pathogenesis of alcoholic liver disease is complex and still remains unclear, the metabolites of the oxidative metabolism in the liver; acetaldehyde and reactive oxygen species are thought to be involved in the toxic effects of ethanol on the liver.<ref name="pmid25548474">{{cite journal |vauthors=Ceni E, Mello T, Galli A |title=Pathogenesis of alcoholic liver disease: role of oxidative metabolism |journal=World J. Gastroenterol. |volume=20 |issue=47 |pages=17756–72 |year=2014 |pmid=25548474 |pmc=4273126 |doi=10.3748/wjg.v20.i47.17756 |url=}}</ref>
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Treatment of ADPKD is targeted at the management of symptoms and complications of the disease including tight blood pressure control with ACEIs or ARBs, pain control, antibiotics in cases of cyst infections or pyelonephritis, and avoidance of abdominal trauma.
  
==Pathophysiology==
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==Treatment==
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Treatment of ADPKD is targeted at managing symptoms and disease complications. There have been no treatments associated with disease regression or slowing of cysts formation.<ref name="pmid18832246">{{cite journal| author=Grantham JJ| title=Clinical practice. Autosomal dominant polycystic kidney disease. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 14 | pages= 1477-85 | pmid=18832246 | doi=10.1056/NEJMcp0804458 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18832246  }} </ref> No professional society has proposed guidelines for the management of patients with ADPKD.
  
===Pathogenesis===
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===Hypertension===
*Ethanol metabolism in the liver is carried out mainly by two enzymes; alcohol dehydrogenase and aldehyde dehydrogenase. Both of these enzymes use NAD+ as a cofactor. Alcohol is converted to acetaldehyde and acetaldehyde is then further oxidized to acetate. Acetaldehyde is the toxic metabolite in this process.<ref name="pmid25548474">{{cite journal |vauthors=Ceni E, Mello T, Galli A |title=Pathogenesis of alcoholic liver disease: role of oxidative metabolism |journal=World J. Gastroenterol. |volume=20 |issue=47 |pages=17756–72 |year=2014 |pmid=25548474 |pmc=4273126 |doi=10.3748/wjg.v20.i47.17756 |url=}}</ref>
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Up to 75% of patients with ADPKD on imaging without any renal insufficiency are hypertensive.<ref name="pmid2239929">{{cite journal| author=Gabow PA| title=Autosomal dominant polycystic kidney disease--more than a renal disease. | journal=Am J Kidney Dis | year= 1990 | volume= 16 | issue= 5 | pages= 403-13 | pmid=2239929 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2239929 }} </ref> Even in young patients, 50% of those aged 20-34 years are hypertensive despite normal renal function.<ref name="pmid15533729">{{cite journal| author=Kelleher CL, McFann KK, Johnson AM, Schrier RW| title=Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population. | journal=Am J Hypertens | year= 2004 | volume= 17 | issue= 11 Pt 1 | pages= 1029-34 | pmid=15533729 | doi=10.1016/j.amjhyper.2004.06.020 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15533729 }} </ref> Treatment is recommended when blood pressure exceeds 130/80 mm Hg for adults, or sex and age adjusted norms for children. ACE inhibitors and ARBs are highly recommended as observational studies have shown better preservation of renal function with these agents. Eventual resistance or blunting of the effects of the these agents with increased volume retention can be encountered. Salt restriction, with addition of thiazide diuretics initially or loop diuretics as a second line, is justified.<ref name="pmid18832246">{{cite journal| author=Grantham JJ| title=Clinical practice. Autosomal dominant polycystic kidney disease. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 14 | pages= 1477-85 | pmid=18832246 | doi=10.1056/NEJMcp0804458 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18832246  }} </ref> The first randomized clinical trial evaluating the use of lisinopril and telmisartan and their effect on progression of kidney disease in ADPKD patients, the HALT Progression of Polycystic Kidney Disease (HALT PKD), is expected to conclude by June 2014.<ref name="pmid22205355">{{cite journal| author=Torres VE, Chapman AB, Perrone RD, Bae KT, Abebe KZ, Bost JE et al.| title=Analysis of baseline parameters in the HALT polycystic kidney disease trials. | journal=Kidney Int | year= 2012 | volume= 81 | issue= 6 | pages= 577-85 | pmid=22205355 | doi=10.1038/ki.2011.411 | pmc=PMC3580956 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22205355  }} </ref>
*The metabolism of alcohol in the liver ends up producing an excess of reduced nicotinamide adenine dinucleotide(NADH). This changes the reduction-oxidation potential in the liver and inhibits key metabolic processes in the liver such as, the tricarboxylic acid cycle and the oxidation of fatty acids and thereby ends up promoting lipogenesis.<ref name="pmid15194557">{{cite journal |vauthors=You M, Crabb DW |title=Recent advances in alcoholic liver disease II. Minireview: molecular mechanisms of alcoholic fatty liver |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=287 |issue=1 |pages=G1–6 |year=2004 |pmid=15194557 |doi=10.1152/ajpgi.00056.2004 |url=}}</ref>
 
*Since acetaldehyde has an electrophilic nature it can form covalent chemical bonds with proteins, lipids and DNA. These covalent bonds that are formed are extremely pathogenic, as they have the ability to alter cell environments, protein structures and they can enable DNA damage and mutation.<ref name="pmid16088993">{{cite journal |vauthors=Freeman TL, Tuma DJ, Thiele GM, Klassen LW, Worrall S, Niemelä O, Parkkila S, Emery PW, Preedy VR |title=Recent advances in alcohol-induced adduct formation |journal=Alcohol. Clin. Exp. Res. |volume=29 |issue=7 |pages=1310–6 |year=2005 |pmid=16088993 |doi= |url=}}</ref><ref name="pmid17590995">{{cite journal |vauthors=Niemelä O |title=Acetaldehyde adducts in circulation |journal=Novartis Found. Symp. |volume=285 |issue= |pages=183–92; discussion 193–7 |year=2007 |pmid=17590995 |doi= |url=}}</ref><ref name="pmid11841919">{{cite journal |vauthors=Tuma DJ |title=Role of malondialdehyde-acetaldehyde adducts in liver injury |journal=Free Radic. Biol. Med. |volume=32 |issue=4 |pages=303–8 |year=2002 |pmid=11841919 |doi= |url=}}</ref><ref name="pmid15540799">{{cite journal |vauthors=Tuma DJ, Casey CA |title=Dangerous byproducts of alcohol breakdown--focus on adducts |journal=Alcohol Res Health |volume=27 |issue=4 |pages=285–90 |year=2003 |pmid=15540799 |doi= |url=}}</ref><ref name="pmid16054980">{{cite journal |vauthors=Brooks PJ, Theruvathu JA |title=DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis |journal=Alcohol |volume=35 |issue=3 |pages=187–93 |year=2005 |pmid=16054980 |doi=10.1016/j.alcohol.2005.03.009 |url=}}</ref><ref name="pmid17718399">{{cite journal |vauthors=Seitz HK, Becker P |title=Alcohol metabolism and cancer risk |journal=Alcohol Res Health |volume=30 |issue=1 |pages=38–41, 44–7 |year=2007 |pmid=17718399 |pmc=3860434 |doi= |url=}}</ref><ref name="pmid9857222">{{cite journal |vauthors=Biewald J, Nilius R, Langner J |title=Occurrence of acetaldehyde protein adducts formed in various organs of chronically ethanol fed rats: an immunohistochemical study |journal=Int. J. Mol. Med. |volume=2 |issue=4 |pages=389–96 |year=1998 |pmid=9857222 |doi= |url=}}</ref><ref name="pmid17543846">{{cite journal |vauthors=Seitz HK, Meier P |title=The role of acetaldehyde in upper digestive tract cancer in alcoholics |journal=Transl Res |volume=149 |issue=6 |pages=293–7 |year=2007 |pmid=17543846 |doi=10.1016/j.trsl.2006.12.002 |url=}}</ref>
 
  
*The cytochrome P450 enzymes (CYP) are a part of the microsomal ethanol oxidizing system. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.<ref name="pmid3678578">{{cite journal |vauthors=Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV |title=Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans |journal=Biochem. Soc. Trans. |volume=15 |issue=4 |pages=576–8 |year=1987 |pmid=3678578 |doi= |url=}}</ref>
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===Hematuria===
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Gross hematuria with significant renal colic secondary to collecting system clots is not uncommon. Treatment usually involves analgesia, bed rest and hydration to increase urinary flow rate to 2-3 liters daily. In most patients, gross hematuria regresses to microscopic hematuria in a few days. Patients should be
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advised to avoid sports with risk of abdominal trauma to prevent recurrent episodes.<ref name="pmid18832246">{{cite journal| author=Grantham JJ| title=Clinical practice. Autosomal dominant polycystic kidney disease. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 14 | pages= 1477-85 | pmid=18832246 | doi=10.1056/NEJMcp0804458 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18832246  }} </ref>
  
*There is an ethanol inducible form of CYP enzymes that is working in a small amount under normal physiological conditions. This enzyme CYP2E1 is converting ethanol to acetaldehyde and then to acetate. When there is chronic alcohol abuse, there is induction of the microsomal system and there is an increase in the expression of CYP2E1. This increase in CYP2E1 expression under chronic ethanol consumption can be hazardous, as this oxidation reaction can produces many different ROS; O<sub>2</sub><sup>-</sup>, H<sub>2</sub>O<sub>2</sub>, OH<sup>-</sup> and hydroxyethyl radical (HER).<ref name="pmid36785782">{{cite journal |vauthors=Guengerich FP, Beaune PH, Umbenhauer DR, Churchill PF, Bork RW, Dannan GA, Knodell RG, Lloyd RS, Martin MV |title=Cytochrome P-450 enzymes involved in genetic polymorphism of drug oxidation in humans |journal=Biochem. Soc. Trans. |volume=15 |issue=4 |pages=576–8 |year=1987 |pmid=3678578 |doi= |url=}}</ref><ref name="pmid5009602">{{cite journal |vauthors=Lieber CS |title=Metabolism of ethanol and alcoholism: racial and acquired factors |journal=Ann. Intern. Med. |volume=76 |issue=2 |pages=326–7 |year=1972 |pmid=5009602 |doi= |url=}}</ref><ref name="pmid4402282">{{cite journal |vauthors=Lieber CS, DeCarli LM |title=The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo |journal=J. Pharmacol. Exp. Ther. |volume=181 |issue=2 |pages=279–87 |year=1972 |pmid=4402282 |doi= |url=}}</ref><ref name="pmid9114822">{{cite journal |vauthors=Lieber CS |title=Cytochrome P-4502E1: its physiological and pathological role |journal=Physiol. Rev. |volume=77 |issue=2 |pages=517–44 |year=1997 |pmid=9114822 |doi= |url=}}</ref><ref name="pmid2333153">{{cite journal |vauthors=Hansson T, Tindberg N, Ingelman-Sundberg M, Köhler C |title=Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system |journal=Neuroscience |volume=34 |issue=2 |pages=451–63 |year=1990 |pmid=2333153 |doi= |url=}}</ref><ref name="pmid17760783">{{cite journal |vauthors=Donohue TM, Cederbaum AI, French SW, Barve S, Gao B, Osna NA |title=Role of the proteasome in ethanol-induced liver pathology |journal=Alcohol. Clin. Exp. Res. |volume=31 |issue=9 |pages=1446–59 |year=2007 |pmid=17760783 |doi=10.1111/j.1530-0277.2007.00454.x |url=}}</ref><ref name="pmid17854134">{{cite journal |vauthors=Osna NA, Donohue TM |title=Implication of altered proteasome function in alcoholic liver injury |journal=World J. Gastroenterol. |volume=13 |issue=37 |pages=4931–7 |year=2007 |pmid=17854134 |pmc=4434615 |doi= |url=}}</ref><ref name="pmid18078827">{{cite journal |vauthors=Lu Y, Cederbaum AI |title=CYP2E1 and oxidative liver injury by alcohol |journal=Free Radic. Biol. Med. |volume=44 |issue=5 |pages=723–38 |year=2008 |pmid=18078827 |pmc=2268632 |doi=10.1016/j.freeradbiomed.2007.11.004 |url=}}</ref><ref name="pmid1545775">{{cite journal |vauthors=Yun YP, Casazza JP, Sohn DH, Veech RL, Song BJ |title=Pretranslational activation of cytochrome P450IIE during ketosis induced by a high fat diet |journal=Mol. Pharmacol. |volume=41 |issue=3 |pages=474–9 |year=1992 |pmid=1545775 |doi= |url=}}</ref><ref name="pmid2005876">{{cite journal |vauthors=Raucy JL, Lasker JM, Kraner JC, Salazar DE, Lieber CS, Corcoran GB |title=Induction of cytochrome P450IIE1 in the obese overfed rat |journal=Mol. Pharmacol. |volume=39 |issue=3 |pages=275–80 |year=1991 |pmid=2005876 |doi= |url=}}</ref><ref name="pmid11826398">{{cite journal |vauthors=Woodcroft KJ, Hafner MS, Novak RF |title=Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression |journal=Hepatology |volume=35 |issue=2 |pages=263–73 |year=2002 |pmid=11826398 |doi=10.1053/jhep.2002.30691 |url=}}</ref><ref name="pmid7700245">{{cite journal |vauthors=De Waziers I, Garlatti M, Bouguet J, Beaune PH, Barouki R |title=Insulin down-regulates cytochrome P450 2B and 2E expression at the post-transcriptional level in the rat hepatoma cell line |journal=Mol. Pharmacol. |volume=47 |issue=3 |pages=474–9 |year=1995 |pmid=7700245 |doi= |url=}}</ref><ref name="pmid9765518">{{cite journal |vauthors=Peng HM, Coon MJ |title=Regulation of rabbit cytochrome P450 2E1 expression in HepG2 cells by insulin and thyroid hormone |journal=Mol. Pharmacol. |volume=54 |issue=4 |pages=740–7 |year=1998 |pmid=9765518 |doi= |url=}}</ref><ref name="pmid1822117">{{cite journal |vauthors=Terelius Y, Norsten-Höög C, Cronholm T, Ingelman-Sundberg M |title=Acetaldehyde as a substrate for ethanol-inducible cytochrome P450 (CYP2E1) |journal=Biochem. Biophys. Res. Commun. |volume=179 |issue=1 |pages=689–94 |year=1991 |pmid=1822117 |doi= |url=}}</ref><ref name="pmid9726291">{{cite journal |vauthors=Wu YS, Salmela KS, Lieber CS |title=Microsomal acetaldehyde oxidation is negligible in the presence of ethanol |journal=Alcohol. Clin. Exp. Res. |volume=22 |issue=5 |pages=1165–9 |year=1998 |pmid=9726291 |doi= |url=}}</ref><ref name="pmid9309320">{{cite journal |vauthors=Brooks PJ |title=DNA damage, DNA repair, and alcohol toxicity--a review |journal=Alcohol. Clin. Exp. Res. |volume=21 |issue=6 |pages=1073–82 |year=1997 |pmid=9309320 |doi= |url=}}</ref>
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===Urinary Tract Infections===
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Women are at a higher risk for UTIs and cyst infections with gram negative rods being the most common pathogens. Symptomatic cyst infections or acute pyelonephritis require hospital admission with floroquinolone therapy until pain, fever, and leukocytosis resolve.<ref name="pmid9794537">{{cite journal| author=Gibson P, Watson ML| title=Cyst infection in polycystic kidney disease: a clinical challenge. | journal=Nephrol Dial Transplant | year= 1998 | volume= 13 | issue= 10 | pages= 2455-7 | pmid=9794537 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9794537  }} </ref>
  
*Ethanol metabolism additionally promotes lipogenesis through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound transcription factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.<ref name="pmid12791698">{{cite journal |vauthors=Fischer M, You M, Matsumoto M, Crabb DW |title=Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice |journal=J. Biol. Chem. |volume=278 |issue=30 |pages=27997–8004 |year=2003 |pmid=12791698 |doi=10.1074/jbc.M302140200 |url=}}</ref><ref name="pmid15578517">{{cite journal |vauthors=You M, Matsumoto M, Pacold CM, Cho WK, Crabb DW |title=The role of AMP-activated protein kinase in the action of ethanol in the liver |journal=Gastroenterology |volume=127 |issue=6 |pages=1798–808 |year=2004 |pmid=15578517 |doi= |url=}}</ref><ref name="pmid16879892">{{cite journal |vauthors=Ji C, Chan C, Kaplowitz N |title=Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model |journal=J. Hepatol. |volume=45 |issue=5 |pages=717–24 |year=2006 |pmid=16879892 |doi=10.1016/j.jhep.2006.05.009 |url=}}</ref>
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===Pain===
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Severe flank or abdominal pain in the absence of cyst complications is very common. Several options for treatment exist including regular analgesics, local anesthetic injections, surgical cyst unroofing, transcutaneous stimulation, and surgical renal denervation. No randomized control trials have been conducted to evaluate the efficacy of each of these treatments. Generally, invasive procedures are reserved for patients with intractable pain that is not responding to classical pain management. <ref name="pmid11703580‎">{{cite journal| author=Bajwa ZH, Gupta S, Warfield CA, Steinman TI| title=Pain management in polycystic kidney disease. | journal=Kidney Int | year= 2001 | volume= 60 | issue= 5 | pages= 1631-44 | pmid=11703580‎ | doi=10.1046/j.1523-1755.2001.00985.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11703580  }} </ref>
  
*Based on animal studies, 2 key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are endotoxin and gut permeability. Endotoxin is associated to the lipopolysaccharide (LPS) component of the outer wall of gram-negative bacteria and is thought to be the key trigger in this inflammatory process. Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation, it is seen to be altered in response to long term exposure to alcohol. This fact has been observed in humans as gut permeability and LPS-endotoxin levels have been found to be elevated in patients with alcoholic liver injury.<ref name="pmid6433728">{{cite journal |vauthors=Tsukamoto H, Reidelberger RD, French SW, Largman C |title=Long-term cannulation model for blood sampling and intragastric infusion in the rat |journal=Am. J. Physiol. |volume=247 |issue=3 Pt 2 |pages=R595–9 |year=1984 |pmid=6433728 |doi= |url=}}</ref><ref name="pmid11431739">{{cite journal |vauthors=Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG |title=Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice |journal=Hepatology |volume=34 |issue=1 |pages=101–8 |year=2001 |pmid=11431739 |doi=10.1053/jhep.2001.25350 |url=}}</ref><ref name="pmid15723320">{{cite journal |vauthors=Wiest R, Garcia-Tsao G |title=Bacterial translocation (BT) in cirrhosis |journal=Hepatology |volume=41 |issue=3 |pages=422–33 |year=2005 |pmid=15723320 |doi=10.1002/hep.20632 |url=}}</ref><ref name="pmid8171045">{{cite journal |vauthors=Nanji AA, Khettry U, Sadrzadeh SM |title=Lactobacillus feeding reduces endotoxemia and severity of experimental alcoholic liver (disease) |journal=Proc. Soc. Exp. Biol. Med. |volume=205 |issue=3 |pages=243–7 |year=1994 |pmid=8171045 |doi= |url=}}</ref><ref name="pmid7806045">{{cite journal |vauthors=Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG |title=Antibiotics prevent liver injury in rats following long-term exposure to ethanol |journal=Gastroenterology |volume=108 |issue=1 |pages=218–24 |year=1995 |pmid=7806045 |doi= |url=}}</ref><ref name="pmid6141332">{{cite journal |vauthors=Bjarnason I, Peters TJ, Wise RJ |title=The leaky gut of alcoholism: possible route of entry for toxic compounds |journal=Lancet |volume=1 |issue=8370 |pages=179–82 |year=1984 |pmid=6141332 |doi= |url=}}</ref><ref name="pmid11236841">{{cite journal |vauthors=Urbaschek R, McCuskey RS, Rudi V, Becker KP, Stickel F, Urbaschek B, Seitz HK |title=Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease |journal=Alcohol. Clin. Exp. Res. |volume=25 |issue=2 |pages=261–8 |year=2001 |pmid=11236841 |doi= |url=}}</ref>
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===Renal Failure===
 
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Renal failure is the eventual complication of almost all patients with ADPKD. Treatment is usually with the 3 major forms of renal replacement with special considerations required for some cases. Peritoneal dialysis is usually not recommended in patients with aortic aneurysms. Hemodialysis, although the most common form of renal replacement, required significant anticoagulation that may complicate existing hematuria. Ultimately, renal transplantation is the preferred renal replacement modality with outcomes similar to patients with other baseline kidney diseases leading to ESRD.<ref name="pmid18832246">{{cite journal| author=Grantham JJ| title=Clinical practice. Autosomal dominant polycystic kidney disease. | journal=N Engl J Med | year= 2008 | volume= 359 | issue= 14 | pages= 1477-85 | pmid=18832246 | doi=10.1056/NEJMcp0804458 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18832246  }} </ref>
*Experimental studies in animals have led to a better understanding of the disease process and how the factors mentioned above contribute to these processes. After the entry of LPS-endotoxin in to the portal circulation it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to alcohol ingestion.The LPS-Lps binding protein complex binds to the CD14 receptor on the cell surface membrane of the Kupffer cells in the liver. Activation of these Kupffer cells requires 3 main cellular proteins: CD 14 (monocyte differentiation antigen), toll-like receptor 4 (TLR4) and a protein known as MD2, this protein binds TLR4 with LPS-LPS binding protein. The TLR4 then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor. The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells. EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production; in mice the absence of EGR1 prevents alcohol induced liver injury.<ref name="pmid11884468">{{cite journal |vauthors=Uesugi T, Froh M, Arteel GE, Bradford BU, Wheeler MD, Gäbele E, Isayama F, Thurman RG |title=Role of lipopolysaccharide-binding protein in early alcohol-induced liver injury in mice |journal=J. Immunol. |volume=168 |issue=6 |pages=2963–9 |year=2002 |pmid=11884468 |doi= |url=}}</ref><ref name="pmid8045507">{{cite journal |vauthors=Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG |title=Inactivation of Kupffer cells prevents early alcohol-induced liver injury |journal=Hepatology |volume=20 |issue=2 |pages=453–60 |year=1994 |pmid=8045507 |doi= |url=}}</ref><ref name="pmid11477402">{{cite journal |vauthors=Akira S, Takeda K, Kaisho T |title=Toll-like receptors: critical proteins linking innate and acquired immunity |journal=Nat. Immunol. |volume=2 |issue=8 |pages=675–80 |year=2001 |pmid=11477402 |doi=10.1038/90609 |url=}}</ref><ref name="pmid11254735">{{cite journal |vauthors=Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM, Thurman RG |title=Reduced early alcohol-induced liver injury in CD14-deficient mice |journal=J. Immunol. |volume=166 |issue=7 |pages=4737–42 |year=2001 |pmid=11254735 |doi= |url=}}</ref><ref name="pmid15940638">{{cite journal |vauthors=McMullen MR, Pritchard MT, Wang Q, Millward CA, Croniger CM, Nagy LE |title=Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice |journal=Gastroenterology |volume=128 |issue=7 |pages=2066–76 |year=2005 |pmid=15940638 |pmc=1959407 |doi= |url=}}</ref><ref name="pmid18713975">{{cite journal |vauthors=Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK |title=TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol |journal=J. Immunol. |volume=181 |issue=5 |pages=3049–56 |year=2008 |pmid=18713975 |pmc=3690475 |doi= |url=}}</ref><ref name="pmid18792393">{{cite journal |vauthors=Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K, Kurt-Jones E, Szabo G |title=The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88 |journal=Hepatology |volume=48 |issue=4 |pages=1224–31 |year=2008 |pmid=18792393 |doi=10.1002/hep.22470 |url=}}</ref>
 
 
 
*Ethanol administration stimulates the release of mitochondrial cytochrome c and the expression of the Fas ligand, this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway. The cumulative effect of TNF-α and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the liver.<ref name="pmid11438480">{{cite journal |vauthors=Zhou Z, Sun X, Kang YJ |title=Ethanol-induced apoptosis in mouse liver: Fas- and cytochrome c-mediated caspase-3 activation pathway |journal=Am. J. Pathol. |volume=159 |issue=1 |pages=329–38 |year=2001 |pmid=11438480 |pmc=1850406 |doi=10.1016/S0002-9440(10)61699-9 |url=}}</ref><ref name="pmid15131799">{{cite journal |vauthors=Minagawa M, Deng Q, Liu ZX, Tsukamoto H, Dennert G |title=Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption |journal=Gastroenterology |volume=126 |issue=5 |pages=1387–99 |year=2004 |pmid=15131799 |doi= |url=}}</ref>
 
 
 
==Genetics==
 
*[Disease name] is transmitted in [mode of genetic transmission] pattern.
 
*Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
 
*The development of [disease name] is the result of multiple genetic mutations.
 
 
 
==Associated Conditions==
 
 
 
==Gross Pathology==
 
*On gross pathology, characteristic findings of alcoholic liver disease include:<ref name="pmid24739823">{{cite journal |vauthors=Agrawal P, Vaiphei K |title=Histomorphological features of pancreas and liver in chronic alcoholics--an analytical study in 390 autopsy cases |journal=Indian J Pathol Microbiol |volume=57 |issue=1 |pages=2–8 |year=2014 |pmid=24739823 |doi=10.4103/0377-4929.130842 |url=}}</ref>
 
**Hepatomegaly
 
**Nodules
 
***Macronodules
 
***Micronodules
 
**Firm in consistency
 
**Portal vein dilation
 
 
 
==Microscopic Pathology==
 
*On microscopic histopathological analysis, steatosis (macrovesicular steatosis-the cytoplasm of hepatocytes is occupied by large lipid droplets that end up displacing the nucleus and other organelles peripherally), proliferation of the smooth endoplasmic reticulum, distortion of the mitochondria (giant mitochondria) and hepatocyte balooning (Mallory-Denk bodies) are characteristic findings of alcoholic liver disease.<ref name="pmid15763228">{{cite journal |vauthors=Lefkowitch JH |title=Morphology of alcoholic liver disease |journal=Clin Liver Dis |volume=9 |issue=1 |pages=37–53 |year=2005 |pmid=15763228 |doi=10.1016/j.cld.2004.11.001 |url=}}</ref><ref name="pmid5641156">{{cite journal |vauthors=Rubin E, Lieber CS |title=Alcohol-induced hepatic injury in nonalcoholic volunteers |journal=N. Engl. J. Med. |volume=278 |issue=16 |pages=869–76 |year=1968 |pmid=5641156 |doi=10.1056/NEJM196804182781602 |url=}}</ref><ref name="pmid7806041">{{cite journal |vauthors=Fromenty B, Grimbert S, Mansouri A, Beaugrand M, Erlinger S, Rötig A, Pessayre D |title=Hepatic mitochondrial DNA deletion in alcoholics: association with microvesicular steatosis |journal=Gastroenterology |volume=108 |issue=1 |pages=193–200 |year=1995 |pmid=7806041 |doi= |url=}}</ref><ref name="pmid3699404">{{cite journal |vauthors=Chedid A, Mendenhall CL, Tosch T, Chen T, Rabin L, Garcia-Pont P, Goldberg SJ, Kiernan T, Seeff LB, Sorrell M |title=Significance of megamitochondria in alcoholic liver disease |journal=Gastroenterology |volume=90 |issue=6 |pages=1858–64 |year=1986 |pmid=3699404 |doi= |url=}}</ref><ref name="pmid6700382">{{cite journal |vauthors=Uchida T, Kronborg I, Peters RL |title=Giant mitochondria in the alcoholic liver diseases--their identification, frequency and pathologic significance |journal=Liver |volume=4 |issue=1 |pages=29–38 |year=1984 |pmid=6700382 |doi= |url=}}</ref>
 
 
 
*A cirrhotic liver will show fibrous septae that are made up of collagen surrounding the hepatocytes which results in pseudo lobule formation. This produces a nodular appearance of the liver and then progresses from micro nodular to macro nodular cirrhosis with time. Proliferation of the bile ducts may also be seen.<ref name="pmid6629323">{{cite journal |vauthors=Fauerholdt L, Schlichting P, Christensen E, Poulsen H, Tygstrup N, Juhl E |title=Conversion of micronodular cirrhosis into macronodular cirrhosis |journal=Hepatology |volume=3 |issue=6 |pages=928–31 |year=1983 |pmid=6629323 |doi= |url=}}</ref><ref name="pmid649765">{{cite journal |vauthors=Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH |title=The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization |journal=J. Clin. Pathol. |volume=31 |issue=5 |pages=395–414 |year=1978 |pmid=649765 |pmc=1145292 |doi= |url=}}</ref><ref name="pmid2466751">{{cite journal |vauthors=Van Eyken P, Sciot R, Desmet VJ |title=A cytokeratin immunohistochemical study of alcoholic liver disease: evidence that hepatocytes can express 'bile duct-type' cytokeratins |journal=Histopathology |volume=13 |issue=6 |pages=605–17 |year=1988 |pmid=2466751 |doi= |url=}}</ref>
 
  
 
==References==
 
==References==
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Latest revision as of 18:56, 7 June 2018

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:

Overview

Treatment of ADPKD is targeted at the management of symptoms and complications of the disease including tight blood pressure control with ACEIs or ARBs, pain control, antibiotics in cases of cyst infections or pyelonephritis, and avoidance of abdominal trauma.

Treatment

Treatment of ADPKD is targeted at managing symptoms and disease complications. There have been no treatments associated with disease regression or slowing of cysts formation.[1] No professional society has proposed guidelines for the management of patients with ADPKD.

Hypertension

Up to 75% of patients with ADPKD on imaging without any renal insufficiency are hypertensive.[2] Even in young patients, 50% of those aged 20-34 years are hypertensive despite normal renal function.[3] Treatment is recommended when blood pressure exceeds 130/80 mm Hg for adults, or sex and age adjusted norms for children. ACE inhibitors and ARBs are highly recommended as observational studies have shown better preservation of renal function with these agents. Eventual resistance or blunting of the effects of the these agents with increased volume retention can be encountered. Salt restriction, with addition of thiazide diuretics initially or loop diuretics as a second line, is justified.[1] The first randomized clinical trial evaluating the use of lisinopril and telmisartan and their effect on progression of kidney disease in ADPKD patients, the HALT Progression of Polycystic Kidney Disease (HALT PKD), is expected to conclude by June 2014.[4]

Hematuria

Gross hematuria with significant renal colic secondary to collecting system clots is not uncommon. Treatment usually involves analgesia, bed rest and hydration to increase urinary flow rate to 2-3 liters daily. In most patients, gross hematuria regresses to microscopic hematuria in a few days. Patients should be advised to avoid sports with risk of abdominal trauma to prevent recurrent episodes.[1]

Urinary Tract Infections

Women are at a higher risk for UTIs and cyst infections with gram negative rods being the most common pathogens. Symptomatic cyst infections or acute pyelonephritis require hospital admission with floroquinolone therapy until pain, fever, and leukocytosis resolve.[5]

Pain

Severe flank or abdominal pain in the absence of cyst complications is very common. Several options for treatment exist including regular analgesics, local anesthetic injections, surgical cyst unroofing, transcutaneous stimulation, and surgical renal denervation. No randomized control trials have been conducted to evaluate the efficacy of each of these treatments. Generally, invasive procedures are reserved for patients with intractable pain that is not responding to classical pain management. [6]

Renal Failure

Renal failure is the eventual complication of almost all patients with ADPKD. Treatment is usually with the 3 major forms of renal replacement with special considerations required for some cases. Peritoneal dialysis is usually not recommended in patients with aortic aneurysms. Hemodialysis, although the most common form of renal replacement, required significant anticoagulation that may complicate existing hematuria. Ultimately, renal transplantation is the preferred renal replacement modality with outcomes similar to patients with other baseline kidney diseases leading to ESRD.[1]

References

  1. 1.0 1.1 1.2 1.3 Grantham JJ (2008). "Clinical practice. Autosomal dominant polycystic kidney disease.". N Engl J Med. 359 (14): 1477–85. PMID 18832246. doi:10.1056/NEJMcp0804458. 
  2. Gabow PA (1990). "Autosomal dominant polycystic kidney disease--more than a renal disease.". Am J Kidney Dis. 16 (5): 403–13. PMID 2239929. 
  3. Kelleher CL, McFann KK, Johnson AM, Schrier RW (2004). "Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population.". Am J Hypertens. 17 (11 Pt 1): 1029–34. PMID 15533729. doi:10.1016/j.amjhyper.2004.06.020. 
  4. Torres VE, Chapman AB, Perrone RD, Bae KT, Abebe KZ, Bost JE; et al. (2012). "Analysis of baseline parameters in the HALT polycystic kidney disease trials.". Kidney Int. 81 (6): 577–85. PMC 3580956Freely accessible. PMID 22205355. doi:10.1038/ki.2011.411. 
  5. Gibson P, Watson ML (1998). "Cyst infection in polycystic kidney disease: a clinical challenge.". Nephrol Dial Transplant. 13 (10): 2455–7. PMID 9794537. 
  6. Bajwa ZH, Gupta S, Warfield CA, Steinman TI (2001). "Pain management in polycystic kidney disease.". Kidney Int. 60 (5): 1631–44. PMID 11703580‎ . doi:10.1046/j.1523-1755.2001.00985.x. 



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