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* Mixed Cryoglobulinemia is a combination of both types II and III. | |||
* Mixed CGs is associated with following conditions: | |||
** '''SLE (systemic lupus erythematous)''' | |||
** '''Sjögren's syndrome,''' | |||
** '''HCV''' | |||
** '''Lymphoproliferative disorders''' | |||
* Al the above mentioned disorders can cause excessive production of B-cell which can further lead to selective expansion of Cryoglobulinemia producing B-cell clones. | |||
* In HCV infected patients the HCV complexes such as HCV-IgG, HCV-lipoprotein cause B-cell hyper-proliferation through the CD81 leading to expansion of specific B-cell clones such as WA idiotype or V(H)1-69. | |||
* HCV particles are often found in such patients' serum CG complexes, but, at the same time, CG development in hepatitis C infection does not directly require the HCV virion or its components [38]. In this sense, CG development may, in fact, reflect a normal, expected response to regulate immune complexes in states of chronic immune activation. | |||
* Among patients with HCV infection, the number of circulating T cells with surface markers compatible with a suppressor phenotype may be a feature that differs between patients with cryoglobulinemic vasculitis and those with asymptomatic CG. | |||
* This was illustrated in a study that compared the percentage of "regulatory" T cells in 69 patients with HCV infection who had symptomatic CG with others with asymptomatic HCV infection [39]. | |||
* The mean levels of regulatory T cells were significantly lower in those with symptomatic HCV-associated CG than asymptomatic subjects (2.6 versus 7.4 percent, respectively). | |||
* Whether the diminished proportion of regulatory T cells plays a role in causing vasculitis is uncertain but warrants further exploration. | |||
== | === Differentiating uremia from other diseases === | ||
Uremia and uremic encephalopathy must be differentiated from other diseases that cause [[personality changes]], altered level of [[consciousness]] and hand [[tremors]] ([[asterixis]]). The differentials include the following:<nowiki/><ref name="pmid20495225">{{cite journal| author=Meparidze MM, Kodua TE, Lashkhi KS| title=[Speech impairment predisposes to cognitive deterioration in hepatic encephalopathy]. | journal=Georgian Med News | year= 2010 | volume= | issue= 181 | pages= 43-9 | pmid=20495225 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20495225 }} </ref><ref name="pmid25013309">{{cite journal| author=Kattimani S, Bharadwaj B| title=Clinical management of alcohol withdrawal: A systematic review. | journal=Ind Psychiatry J | year= 2013 | volume= 22 | issue= 2 | pages= 100-8 | pmid=25013309 | doi=10.4103/0972-6748.132914 | pmc=4085800 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25013309 }} </ref><ref name="pmid12813481">{{cite journal| author=Roldán J, Frauca C, Dueñas A| title=[Alcohol intoxication]. | journal=An Sist Sanit Navar | year= 2003 | volume= 26 Suppl 1 | issue= | pages= 129-39 | pmid=12813481 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12813481 }} </ref><ref name="pmid21590619">{{cite journal| author=Seifter JL, Samuels MA| title=Uremic encephalopathy and other brain disorders associated with renal failure. | journal=Semin Neurol | year= 2011 | volume= 31 | issue= 2 | pages= 139-43 | pmid=21590619 | doi=10.1055/s-0031-1277984 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21590619 }} </ref><ref name="pmid6864698">{{cite journal| author=Handler CE, Perkin GD| title=Wernicke's encephalopathy. | journal=J R Soc Med | year= 1983 | volume= 76 | issue= 5 | pages= 339-42 | pmid=6864698 | doi= | pmc=1439130 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6864698 }} </ref><ref name="pmid23251840">{{cite journal| author=Kim Y, Kim JW| title=Toxic encephalopathy. | journal=Saf Health Work | year= 2012 | volume= 3 | issue= 4 | pages= 243-56 | pmid=23251840 | doi=10.5491/SHAW.2012.3.4.243 | pmc=3521923 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23251840 }} </ref><ref name="pmid2497395">{{cite journal| author=Hartmann A, Buttinger C, Rommel T, Czernicki Z, Trtinjiak F| title=Alteration of intracranial pressure, cerebral blood flow, autoregulation and carbondioxide-reactivity by hypotensive agents in baboons with intracranial hypertension. | journal=Neurochirurgia (Stuttg) | year= 1989 | volume= 32 | issue= 2 | pages= 37-43 | pmid=2497395 | doi=10.1055/s-2008-1053998 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2497395 }} </ref><ref name="pmid21590622">{{cite journal| author=Kumar N| title=Acute and subacute encephalopathies: deficiency states (nutritional). | journal=Semin Neurol | year= 2011 | volume= 31 | issue= 2 | pages= 169-83 | pmid=21590622 | doi=10.1055/s-0031-1277986 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21590622 }} </ref><ref name="pmid23035103">{{cite journal| author=Chiu GS, Chatterjee D, Darmody PT, Walsh JP, Meling DD, Johnson RW et al.| title=Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1. | journal=J Neurosci | year= 2012 | volume= 32 | issue= 40 | pages= 13945-55 | pmid=23035103 | doi=10.1523/JNEUROSCI.0704-12.2012 | pmc=3476834 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23035103 }} </ref><ref name="pmid15284663">{{cite journal| author=Peate I| title=An overview of meningitis: signs, symptoms, treatment and support. | journal=Br J Nurs | year= 2004 | volume= 13 | issue= 13 | pages= 796-801 | pmid=15284663 | doi=10.12968/bjon.2004.13.13.13501 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15284663 }} </ref><ref name="pmid25821643">{{cite journal| author=Abdelhafiz AH, Rodríguez-Mañas L, Morley JE, Sinclair AJ| title=Hypoglycemia in older people - a less well recognized risk factor for frailty. | journal=Aging Dis | year= 2015 | volume= 6 | issue= 2 | pages= 156-67 | pmid=25821643 | doi=10.14336/AD.2014.0330 | pmc=4365959 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25821643 }} </ref> | |||
{| | |||
|- style="background: #4479BA; color: #FFFFFF; text-align: center;" | |||
! rowspan="2" |Diseases | |||
! colspan="3" |History and Symptoms | |||
== | ! colspan="4" |Physical Examination | ||
! colspan="3" |Laboratory Findings | |||
|- style="background: #4479BA; color: #FFFFFF; text-align: center;" | |||
!Personality changes | |||
!Altered level of consciousness | |||
=== | !Hand tremors (asterixis) | ||
!Slurred speech | |||
!Writing disturbances | |||
!Voice monotonous | |||
!Impaired '''memory''' | |||
!Elevated blood ammonia | |||
!Hyponatremia | |||
!hypokalemia | |||
''' | |||
! | |||
|- | |- | ||
| | |'''Hepatic encephalopathy''' | ||
| ++ | |||
| ++ | |||
| ++ | |||
|<nowiki>++</nowiki> | |||
|<nowiki>++</nowiki> | |||
|<nowiki>++</nowiki> | |||
|<nowiki>++</nowiki> | |||
|<nowiki>++</nowiki> | |||
|<nowiki>++</nowiki> | |||
|<nowiki>++</nowiki> | |||
|- | |- | ||
| | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Alcohol intoxication]]''' | ||
| | | style="background: #F5F5F5; padding: 5px;" | + | ||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | ++ | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
|- | |- | ||
| | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Alcohol withdrawal]]''' | ||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | ++ | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| | | style="background: #F5F5F5; padding: 5px;" | + | ||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| | | style="background: #F5F5F5; padding: 5px;" | -/+ | ||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
|- | |- | ||
| | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Uremia]]''' | ||
| style="background: #F5F5F5; padding: 5px;" | ++ | |||
| style="background: #F5F5F5; padding: 5px;" | ++ | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | ++ | |||
| style="background: #F5F5F5; padding: 5px;" |[[Hyperkalemia]] | |||
|- | |- | ||
| | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Wernicke encephalopathy]]''' | ||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| | | style="background: #F5F5F5; padding: 5px;" | -/+ | ||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| | | style="background: #F5F5F5; padding: 5px;" | + | ||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | ++ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
|- | |- | ||
| | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Toxic encephalopathy]] from drugs''' | ||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| | | style="background: #F5F5F5; padding: 5px;" | + | ||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
|- | |- | ||
| | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''Altered [[intracranial pressure]]''' | ||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
''' | |||
| | |||
| | |||
| | |||
|- | |- | ||
| | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''Intoxication by chemical agents''' | ||
| | | style="background: #F5F5F5; padding: 5px;" | -/+ | ||
| | | style="background: #F5F5F5; padding: 5px;" | -/+ | ||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
|- | |- | ||
|[[ | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Malnutrition]]''' | ||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
|- | |- | ||
|[[ | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Hypoxic brain injury]]''' | ||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
|- | |- | ||
|[[ | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Meningitis]] and [[encephalitis]]''' | ||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | + | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| style="background: #F5F5F5; padding: 5px;" | - | |||
|- | |- | ||
| | | style="background: #DCDCDC; padding: 5px; text-align: center;" |'''[[Hypoglycemia]]''' | ||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
|[[ | | style="background: #F5F5F5; padding: 5px;" | -/+ | ||
| | | style="background: #F5F5F5; padding: 5px;" | - | ||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
|- | | style="background: #F5F5F5; padding: 5px;" | -/+ | ||
| | | style="background: #F5F5F5; padding: 5px;" | - | ||
| style="background: #F5F5F5; padding: 5px;" | - | |||
|- | | style="background: #F5F5F5; padding: 5px;" | - | ||
| | | style="background: #F5F5F5; padding: 5px;" | -/+ | ||
| style="background: #F5F5F5; padding: 5px;" | -/+ | |||
| | |||
|- | |||
| | |||
= | |||
|- | |||
| | |||
|} | |} | ||
Latest revision as of 19:56, 1 June 2018
- Mixed Cryoglobulinemia is a combination of both types II and III.
- Mixed CGs is associated with following conditions:
- SLE (systemic lupus erythematous)
- Sjögren's syndrome,
- HCV
- Lymphoproliferative disorders
- Al the above mentioned disorders can cause excessive production of B-cell which can further lead to selective expansion of Cryoglobulinemia producing B-cell clones.
- In HCV infected patients the HCV complexes such as HCV-IgG, HCV-lipoprotein cause B-cell hyper-proliferation through the CD81 leading to expansion of specific B-cell clones such as WA idiotype or V(H)1-69.
- HCV particles are often found in such patients' serum CG complexes, but, at the same time, CG development in hepatitis C infection does not directly require the HCV virion or its components [38]. In this sense, CG development may, in fact, reflect a normal, expected response to regulate immune complexes in states of chronic immune activation.
- Among patients with HCV infection, the number of circulating T cells with surface markers compatible with a suppressor phenotype may be a feature that differs between patients with cryoglobulinemic vasculitis and those with asymptomatic CG.
- This was illustrated in a study that compared the percentage of "regulatory" T cells in 69 patients with HCV infection who had symptomatic CG with others with asymptomatic HCV infection [39].
- The mean levels of regulatory T cells were significantly lower in those with symptomatic HCV-associated CG than asymptomatic subjects (2.6 versus 7.4 percent, respectively).
- Whether the diminished proportion of regulatory T cells plays a role in causing vasculitis is uncertain but warrants further exploration.
Differentiating uremia from other diseases
Uremia and uremic encephalopathy must be differentiated from other diseases that cause personality changes, altered level of consciousness and hand tremors (asterixis). The differentials include the following:[1][2][3][4][5][6][7][8][9][10][11]
Diseases | History and Symptoms | Physical Examination | Laboratory Findings | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Personality changes | Altered level of consciousness | Hand tremors (asterixis) | Slurred speech | Writing disturbances | Voice monotonous | Impaired memory | Elevated blood ammonia | Hyponatremia | hypokalemia | |
Hepatic encephalopathy | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ | ++ |
Alcohol intoxication | + | + | -/+ | ++ | + | - | + | - | -/+ | -/+ |
Alcohol withdrawal | + | + | - | ++ | + | - | + | - | -/+ | -/+ |
Uremia | ++ | ++ | + | -/+ | -/+ | -/+ | - | ++ | Hyperkalemia | |
Wernicke encephalopathy | + | + | -/+ | + | + | + | ++ | - | - | - |
Toxic encephalopathy from drugs | + | + | -/+ | -/+ | + | -/+ | + | + | -/+ | -/+ |
Altered intracranial pressure | + | -/+ | - | -/+ | -/+ | - | -/+ | - | - | - |
Intoxication by chemical agents | -/+ | -/+ | -/+ | -/+ | -/+ | - | - | - | -/+ | -/+ |
Malnutrition | -/+ | - | - | - | -/+ | - | -/+ | - | -/+ | -/+ |
Hypoxic brain injury | - | -/+ | - | -/+ | -/+ | -/+ | -/+ | - | - | - |
Meningitis and encephalitis | -/+ | -/+ | - | -/+ | + | - | - | - | -/+ | - |
Hypoglycemia | -/+ | -/+ | - | -/+ | -/+ | - | - | - | -/+ | -/+ |
- ↑ Meparidze MM, Kodua TE, Lashkhi KS (2010). "[Speech impairment predisposes to cognitive deterioration in hepatic encephalopathy]". Georgian Med News (181): 43–9. PMID 20495225.
- ↑ Kattimani S, Bharadwaj B (2013). "Clinical management of alcohol withdrawal: A systematic review". Ind Psychiatry J. 22 (2): 100–8. doi:10.4103/0972-6748.132914. PMC 4085800. PMID 25013309.
- ↑ Roldán J, Frauca C, Dueñas A (2003). "[Alcohol intoxication]". An Sist Sanit Navar. 26 Suppl 1: 129–39. PMID 12813481.
- ↑ Seifter JL, Samuels MA (2011). "Uremic encephalopathy and other brain disorders associated with renal failure". Semin Neurol. 31 (2): 139–43. doi:10.1055/s-0031-1277984. PMID 21590619.
- ↑ Handler CE, Perkin GD (1983). "Wernicke's encephalopathy". J R Soc Med. 76 (5): 339–42. PMC 1439130. PMID 6864698.
- ↑ Kim Y, Kim JW (2012). "Toxic encephalopathy". Saf Health Work. 3 (4): 243–56. doi:10.5491/SHAW.2012.3.4.243. PMC 3521923. PMID 23251840.
- ↑ Hartmann A, Buttinger C, Rommel T, Czernicki Z, Trtinjiak F (1989). "Alteration of intracranial pressure, cerebral blood flow, autoregulation and carbondioxide-reactivity by hypotensive agents in baboons with intracranial hypertension". Neurochirurgia (Stuttg). 32 (2): 37–43. doi:10.1055/s-2008-1053998. PMID 2497395.
- ↑ Kumar N (2011). "Acute and subacute encephalopathies: deficiency states (nutritional)". Semin Neurol. 31 (2): 169–83. doi:10.1055/s-0031-1277986. PMID 21590622.
- ↑ Chiu GS, Chatterjee D, Darmody PT, Walsh JP, Meling DD, Johnson RW; et al. (2012). "Hypoxia/reoxygenation impairs memory formation via adenosine-dependent activation of caspase 1". J Neurosci. 32 (40): 13945–55. doi:10.1523/JNEUROSCI.0704-12.2012. PMC 3476834. PMID 23035103.
- ↑ Peate I (2004). "An overview of meningitis: signs, symptoms, treatment and support". Br J Nurs. 13 (13): 796–801. doi:10.12968/bjon.2004.13.13.13501. PMID 15284663.
- ↑ Abdelhafiz AH, Rodríguez-Mañas L, Morley JE, Sinclair AJ (2015). "Hypoglycemia in older people - a less well recognized risk factor for frailty". Aging Dis. 6 (2): 156–67. doi:10.14336/AD.2014.0330. PMC 4365959. PMID 25821643.