wikidoc - User contributions [en]

User:Imam Ali Shah

2025-10-09T20:11:44Z

Imam Ali Shah: /* Imam Ali Shah, MBBS */

==[[Imam Ali Shah '''Imam Ali Shah, MBBS'''|'''Imam Ali Shah, MBBS''']]==
[[Imam Ali Shah, MBBS Contact:Email: imamshah.med@gmail.com|Contact]]

[[Imam Ali Shah, MBBS Contact:Email: imamshah.med@gmail.com|Email: imamshah.med@gmail.com]]

==[[Imam Ali Shah Medical Education|Medical Education]]==
*[[Medical Education '''2017-2022'''|'''2017-2022''']]
**[[2017-2022 MBBS Chandka Medical College, Pakistan|MBBS - Chandka Medical College, Pakistan]]

==[[Imam Ali Shah Professional Affiliations|Professional Affiliations]]==
*[[Profesional Affiliations Pakistan Medical & Dental Council, Pakistan|Pakistan Medical & Dental Council, Pakistan]]

==[[Imam Ali Shah Professional Experience|Professional Experience]]==
*[[Administrative Experience '''February 2024-Present'''|'''February 2024-Present''']]
**[[Karachi Medical & Diagnostic Center Larkana|Medical Officer-Government of Pakistan]]
*[[Clinical Experience '''July 2022-July 2023'''|'''July 2022-July 2023''']]
**[[July 2022-July 2023 House Officer Intern, Chandka Medical College Hospital, Larkana Pakistan|House Officer Intern, Chandka Medical College Hospital, Larkana Pakistan]]

== [[Imam Ali Shah Research Publications|Peer-reviewed Publications]] ==
*[https://www.cureus.com/articles/231128-navigating-the-uncharted-territory-of-pediatric-onset-multiple-sclerosis-in-a-12-year-old-male-a-case-study#!/ Navigating the Uncharted Territory of Pediatric-Onset Multiple Sclerosis in a 12-Year-Old Male: A Case Study]
*[https://doi.org/10.1016/j.radcr.2024.03.069 Cryptogenic Cirrhosis: Decoding Diagnostic Challenges through Radiological Insights]
*[https://www.cureus.com/articles/227358-arsenic-in-the-food-chain-in-pakistan-assessing-risks-to-human-health-and-ensuring-food-security-through-comprehensive-contamination-mitigation-strategies#!/ Arsenic in the Food Chain in Pakistan: Assessing Risks to Human Health and Ensuring Food Security Through Comprehensive Contamination Mitigation Strategies]
*[https://pubmed.ncbi.nlm.nih.gov/39659008/ Symptoms of panic disorder may lead to a potential misdiagnosis as a cardiopulmonary disease, particularly in rural areas]
==[[Imam Ali Shah Certifications|Certifications]]==
*[[January 2024 '''USMLE Step 1-Pass'''|'''USMLE Step 1-Pass''']]
*'''USMLE STEP 2 - 269'''
*'''ECFMG Certified - 2025'''
*[['''EF Standard English Test-C2 Proficient'''|'''EF Standard English Test-C2 Proficient''']]
*[['''Pakistan Medical & Dental Council-Permenantly Certified'''|'''Pakistan Medical & Dental Council-Permenantly Certified''']]

==[[Imam Ali Shah Communication Languages|Communication Languages]]==
*[[Communication Languages English|English]]
*[[Communication Languages Urdu|Urdu]]
*[[Communication Languages Sindhi|Sindhi]]
*[[Communication Languages Punjabi|Punjabi]]

User:Imam Ali Shah

2025-10-09T20:11:17Z

Imam Ali Shah: /* Certifications */

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

2025-10-09T20:06:14Z

Imam Ali Shah:

__NOTOC__
{{SI}}
{{CMG}}; {{AE}} {{IAS}}

{{Infobox_Disease |
Name = Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes |
Image = |
Caption = |
DiseasesDB = 8254 |
ICD10 = |
ICD9 = |
ICDO = |
OMIM = 540000 |
MedlinePlus = |
MeshID = D017241 |
}}

==Overview==
'''Mitochondrial [[myopathy]], [[encephalopathy]], [[lactic acidosis]], stroke-like episodes''', abbreviated to '''MELAS''' is one of the family of [[mitochondrial cytopathies]], which also include [[MERRF]], and [[Leber's Hereditary Optic Atrophy]]. <ref name="pmid6093682">{{cite journal |author=Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP |title=Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome |journal=Ann. Neurol. |volume=16 |issue=4 |pages=481–8 |year=1984 |month=October |pmid=6093682 |doi=10.1002/ana.410160409 |url=}}</ref> A feature of these diseases is that they are caused by defects in the [[mitochondrial]] [[genome]] which is inherited purely from the female parent. The disease can manifest in both sexes. <ref name="urlMELAS - Genetics Home Reference">{{cite web |url=http://ghr.nlm.nih.gov/condition/mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-episodes |title=MELAS - Genetics Home Reference |format= |work= |accessdate=}}</ref>

==Historical Perspective==

==Pathophysiology==
The genetic hallmark of MELAS is heteroplasmy, a state in which each somatic cell contains a heterogeneous population of mitochondrial DNA (mtDNA) genomes. Over an individual's lifespan, the accumulation of damage can alter this mitochondrial genome. Consequently, a mixture of normal (wild-type) and mutated mtDNA coexists within cells. The proportion of mutated to normal mtDNA, often termed the "mutational load," varies significantly across different tissues of a single individual<ref name="urlMelas Syndrome - StatPearls - NCBI Bookshelf">{{cite web|url=https://www.ncbi.nlm.nih.gov/books/NBK532959/|title=Melas Syndrome - StatPearls - NCBI Bookshelf|format=|work=|accessdate=}}</ref>.

This tissue-specific mosaicism underpins the profound clinical heterogeneity observed both among different patients with MELAS and within the various organ systems of an affected person. The clinical expression of the disease in a particular tissue is contingent upon its mutational load, creating a complex and variable presentation. This phenomenon poses significant diagnostic challenges. For instance, analyses of readily accessible samples like blood or urine may yield false-negative results if the mutational load in these cell lines is below the pathogenic threshold. In such diagnostically ambiguous cases, a muscle biopsy is often required, as skeletal muscle's high energy requirements typically ensure a higher, more detectable concentration of the mutated mitochondria.<ref name="urlMELAS Syndrome - Symptoms, Causes, Treatment | NORD">{{cite web|url=https://rarediseases.org/rare-diseases/melas-syndrome/|title=MELAS Syndrome - Symptoms, Causes, Treatment | NORD|format=|work=|accessdate=}}</ref>

Two primary, potentially complementary, hypotheses have been proposed to explain the pathophysiology of MELAS syndrome:

1. '''The Cytopathic Hypothesis''': This theory posits that the fundamental defect lies within the energy-producing cells themselves. The mitochondrial mutations lead to defective oxidative phosphorylation (OXPHOS), resulting in a critical energy deficit. During periods of elevated metabolic demand, this bioenergetic failure precipitates neuronal dysfunction and, ultimately, cell death. This model effectively explains the selective vulnerability of high-energy brain regions, such as the visual cortex, which are often affected early and severely.<ref name="pmid39766231">{{cite journal|vauthors=Na JH, Lee YM|title=Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome|journal=Biomolecules|volume=14|issue=12|pages=|date=November 2024|pmid=39766231|pmc=11672891|doi=10.3390/biom14121524|url=}}</ref>

2. '''The Angiopathic Hypothesis''': This model proposes that the primary pathology is rooted in the vascular system. According to this theory, the mitochondrial defect within the endothelial cells lining small blood vessels causes significant dysfunction. This leads to impaired vascular autoregulation and a failure to adequately control regional blood flow, resulting in neuronal ischemia. Tissues with the highest metabolic activity, including the brain, skeletal muscle, heart, eyes, and inner ear, are most susceptible to this vascular insufficiency.<ref name="urlMelas Syndrome - StatPearls - NCBI Bookshelf2">{{cite web|url=https://www.ncbi.nlm.nih.gov/books/NBK532959/|title=Melas Syndrome - StatPearls - NCBI Bookshelf|format=|work=|accessdate=}}</ref>

The neurological manifestations in MELAS are likely a consequence of a confluence of these parenchymal and vascular defects. Impaired OXPHOS not only starves cells of energy but also increases the production of damaging free radicals (reactive oxygen species). These molecules can induce vasoconstriction, counteracting the effects of crucial vasodilators like nitric oxide. Furthermore, MELAS is specifically associated with a state of nitric oxide deficiency, which arises from both impaired production and enhanced postproduction sequestration. This lack of nitric oxide, combined with microvascular angiopathy and the underlying cellular energy crisis, severely compromises cerebral vasodilation, preventing an adequate increase in blood flow to meet metabolic demands and exacerbating ischemic damage. A systemic consequence of this impaired aerobic metabolism is a compensatory increase in anaerobic glycolysis, which leads to the characteristic elevation of lactic acid, especially during acute metabolic crises.

===Genetics===
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes is a condition related to changes in mitochondrial DNA. Mutations in the {{Gene|MT-ND1}}, {{Gene|MT-ND5}}, {{Gene|MT-TH}}, {{Gene|MT-TL1}}, and {{Gene|MT-TV}} genes cause mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The genes associated with MELAS are contained in [[mitochondrial DNA]]. Some of the genes related to MELAS provide instructions for making proteins involved in normal mitochondrial function. These proteins are part of a large enzyme complex in mitochondria that helps convert oxygen and simple sugars to energy. Other genes associated with this disorder provide instructions for making molecules called transfer RNAs ([[tRNA]]s), which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria.

Mutations in a particular transfer RNA gene, ''MT-TL1'', cause more than 80 percent of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.<ref name="pmid8151079">{{cite journal |author=Hirano M, Pavlakis SG |title=Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts |journal=J. Child Neurol. |volume=9 |issue=1 |pages=4–13 |year=1994 |month=January |pmid=8151079 |doi= |url=}}</ref>

This condition is inherited in a mitochondrial pattern, which is also known as [[maternal inheritance]]. This pattern of inheritance applies to genes contained in mitochondrial DNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, only females pass mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. In most cases, people with MELAS inherit an altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MELAS.

==Epidemiology and Demographics==
MELAS is recognized as one of the most common mitochondrial disorders, affecting approximately 1 in every 4000 individuals.<ref name="pmid304225542">{{cite journal|author=|title=StatPearls|journal=|year=2024|volume=|issue=|pages=|pmid=30422554|doi=|pmc=|url=}}</ref> While both sexes are equally susceptible to developing the condition, only females can transmit MELAS due to the unique nature of mitochondrial inheritance. Mitochondria are carried within the tails of sperm cells, which are shed outside the zygote during fertilization and are therefore not transmitted, resulting in this gender-specific inheritance pattern. Notably, there is no discernible racial preference associated with MELAS.<ref name="pmid30422554">{{cite journal|author=|title=StatPearls|journal=|year=2024|volume=|issue=|pages=|pmid=30422554|doi=|pmc=|url=}}</ref>

==Natural History, Complications and Prognosis==
===Prognosis===
There is no known treatment for the underlying disease, which is progressive and fatal. Patients are managed according to what areas of the body are affected at a particular time. Antioxidants and vitamins have been used, but there have been no consistent successes reported.

== Diagnosis ==
Diagnosing MELAS is a multifaceted process that integrates clinical presentation, biochemical markers, neuroimaging, histopathology, and molecular genetic analysis. Due to the significant clinical heterogeneity and multisystemic nature of the disorder, a definitive diagnosis relies on a constellation of findings rather than a single pathognomonic feature.

=== Clinical and Biochemical Evaluation ===
The first step in diagnosis is a comprehensive clinical evaluation, including a detailed patient history and neurological examination. This focuses on key symptoms such as recurrent headaches, seizures, myopathy, sensorineural hearing loss, and cognitive decline. The hallmark feature is the occurrence of stroke-like episodes in individuals under 40 years of age, which may present with transient hemiparesis, cortical blindness, or aphasia.

A cardinal feature is the presence of elevated lactate levels in both the blood and cerebrospinal fluid (CSF), particularly during acute metabolic stress or following a stroke-like event. An elevated lactate-to-pyruvate ratio also suggests a respiratory chain defect.<ref name="pmid116523432">{{cite journal|vauthors=Hewa S|title=The AIDS crisis and human rights in Canada|journal=Int Rev Mod Sociol|volume=22|issue=1|pages=43–53|date=1992|pmid=11652343|doi=|url=}}</ref>

=== Neuroimaging and Histopathology ===
Magnetic Resonance Imaging (MRI) of the brain is the preferred modality. It typically reveals multifocal, cortical, or subcortical T2-hyperintense lesions that are incongruent with the distribution of major vascular territories.<ref name="pmid35222261">{{cite journal|vauthors=Cheng W, Zhang Y, He L|title=MRI Features of Stroke-Like Episodes in Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes|journal=Front Neurol|volume=13|issue=|pages=843386|date=2022|pmid=35222261|pmc=8863858|doi=10.3389/fneur.2022.843386|url=}}</ref> These stroke-like lesions demonstrate a predilection for the posterior cerebral regions (including the occipital, parietal, and temporal lobes) and may exhibit transient and migratory behavior on serial imaging.<ref name="urlAcute Cortical Lesions in MELAS Syndrome: Anatomic Distribution, Symmetry, and Evolution | American Journal of Neuroradiology">{{cite web|url=https://www.ajnr.org/content/41/1/167#:~:text=Diffusion%20restriction%20with%20cortical%20laminar,more%20frequently%20than%20previously%20described.|title=Acute Cortical Lesions in MELAS Syndrome: Anatomic Distribution, Symmetry, and Evolution | American Journal of Neuroradiology|format=|work=|accessdate=}}</ref> During the acute phase, Diffusion-Weighted Imaging (DWI) can show restricted diffusion. Furthermore, Magnetic Resonance Spectroscopy (MRS) can detect an elevated lactate peak within the affected brain parenchyma, providing in vivo evidence of impaired oxidative metabolism.

A muscle biopsy is a key diagnostic procedure, especially when genetic testing from blood is inconclusive. The biopsy classically shows '''ragged-red fibers (RRF)''', which are myocytes with subsarcolemmal accumulations of abnormal mitochondria. While RRF indicate mitochondrial dysfunction, they are not specific to MELAS. A more specific finding is the presence of '''strongly succinate dehydrogenase-reactive blood vessels (SSVs)''', which reflects mitochondrial proliferation in the smooth muscle and endothelial cells of intramuscular arterioles and capillaries.<ref name="pmid1892363">{{cite journal|vauthors=Hasegawa H, Matsuoka T, Goto Y, Nonaka I|title=Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes|journal=Ann Neurol|volume=29|issue=6|pages=601–5|date=June 1991|pmid=1892363|doi=10.1002/ana.410290606|url=}}</ref>

=== Molecular Genetic Testing ===
Molecular genetic testing to identify a pathogenic mutation in mitochondrial DNA (mtDNA) is the confirmatory diagnostic test. The most prevalent mutation, found in approximately 80% of affected patients, is an A-to-G transition at nucleotide position 3243 (m.3243A>G) in the mitochondrial tRNA^(Leu(UUR)) gene (''MT-TL1''). Other less common point mutations in ''MT-TL1'' (e.g., m.3271T>C) and other mtDNA genes have also been implicated.<ref name="pmid397662313">{{cite journal|vauthors=Na JH, Lee YM|title=Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome|journal=Biomolecules|volume=14|issue=12|pages=|date=November 2024|pmid=39766231|pmc=11672891|doi=10.3390/biom14121524|url=}}</ref>

Due to heteroplasmy, a blood sample may have a low or undetectable level of the mutation, leading to a false-negative result. If clinical suspicion remains high, genetic analysis should be performed on other tissues (such as urine sediment, skin fibroblasts, or, most reliably, skeletal muscle) which typically harbor a higher mutational load.

=== Formal Diagnostic Criteria ===
To standardize the diagnosis, formal clinical criteria were established by Hirano et al. (1992).<ref name="urlMELAS - GeneReviews® - NCBI Bookshelf">{{cite web|url=https://www.ncbi.nlm.nih.gov/books/NBK1233/#:~:text=Clinical%20diagnostic%20criteria%20for%20MELAS,published%20%5BHirano%20et%20al%201992%2C|title=MELAS - GeneReviews® - NCBI Bookshelf|format=|work=|accessdate=}}</ref>

A diagnosis of MELAS requires the presence of '''all three''' of the following definitive criteria:

# Stroke-like episodes before the age of 40.
# Encephalopathy characterized by seizures and/or dementia.
# Evidence of mitochondrial dysfunction, confirmed by either:
#* Lactic acidosis, or
#* Ragged-red fibers (RRF) on muscle biopsy.

The diagnosis is considered '''secure''' if a patient meets the three definitive criteria and also exhibits '''at least two''' of the following supportive findings:

# Normal early psychomotor development.
# Recurrent headaches.
# Recurrent vomiting episodes.

In contemporary practice, these clinical criteria serve as a robust framework to guide the diagnostic process, which is ultimately confirmed by identifying a causative mtDNA mutation.

=== History and Symptoms ===
MELAS is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). In most cases, the signs and symptoms of this disorder appear in childhood following a period of normal development.
Early symptoms may include
* [[Muscle weakness]]
* [[Muscle pain]]
* Recurrent [[headaches]]
* [[Loss of appetite]]
* [[Vomiting]]
* [[Seizures]]
* [[Abdominal pain]]
* Extreme tiredness ([[fatigue]])
* [[Difficulty breathing]]

===Physical Examination===
====Eye====
* [[Vision abnormalities]]

====Ear====
* [[Hearing loss]]

====Extremeties====
* [[Myoclonus]]

====Neurologic====
* [[Stroke]]-like episodes beginning before age 40 <ref name="pmid1422200">{{cite journal |author=Hirano M, Ricci E, Koenigsberger MR, ''et al.'' |title=Melas: an original case and clinical criteria for diagnosis |journal=Neuromuscul. Disord. |volume=2 |issue=2 |pages=125–35 |year=1992 |pmid=1422200 |doi= |url=}}</ref>
* Temporary [[muscle weakness]] on one side of the body ([[hemiparesis]])
* [[Confusion|Altered consciousness]]
* [[Ataxia]]
* [[Seizures]]
* [[Dementia]]

===Laboratory Findings===
Laboratory workup involves assessing serum pyruvic acid, serum lactic acid, cerebrospinal fluid (CSF) pyruvic acid, and CSF lactic acid. An elevation in [[lactic acid]] levels, especially during an acute stroke-like episode, is a frequent initial finding. However, lactic acids may be normal in some people and an increased CSF lactic acid level has been shown to be a more reliable indicator of disease.<ref name="pmid21875773">{{cite journal|author=Yamada K, Toribe Y, Yanagihara K, Mano T, Akagi M, Suzuki Y|title=Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system.|journal=Brain Dev|year=2012|volume=34|issue=2|pages=92-7|pmid=21875773|doi=10.1016/j.braindev.2011.08.004|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21875773}}</ref> <ref name="pmid21075023">{{cite journal|author=Magner M, Szentiványi K, Svandová I, Ješina P, Tesařová M, Honzík T|display-authors=etal|title=Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures.|journal=Eur J Paediatr Neurol|year=2011|volume=15|issue=2|pages=101-8|pmid=21075023|doi=10.1016/j.ejpn.2010.10.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21075023}}</ref>However, systemic metabolic acidosis does not occur.

==Treatment==
===Medical Therapy===

===Surgery===

===Prevention===

==References==
{{reflist|2}}

{{Mitochondrial diseases}}

[[index.php?title=Category:Endocrinology]]
[[index.php?title=Category:Disease]]

[[ja:MELAS]]

{{WS}}
{{WH}}

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

2025-10-09T20:05:13Z

Imam Ali Shah: /* Diagnosis Criteria */

__NOTOC__
{{SI}}
{{CMG}}; {{AE}} {{IAS}}

{{Infobox_Disease |
Name = Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes |
Image = |
Caption = |
DiseasesDB = 8254 |
ICD10 = |
ICD9 = |
ICDO = |
OMIM = 540000 |
MedlinePlus = |
MeshID = D017241 |
}}

==Overview==
'''Mitochondrial [[myopathy]], [[encephalopathy]], [[lactic acidosis]], stroke-like episodes''', abbreviated to '''MELAS''' is one of the family of [[mitochondrial cytopathies]], which also include [[MERRF]], and [[Leber's Hereditary Optic Atrophy]]. <ref name="pmid6093682">{{cite journal |author=Pavlakis SG, Phillips PC, DiMauro S, De Vivo DC, Rowland LP |title=Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome |journal=Ann. Neurol. |volume=16 |issue=4 |pages=481–8 |year=1984 |month=October |pmid=6093682 |doi=10.1002/ana.410160409 |url=}}</ref> A feature of these diseases is that they are caused by defects in the [[mitochondrial]] [[genome]] which is inherited purely from the female parent. The disease can manifest in both sexes. <ref name="urlMELAS - Genetics Home Reference">{{cite web |url=http://ghr.nlm.nih.gov/condition/mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-episodes |title=MELAS - Genetics Home Reference |format= |work= |accessdate=}}</ref>

==Historical Perspective==

==Pathophysiology==
The genetic hallmark of MELAS is heteroplasmy, a state in which each somatic cell contains a heterogeneous population of mitochondrial DNA (mtDNA) genomes. Over an individual's lifespan, the accumulation of damage can alter this mitochondrial genome. Consequently, a mixture of normal (wild-type) and mutated mtDNA coexists within cells. The proportion of mutated to normal mtDNA, often termed the "mutational load," varies significantly across different tissues of a single individual<ref name="urlMelas Syndrome - StatPearls - NCBI Bookshelf">{{cite web|url=https://www.ncbi.nlm.nih.gov/books/NBK532959/|title=Melas Syndrome - StatPearls - NCBI Bookshelf|format=|work=|accessdate=}}</ref>.

This tissue-specific mosaicism underpins the profound clinical heterogeneity observed both among different patients with MELAS and within the various organ systems of an affected person. The clinical expression of the disease in a particular tissue is contingent upon its mutational load, creating a complex and variable presentation. This phenomenon poses significant diagnostic challenges. For instance, analyses of readily accessible samples like blood or urine may yield false-negative results if the mutational load in these cell lines is below the pathogenic threshold. In such diagnostically ambiguous cases, a muscle biopsy is often required, as skeletal muscle's high energy requirements typically ensure a higher, more detectable concentration of the mutated mitochondria.<ref name="urlMELAS Syndrome - Symptoms, Causes, Treatment | NORD">{{cite web|url=https://rarediseases.org/rare-diseases/melas-syndrome/|title=MELAS Syndrome - Symptoms, Causes, Treatment | NORD|format=|work=|accessdate=}}</ref>

Two primary, potentially complementary, hypotheses have been proposed to explain the pathophysiology of MELAS syndrome:

1. '''The Cytopathic Hypothesis''': This theory posits that the fundamental defect lies within the energy-producing cells themselves. The mitochondrial mutations lead to defective oxidative phosphorylation (OXPHOS), resulting in a critical energy deficit. During periods of elevated metabolic demand, this bioenergetic failure precipitates neuronal dysfunction and, ultimately, cell death. This model effectively explains the selective vulnerability of high-energy brain regions, such as the visual cortex, which are often affected early and severely.<ref name="pmid39766231">{{cite journal|vauthors=Na JH, Lee YM|title=Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome|journal=Biomolecules|volume=14|issue=12|pages=|date=November 2024|pmid=39766231|pmc=11672891|doi=10.3390/biom14121524|url=}}</ref>

2. '''The Angiopathic Hypothesis''': This model proposes that the primary pathology is rooted in the vascular system. According to this theory, the mitochondrial defect within the endothelial cells lining small blood vessels causes significant dysfunction. This leads to impaired vascular autoregulation and a failure to adequately control regional blood flow, resulting in neuronal ischemia. Tissues with the highest metabolic activity, including the brain, skeletal muscle, heart, eyes, and inner ear, are most susceptible to this vascular insufficiency.<ref name="urlMelas Syndrome - StatPearls - NCBI Bookshelf2">{{cite web|url=https://www.ncbi.nlm.nih.gov/books/NBK532959/|title=Melas Syndrome - StatPearls - NCBI Bookshelf|format=|work=|accessdate=}}</ref>

The neurological manifestations in MELAS are likely a consequence of a confluence of these parenchymal and vascular defects. Impaired OXPHOS not only starves cells of energy but also increases the production of damaging free radicals (reactive oxygen species). These molecules can induce vasoconstriction, counteracting the effects of crucial vasodilators like nitric oxide. Furthermore, MELAS is specifically associated with a state of nitric oxide deficiency, which arises from both impaired production and enhanced postproduction sequestration. This lack of nitric oxide, combined with microvascular angiopathy and the underlying cellular energy crisis, severely compromises cerebral vasodilation, preventing an adequate increase in blood flow to meet metabolic demands and exacerbating ischemic damage. A systemic consequence of this impaired aerobic metabolism is a compensatory increase in anaerobic glycolysis, which leads to the characteristic elevation of lactic acid, especially during acute metabolic crises.

===Genetics===
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes is a condition related to changes in mitochondrial DNA. Mutations in the {{Gene|MT-ND1}}, {{Gene|MT-ND5}}, {{Gene|MT-TH}}, {{Gene|MT-TL1}}, and {{Gene|MT-TV}} genes cause mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The genes associated with MELAS are contained in [[mitochondrial DNA]]. Some of the genes related to MELAS provide instructions for making proteins involved in normal mitochondrial function. These proteins are part of a large enzyme complex in mitochondria that helps convert oxygen and simple sugars to energy. Other genes associated with this disorder provide instructions for making molecules called transfer RNAs ([[tRNA]]s), which are chemical cousins of DNA. These molecules help assemble protein building blocks called amino acids into full-length, functioning proteins within mitochondria.

Mutations in a particular transfer RNA gene, ''MT-TL1'', cause more than 80 percent of all cases of MELAS. These mutations impair the ability of mitochondria to make proteins, use oxygen, and produce energy. Researchers have not determined how changes in mitochondrial DNA lead to the specific signs and symptoms of MELAS. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.<ref name="pmid8151079">{{cite journal |author=Hirano M, Pavlakis SG |title=Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS): current concepts |journal=J. Child Neurol. |volume=9 |issue=1 |pages=4–13 |year=1994 |month=January |pmid=8151079 |doi= |url=}}</ref>

This condition is inherited in a mitochondrial pattern, which is also known as [[maternal inheritance]]. This pattern of inheritance applies to genes contained in mitochondrial DNA. Because egg cells, but not sperm cells, contribute mitochondria to the developing embryo, only females pass mitochondrial conditions to their children. Mitochondrial disorders can appear in every generation of a family and can affect both males and females, but fathers do not pass mitochondrial traits to their children. In most cases, people with MELAS inherit an altered mitochondrial gene from their mother. Less commonly, the disorder results from a new mutation in a mitochondrial gene and occurs in people with no family history of MELAS.

==Epidemiology and Demographics==
MELAS is recognized as one of the most common mitochondrial disorders, affecting approximately 1 in every 4000 individuals.<ref name="pmid304225542">{{cite journal|author=|title=StatPearls|journal=|year=2024|volume=|issue=|pages=|pmid=30422554|doi=|pmc=|url=}}</ref> While both sexes are equally susceptible to developing the condition, only females can transmit MELAS due to the unique nature of mitochondrial inheritance. Mitochondria are carried within the tails of sperm cells, which are shed outside the zygote during fertilization and are therefore not transmitted, resulting in this gender-specific inheritance pattern. Notably, there is no discernible racial preference associated with MELAS.<ref name="pmid30422554">{{cite journal|author=|title=StatPearls|journal=|year=2024|volume=|issue=|pages=|pmid=30422554|doi=|pmc=|url=}}</ref>

==Natural History, Complications and Prognosis==
===Prognosis===
There is no known treatment for the underlying disease, which is progressive and fatal. Patients are managed according to what areas of the body are affected at a particular time. Antioxidants and vitamins have been used, but there have been no consistent successes reported.

== Diagnosis ==
Diagnosing MELAS is a multifaceted process that integrates clinical presentation, biochemical markers, neuroimaging, histopathology, and molecular genetic analysis. Due to the significant clinical heterogeneity and multisystemic nature of the disorder, a definitive diagnosis relies on a constellation of findings rather than a single pathognomonic feature.

=== Clinical and Biochemical Evaluation ===
The first step in diagnosis is a comprehensive clinical evaluation, including a detailed patient history and neurological examination. This focuses on key symptoms such as recurrent headaches, seizures, myopathy, sensorineural hearing loss, and cognitive decline. The hallmark feature is the occurrence of stroke-like episodes in individuals under 40 years of age, which may present with transient hemiparesis, cortical blindness, or aphasia.

A cardinal feature is the presence of elevated lactate levels in both the blood and cerebrospinal fluid (CSF), particularly during acute metabolic stress or following a stroke-like event. An elevated lactate-to-pyruvate ratio also suggests a respiratory chain defect.<ref name="pmid116523432">{{cite journal|vauthors=Hewa S|title=The AIDS crisis and human rights in Canada|journal=Int Rev Mod Sociol|volume=22|issue=1|pages=43–53|date=1992|pmid=11652343|doi=|url=}}</ref>

=== Neuroimaging and Histopathology ===
Magnetic Resonance Imaging (MRI) of the brain is the preferred modality. It typically reveals multifocal, cortical, or subcortical T2-hyperintense lesions that are incongruent with the distribution of major vascular territories.<ref name="pmid35222261">{{cite journal|vauthors=Cheng W, Zhang Y, He L|title=MRI Features of Stroke-Like Episodes in Mitochondrial Encephalomyopathy With Lactic Acidosis and Stroke-Like Episodes|journal=Front Neurol|volume=13|issue=|pages=843386|date=2022|pmid=35222261|pmc=8863858|doi=10.3389/fneur.2022.843386|url=}}</ref> These stroke-like lesions demonstrate a predilection for the posterior cerebral regions (including the occipital, parietal, and temporal lobes) and may exhibit transient and migratory behavior on serial imaging.<ref name="urlAcute Cortical Lesions in MELAS Syndrome: Anatomic Distribution, Symmetry, and Evolution | American Journal of Neuroradiology">{{cite web|url=https://www.ajnr.org/content/41/1/167#:~:text=Diffusion%20restriction%20with%20cortical%20laminar,more%20frequently%20than%20previously%20described.|title=Acute Cortical Lesions in MELAS Syndrome: Anatomic Distribution, Symmetry, and Evolution | American Journal of Neuroradiology|format=|work=|accessdate=}}</ref> During the acute phase, Diffusion-Weighted Imaging (DWI) can show restricted diffusion. Furthermore, Magnetic Resonance Spectroscopy (MRS) can detect an elevated lactate peak within the affected brain parenchyma, providing in vivo evidence of impaired oxidative metabolism.

A muscle biopsy is a key diagnostic procedure, especially when genetic testing from blood is inconclusive. The biopsy classically shows '''ragged-red fibers (RRF)''', which are myocytes with subsarcolemmal accumulations of abnormal mitochondria. While RRF indicate mitochondrial dysfunction, they are not specific to MELAS. A more specific finding is the presence of '''strongly succinate dehydrogenase-reactive blood vessels (SSVs)''', which reflects mitochondrial proliferation in the smooth muscle and endothelial cells of intramuscular arterioles and capillaries.<ref name="pmid1892363">{{cite journal|vauthors=Hasegawa H, Matsuoka T, Goto Y, Nonaka I|title=Strongly succinate dehydrogenase-reactive blood vessels in muscles from patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes|journal=Ann Neurol|volume=29|issue=6|pages=601–5|date=June 1991|pmid=1892363|doi=10.1002/ana.410290606|url=}}</ref>

=== Molecular Genetic Testing ===
Molecular genetic testing to identify a pathogenic mutation in mitochondrial DNA (mtDNA) is the confirmatory diagnostic test. The most prevalent mutation, found in approximately 80% of affected patients, is an A-to-G transition at nucleotide position 3243 (m.3243A>G) in the mitochondrial tRNA^(Leu(UUR)) gene (''MT-TL1''). Other less common point mutations in ''MT-TL1'' (e.g., m.3271T>C) and other mtDNA genes have also been implicated.<ref name="pmid397662313">{{cite journal|vauthors=Na JH, Lee YM|title=Diagnosis and Management of Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome|journal=Biomolecules|volume=14|issue=12|pages=|date=November 2024|pmid=39766231|pmc=11672891|doi=10.3390/biom14121524|url=}}</ref>

Due to heteroplasmy, a blood sample may have a low or undetectable level of the mutation, leading to a false-negative result. If clinical suspicion remains high, genetic analysis should be performed on other tissues (such as urine sediment, skin fibroblasts, or, most reliably, skeletal muscle) which typically harbor a higher mutational load.

=== Formal Diagnostic Criteria ===
To standardize the diagnosis, formal clinical criteria were established by Hirano et al. (1992).<ref name="urlMELAS - GeneReviews® - NCBI Bookshelf">{{cite web|url=https://www.ncbi.nlm.nih.gov/books/NBK1233/#:~:text=Clinical%20diagnostic%20criteria%20for%20MELAS,published%20%5BHirano%20et%20al%201992%2C|title=MELAS - GeneReviews® - NCBI Bookshelf|format=|work=|accessdate=}}</ref>

A diagnosis of MELAS requires the presence of '''all three''' of the following definitive criteria:

# Stroke-like episodes before the age of 40.
# Encephalopathy characterized by seizures and/or dementia.
# Evidence of mitochondrial dysfunction, confirmed by either:
#* Lactic acidosis, or
#* Ragged-red fibers (RRF) on muscle biopsy.

The diagnosis is considered '''secure''' if a patient meets the three definitive criteria and also exhibits '''at least two''' of the following supportive findings:

# Normal early psychomotor development.
# Recurrent headaches.
# Recurrent vomiting episodes.

In contemporary practice, these clinical criteria serve as a robust framework to guide the diagnostic process, which is ultimately confirmed by identifying a causative mtDNA mutation.

=== History and Symptoms ===
MELAS is a condition that affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy). In most cases, the signs and symptoms of this disorder appear in childhood following a period of normal development.
Early symptoms may include
* [[Muscle weakness]]
* [[Muscle pain]]
* Recurrent [[headaches]]
* [[Loss of appetite]]
* [[Vomiting]]
* [[Seizures]]
* [[Abdominal pain]]
* Extreme tiredness ([[fatigue]])
* [[Difficulty breathing]]

===Physical Examination===
====Eye====
* [[Vision abnormalities]]

====Ear====
* [[Hearing loss]]

====Extremeties====
* [[Myoclonus]]

====Neurologic====
* [[Stroke]]-like episodes beginning before age 40 <ref name="pmid1422200">{{cite journal |author=Hirano M, Ricci E, Koenigsberger MR, ''et al.'' |title=Melas: an original case and clinical criteria for diagnosis |journal=Neuromuscul. Disord. |volume=2 |issue=2 |pages=125–35 |year=1992 |pmid=1422200 |doi= |url=}}</ref>
* Temporary [[muscle weakness]] on one side of the body ([[hemiparesis]])
* [[Confusion|Altered consciousness]]
* [[Ataxia]]
* [[Seizures]]
* [[Dementia]]

===Laboratory Findings===
Laboratory workup involves assessing serum pyruvic acid, serum lactic acid, cerebrospinal fluid (CSF) pyruvic acid, and CSF lactic acid. An elevation in [[lactic acid]] levels, especially during an acute stroke-like episode, is a frequent initial finding. However, lactic acids may be normal in some people and an increased CSF lactic acid level has been shown to be a more reliable indicator of disease.<ref name="pmid21875773">{{cite journal|author=Yamada K, Toribe Y, Yanagihara K, Mano T, Akagi M, Suzuki Y|title=Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system.|journal=Brain Dev|year=2012|volume=34|issue=2|pages=92-7|pmid=21875773|doi=10.1016/j.braindev.2011.08.004|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21875773}}</ref> <ref name="pmid21075023">{{cite journal|author=Magner M, Szentiványi K, Svandová I, Ješina P, Tesařová M, Honzík T|display-authors=etal|title=Elevated CSF-lactate is a reliable marker of mitochondrial disorders in children even after brief seizures.|journal=Eur J Paediatr Neurol|year=2011|volume=15|issue=2|pages=101-8|pmid=21075023|doi=10.1016/j.ejpn.2010.10.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21075023}}</ref>However, systemic metabolic acidosis does not occur.

===Imaging Findings===

=== Histopathological Findings ===

===Other Diagnostic Studies===

==Treatment==
===Medical Therapy===

===Surgery===

===Prevention===

==References==
{{reflist|2}}

{{Mitochondrial diseases}}

[[index.php?title=Category:Endocrinology]]
[[index.php?title=Category:Disease]]

[[ja:MELAS]]

{{WS}}
{{WH}}

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

2025-10-09T19:27:11Z

Imam Ali Shah: /* Pathophysiology */

Cryptogenic cirrhosis

2025-10-09T19:14:27Z

Imam Ali Shah: /* Cost-Effectiveness of Therapy */

__NOTOC__
{{SI}}
'''For patient information, click Cryptogenic Cirrhosis'''

{{CMG}} {{AE}} {{IAS}}

{{SK}} Idiopathic Cirrhosis

== Overview ==
Cryptogenic cirrhosis (CC) is defined as [[cirrhosis]] of unknown origin. It is a [[diagnosis of exclusion]] and is only made after extensive investigative workup when the underlying cause of cirrhosis remains elusive. The cause of this condition is, by definition, unknown; however, there are correlations suggesting that [[metabolic dysfunction-associated steatohepatitis (MASH)]] plays a significant role . Advances in investigative methods, understanding of liver disease, and acknowledgment of [[metabolic dysfunction-associated steatohepatitis]] (MASH) as a plausible cause have led to a significant decrease in the use of this term.

==Historical Perspective==

==Pathophysiology==

=== Genetics ===
Genetic factors are increasingly being implicated in the occurrence of CC. Studies have found that thrombophilic and fibrogenic genetic factors and alterations in genes encoding hepatic lipid metabolism regulatory proteins are of particular importance in development and progression of CC.<ref name="pmid291223912">{{cite journal|author=Eslam M, Valenti L, Romeo S|title=Genetics and epigenetics of NAFLD and NASH: Clinical impact.|journal=J Hepatol|year=2018|volume=68|issue=2|pages=268-279|pmid=29122391|doi=10.1016/j.jhep.2017.09.003|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29122391}}</ref> <ref name="pmid31041033">{{cite journal|author=Mercado-Irizarry A, Torres EA|title=Cryptogenic cirrhosis: Current knowledge and future directions.|journal=Clin Liver Dis (Hoboken)|year=2016|volume=7|issue=4|pages=69-72|pmid=31041033|doi=10.1002/cld.539|pmc=6490261|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31041033}}</ref> Genome-wide association studies have uncovered loss-of-function genetic variants that offer protection against liver diseases including CC. Of note is the loss-of-function mutation in one copy of the CIDEB gene, which was identified in a large exome sequencing study to be associated with a lower risk of cirrhosis from any cause.<ref name="pmid35939579">{{cite journal|author=Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P|display-authors=etal|title=Germline Mutations in CIDEB and Protection against Liver Disease.|journal=N Engl J Med|year=2022|volume=387|issue=4|pages=332-344|pmid=35939579|doi=10.1056/NEJMoa2117872|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35939579}}</ref>

=== Associated Conditions===
Cryptogenic cirrhosis has a strong association with metabolic disorders, including [[hypertension]], [[dyslipidemia]], [[diabetes]], and [[hyperuricemia]]. However metabolic-dysfunction associated steatohepatitis must be ruled out to diagnose the condition.

===Gross and Microscopic Pathology===
CC has a similar histopathological findings to non-cryptogenic cirrhosis and is characterized by nodular liver morphology due to fibrous septa formation, dividing the liver into regenerative hepatocyte nodules microscopically. Fibrosis is prominent, disrupting the liver's architecture, with associated hepatocellular changes such as atrophy, hypertrophy, and fatty infiltration. Inflammation and necrosis may be evident, along with features like [[Mallory-Denk bodies]], megamitochondria, and iron deposition, reflecting the chronic liver injury and regenerative processes ongoing within the liver.

== Causes ==
Although the exact cause of cryptogenic cirrhosis remains uncertain, accumulating evidence and research increasingly suggest that metabolic dysfunction-associated steatotic liver disease (MASLD) may be the underlying factor.<ref name="pmid359395792">{{cite journal|author=Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P|display-authors=etal|title=Germline Mutations in CIDEB and Protection against Liver Disease.|journal=N Engl J Med|year=2022|volume=387|issue=4|pages=332-344|pmid=35939579|doi=10.1056/NEJMoa2117872|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35939579}}</ref> Several studies have demonstrated the underlying role of genetic factors in occurrence and progression of CC.<ref name="pmid194186072">{{cite journal|author=Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P|display-authors=etal|title=Hepatocellular carcinoma in patients with cryptogenic cirrhosis.|journal=Clin Gastroenterol Hepatol|year=2009|volume=7|issue=5|pages=580-5|pmid=19418607|doi=10.1016/j.cgh.2009.01.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418607}}</ref> <ref name="pmid264647532">{{cite journal|author=Perumpail RB, Liu A, Wong RJ, Ahmed A, Harrison SA|title=Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways.|journal=World J Hepatol|year=2015|volume=7|issue=22|pages=2384-8|pmid=26464753|doi=10.4254/wjh.v7.i22.2384|pmc=4598608|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26464753}}</ref>

==Differentiating Cryptogenic Cirrhosis from other Diseases==
While there's limited data explicitly differentiating the characteristics of cryptogenic cirrhosis from non-cryptogenic cirrhosis,studies have highlighted the following discernible differences between the two regarding the associations and complications of cirrhosis:

'''Metabolic Syndrome''': Cryptogenic cirrhosis is significantly more prevalent in individuals with underlying metabolic derangements, including hypertension, dyslipidemia, diabetes, and coronary artery disease.

'''Cardiovascular disease''': CC is associated with a higher incidence of cardiovascular disease.

'''Cancer''': Studies have shown higher and earlier occurrence of hepatocellular carcinoma (HCC) and extrahepatic cancer in cryptogenic cirrhosis.<ref name="pmid28293093">{{cite journal|author=Rinaldi L, Nascimbeni F, Giordano M, Masetti C, Guerrera B, Amelia A|display-authors=etal|title=Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis.|journal=World J Gastroenterol|year=2017|volume=23|issue=8|pages=1458-1468|pmid=28293093|doi=10.3748/wjg.v23.i8.1458|pmc=5330831|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28293093}}</ref> HCC also frequently presents at an advanced stage in patients with cryptogenic cirrhosis, likely due to insufficient surveillance measures. Consequently, treatment options are constrained, resulting in shorter survival periods.<ref name="pmid19418607">{{cite journal|author=Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P|display-authors=etal|title=Hepatocellular carcinoma in patients with cryptogenic cirrhosis.|journal=Clin Gastroenterol Hepatol|year=2009|volume=7|issue=5|pages=580-5|pmid=19418607|doi=10.1016/j.cgh.2009.01.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418607}}</ref>

== Epidemiology and Demographics ==
===Age===
Studies indicate that cryptogenic cirrhosis tends to occur more frequently in older individuals compared to non-cryptogenic cirrhosis, with some research suggesting an age difference of approximately ten years <ref name="pmid10051466">{{cite journal|author=Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ|title=Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.|journal=Hepatology|year=1999|volume=29|issue=3|pages=664-9|pmid=10051466|doi=10.1002/hep.510290347|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10051466}}</ref>. Additionally, it is more prevalent among individuals who have obesity, diabetes, and other metabolic comorbidities.

===Gender===
Cryptogenic cirrhosis is more common in females, which can partly be explained by higher prevalence of alcoholic liver disease in men globally.<ref name="pmid100514662">{{cite journal|author=Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ|title=Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.|journal=Hepatology|year=1999|volume=29|issue=3|pages=664-9|pmid=10051466|doi=10.1002/hep.510290347|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10051466}}</ref>

===Race===
No ethnic predilection has been observed in cryptogenic cirrhosis.

===Developed vs. Developing Countries===
Cryptogenic cirrhosis is a more frequent diagnosis in resource-limited and developing economies, probably due to lower availability of more advanced diagnostic modalities.

== Risk Factors ==

== Screening ==

== Natural History, Complications and Prognosis==
Cryptogenic cirrhosis is an irreversible chronic liver disease characterized by chronic liver injury, inflammation, fibrosis, and distortion and nodularity of liver architecture. The natural history of CC characterized by an asymptomatic phase, known as "compensated cirrhosis," followed by a progressive phase known as "decompensated cirrhosis". Decompensated cirrhosis is end-stage liver disease (ESLD) and is marked by the development of complications of portal hypertension and/or liver dysfunction, similar to non-cryptogenic cirrhosis.

=== Complications ===
Patients with cryptogenic cirrhosis are at risk of developing complications associated with advanced liver disease. These include portal hypertension and associated complications, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatocellular carcinoma, and death.

=== Prognosis ===
The prognosis of cryptogenic cirrhosis, like cirrhosis due to other etiologies, depends on various factors including the stage of cirrhosis at diagnosis, the presence of complications, and the response to treatment. An added factor influencing the prognosis of CC is the absence of an underlying cause, adding complexity and uncertainty to the selection and implementation of suitable therapies and interventions. Early diagnosis and intervention may improve outcomes, but cryptogenic cirrhosis still carries a significant risk of morbidity and mortality.

== Diagnosis ==
===Diagnostic Criteria===
There are no standardized diagnostic criteria for CC and it is best defined by exclusion.

=== History and Symptoms ===
Cryptogenic cirrhosis presents with symptoms similar to [[Cirrhosis history and symptoms|cirrhosis]] stemming from other known causes. These may include fatigue, jaundice, abdominal swelling, easy bruising, and confusion. Additionally, individuals might experience weight loss, weakness, and a loss of appetite. It's crucial to note that while the symptoms may resemble those of cirrhosis due to identified causes, the underlying origin in cryptogenic cirrhosis remains unknown.

===Past Medical History===
Diagnosing CC requires a rigorous past medical history evaluations and the presence of any metabolic disorder needs to be ruled to diagnose the condition.

===Laboratory Findings===
[[Cirrhosis laboratory findings|Laboratory tests]] for cryptogenic cirrhosis typically reveal patterns consistent with cirrhosis of other known etiologies. These may include elevated liver enzymes, such as ALT and AST, as well as abnormal bilirubin levels. Additionally, markers of liver function, such as albumin and prothrombin time, may be impaired.

=== Imaging Findings ===
[[Cirrhosis MRI|Imaging studies]] like ultrasound or MRI may show signs of liver damage, such as nodularity or irregularity. CT scans may further corroborate these findings, revealing features like liver atrophy, hypertrophy of the caudate lobe, and evidence of portal hypertension.
[[File:Screenshot (245).jpg|none|thumb|The images are sourced from an article published in Radiology Case Reports (Volume 19; Authors: Wajeeh Ur Rehman, Eeman Ahmad, Arsalan Nadeem, Shahzaib Ahmed, Imam Ali Shah; Title: 'Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights'; Pages: 2735-2740; Copyright Elsevier, 2024).<ref name="pmid386807433">{{cite journal|author=Rehman WU, Ahmad E, Nadeem A, Ahmed S, Shah IA|title=Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights.|journal=Radiol Case Rep|year=2024|volume=19|issue=7|pages=2735-2740|pmid=38680743|doi=10.1016/j.radcr.2024.03.069|pmc=11047172|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38680743}}</ref>[[File:Pre-contrast CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Pre-contrast CT scan of the abdomen and pelvis depicts an irregular nodular margin of the liver (green arrowhead), hypertrophy of the caudate lobe (orange arrow), and the presence of ascites (red arrow).<ref name="pmid38680743" />]][[File:Arterial phase CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Arterial phase CT scan of the abdomen and pelvis shows no enhancing focal lesions in the liver. However, it reveals irregular nodular margins (green arrowhead) and hypertrophy of the caudate lobe (orange arrow), along with the presence of ascites (red arrow).<ref name="pmid38680743">{{cite journal|author=Rehman WU, Ahmad E, Nadeem A, Ahmed S, Shah IA|title=Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights.|journal=Radiol Case Rep|year=2024|volume=19|issue=7|pages=2735-2740|pmid=38680743|doi=10.1016/j.radcr.2024.03.069|pmc=11047172|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38680743}}</ref>]][[File:Portal-venous phase CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Portal/venous phase CT scan of the abdomen and pelvis illustrates heterogeneous liver parenchyma without evident washout. Signs suggestive of a cirrhotic liver include hypertrophy of the caudate lobe and collateral vessels around the perigastric (green circle) and perisplenic (blue circle) areas, accompanied by the presence of ascites.<ref name="pmid38680743" />]][[File:Portal-venous phase CT scan of the abdomen and pelvis in Liver Cirrhosis.png|thumb|Portal/venous phase CT scan of the abdomen and pelvis, the portal vein (green arrow) and its branches appear patent without any signs of thrombosis or obstruction. Furthermore, there are no enhancing focal lesions detected in the liver.<ref name="pmid38680743" />]]]]

== Treatment ==
=== Pharmacotherapy ===

==== Acute Pharmacotherapies ====

==== Chronic Pharmacotherapies ====
While transplantation is the definitive treatment for the disease, medical management prior to transplant is beneficial given the close association between cryptogenic cirrhosis and NASH. Lifestyle modifications and targeted treatments for disease-associated conditions and complications of decompensated cirrhosis are also recommended.

=== Surgery and Device Based Therapy ===

==== Indications for Surgery ====

==== Pre-Operative Assessment ====

==== Post-Operative Management ====

==== Transplantation ====
Liver transplantation is the definitive treatment for cryptogenic cirrhosis.

=== Primary Prevention ===

=== Secondary Prevention ===

=== Cost-Effectiveness of Therapy ===
The estimated cost of a liver transplant in the US was 878,400 USD in 2019, with around 8,000 trqansplanted during the year.<ref name="pmid33856246">{{cite journal|vauthors=Fallowfield JA, Jimenez-Ramos M, Robertson A|title=Emerging synthetic drugs for the treatment of liver cirrhosis|journal=Expert Opin Emerg Drugs|volume=26|issue=2|pages=149–163|date=June 2021|pmid=33856246|doi=10.1080/14728214.2021.1918099|url=}}</ref> Outcomes are excellent, with 1-year and 5-year post–elective deceased-donor transplant survival rates of 94% and 83%, respectively.<ref name="pmid338562462">{{cite journal|vauthors=Fallowfield JA, Jimenez-Ramos M, Robertson A|title=Emerging synthetic drugs for the treatment of liver cirrhosis|journal=Expert Opin Emerg Drugs|volume=26|issue=2|pages=149–163|date=June 2021|pmid=33856246|doi=10.1080/14728214.2021.1918099|url=}}</ref>

=== Future or Investigational Therapies ===

==References==
{{Reflist|2}}
<references />
[[Category:Disease]]

Cryptogenic cirrhosis

2025-10-09T19:09:35Z

Imam Ali Shah: /* Cost-Effectiveness of Therapy */

__NOTOC__
{{SI}}
'''For patient information, click Cryptogenic Cirrhosis'''

{{CMG}} {{AE}} {{IAS}}

{{SK}} Idiopathic Cirrhosis

== Overview ==
Cryptogenic cirrhosis (CC) is defined as [[cirrhosis]] of unknown origin. It is a [[diagnosis of exclusion]] and is only made after extensive investigative workup when the underlying cause of cirrhosis remains elusive. The cause of this condition is, by definition, unknown; however, there are correlations suggesting that [[metabolic dysfunction-associated steatohepatitis (MASH)]] plays a significant role . Advances in investigative methods, understanding of liver disease, and acknowledgment of [[metabolic dysfunction-associated steatohepatitis]] (MASH) as a plausible cause have led to a significant decrease in the use of this term.

==Historical Perspective==

==Pathophysiology==

=== Genetics ===
Genetic factors are increasingly being implicated in the occurrence of CC. Studies have found that thrombophilic and fibrogenic genetic factors and alterations in genes encoding hepatic lipid metabolism regulatory proteins are of particular importance in development and progression of CC.<ref name="pmid291223912">{{cite journal|author=Eslam M, Valenti L, Romeo S|title=Genetics and epigenetics of NAFLD and NASH: Clinical impact.|journal=J Hepatol|year=2018|volume=68|issue=2|pages=268-279|pmid=29122391|doi=10.1016/j.jhep.2017.09.003|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29122391}}</ref> <ref name="pmid31041033">{{cite journal|author=Mercado-Irizarry A, Torres EA|title=Cryptogenic cirrhosis: Current knowledge and future directions.|journal=Clin Liver Dis (Hoboken)|year=2016|volume=7|issue=4|pages=69-72|pmid=31041033|doi=10.1002/cld.539|pmc=6490261|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31041033}}</ref> Genome-wide association studies have uncovered loss-of-function genetic variants that offer protection against liver diseases including CC. Of note is the loss-of-function mutation in one copy of the CIDEB gene, which was identified in a large exome sequencing study to be associated with a lower risk of cirrhosis from any cause.<ref name="pmid35939579">{{cite journal|author=Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P|display-authors=etal|title=Germline Mutations in CIDEB and Protection against Liver Disease.|journal=N Engl J Med|year=2022|volume=387|issue=4|pages=332-344|pmid=35939579|doi=10.1056/NEJMoa2117872|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35939579}}</ref>

=== Associated Conditions===
Cryptogenic cirrhosis has a strong association with metabolic disorders, including [[hypertension]], [[dyslipidemia]], [[diabetes]], and [[hyperuricemia]]. However metabolic-dysfunction associated steatohepatitis must be ruled out to diagnose the condition.

===Gross and Microscopic Pathology===
CC has a similar histopathological findings to non-cryptogenic cirrhosis and is characterized by nodular liver morphology due to fibrous septa formation, dividing the liver into regenerative hepatocyte nodules microscopically. Fibrosis is prominent, disrupting the liver's architecture, with associated hepatocellular changes such as atrophy, hypertrophy, and fatty infiltration. Inflammation and necrosis may be evident, along with features like [[Mallory-Denk bodies]], megamitochondria, and iron deposition, reflecting the chronic liver injury and regenerative processes ongoing within the liver.

== Causes ==
Although the exact cause of cryptogenic cirrhosis remains uncertain, accumulating evidence and research increasingly suggest that metabolic dysfunction-associated steatotic liver disease (MASLD) may be the underlying factor.<ref name="pmid359395792">{{cite journal|author=Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P|display-authors=etal|title=Germline Mutations in CIDEB and Protection against Liver Disease.|journal=N Engl J Med|year=2022|volume=387|issue=4|pages=332-344|pmid=35939579|doi=10.1056/NEJMoa2117872|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35939579}}</ref> Several studies have demonstrated the underlying role of genetic factors in occurrence and progression of CC.<ref name="pmid194186072">{{cite journal|author=Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P|display-authors=etal|title=Hepatocellular carcinoma in patients with cryptogenic cirrhosis.|journal=Clin Gastroenterol Hepatol|year=2009|volume=7|issue=5|pages=580-5|pmid=19418607|doi=10.1016/j.cgh.2009.01.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418607}}</ref> <ref name="pmid264647532">{{cite journal|author=Perumpail RB, Liu A, Wong RJ, Ahmed A, Harrison SA|title=Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways.|journal=World J Hepatol|year=2015|volume=7|issue=22|pages=2384-8|pmid=26464753|doi=10.4254/wjh.v7.i22.2384|pmc=4598608|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26464753}}</ref>

==Differentiating Cryptogenic Cirrhosis from other Diseases==
While there's limited data explicitly differentiating the characteristics of cryptogenic cirrhosis from non-cryptogenic cirrhosis,studies have highlighted the following discernible differences between the two regarding the associations and complications of cirrhosis:

'''Metabolic Syndrome''': Cryptogenic cirrhosis is significantly more prevalent in individuals with underlying metabolic derangements, including hypertension, dyslipidemia, diabetes, and coronary artery disease.

'''Cardiovascular disease''': CC is associated with a higher incidence of cardiovascular disease.

'''Cancer''': Studies have shown higher and earlier occurrence of hepatocellular carcinoma (HCC) and extrahepatic cancer in cryptogenic cirrhosis.<ref name="pmid28293093">{{cite journal|author=Rinaldi L, Nascimbeni F, Giordano M, Masetti C, Guerrera B, Amelia A|display-authors=etal|title=Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis.|journal=World J Gastroenterol|year=2017|volume=23|issue=8|pages=1458-1468|pmid=28293093|doi=10.3748/wjg.v23.i8.1458|pmc=5330831|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28293093}}</ref> HCC also frequently presents at an advanced stage in patients with cryptogenic cirrhosis, likely due to insufficient surveillance measures. Consequently, treatment options are constrained, resulting in shorter survival periods.<ref name="pmid19418607">{{cite journal|author=Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P|display-authors=etal|title=Hepatocellular carcinoma in patients with cryptogenic cirrhosis.|journal=Clin Gastroenterol Hepatol|year=2009|volume=7|issue=5|pages=580-5|pmid=19418607|doi=10.1016/j.cgh.2009.01.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418607}}</ref>

== Epidemiology and Demographics ==
===Age===
Studies indicate that cryptogenic cirrhosis tends to occur more frequently in older individuals compared to non-cryptogenic cirrhosis, with some research suggesting an age difference of approximately ten years <ref name="pmid10051466">{{cite journal|author=Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ|title=Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.|journal=Hepatology|year=1999|volume=29|issue=3|pages=664-9|pmid=10051466|doi=10.1002/hep.510290347|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10051466}}</ref>. Additionally, it is more prevalent among individuals who have obesity, diabetes, and other metabolic comorbidities.

===Gender===
Cryptogenic cirrhosis is more common in females, which can partly be explained by higher prevalence of alcoholic liver disease in men globally.<ref name="pmid100514662">{{cite journal|author=Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ|title=Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.|journal=Hepatology|year=1999|volume=29|issue=3|pages=664-9|pmid=10051466|doi=10.1002/hep.510290347|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10051466}}</ref>

===Race===
No ethnic predilection has been observed in cryptogenic cirrhosis.

===Developed vs. Developing Countries===
Cryptogenic cirrhosis is a more frequent diagnosis in resource-limited and developing economies, probably due to lower availability of more advanced diagnostic modalities.

== Risk Factors ==

== Screening ==

== Natural History, Complications and Prognosis==
Cryptogenic cirrhosis is an irreversible chronic liver disease characterized by chronic liver injury, inflammation, fibrosis, and distortion and nodularity of liver architecture. The natural history of CC characterized by an asymptomatic phase, known as "compensated cirrhosis," followed by a progressive phase known as "decompensated cirrhosis". Decompensated cirrhosis is end-stage liver disease (ESLD) and is marked by the development of complications of portal hypertension and/or liver dysfunction, similar to non-cryptogenic cirrhosis.

=== Complications ===
Patients with cryptogenic cirrhosis are at risk of developing complications associated with advanced liver disease. These include portal hypertension and associated complications, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatocellular carcinoma, and death.

=== Prognosis ===
The prognosis of cryptogenic cirrhosis, like cirrhosis due to other etiologies, depends on various factors including the stage of cirrhosis at diagnosis, the presence of complications, and the response to treatment. An added factor influencing the prognosis of CC is the absence of an underlying cause, adding complexity and uncertainty to the selection and implementation of suitable therapies and interventions. Early diagnosis and intervention may improve outcomes, but cryptogenic cirrhosis still carries a significant risk of morbidity and mortality.

== Diagnosis ==
===Diagnostic Criteria===
There are no standardized diagnostic criteria for CC and it is best defined by exclusion.

=== History and Symptoms ===
Cryptogenic cirrhosis presents with symptoms similar to [[Cirrhosis history and symptoms|cirrhosis]] stemming from other known causes. These may include fatigue, jaundice, abdominal swelling, easy bruising, and confusion. Additionally, individuals might experience weight loss, weakness, and a loss of appetite. It's crucial to note that while the symptoms may resemble those of cirrhosis due to identified causes, the underlying origin in cryptogenic cirrhosis remains unknown.

===Past Medical History===
Diagnosing CC requires a rigorous past medical history evaluations and the presence of any metabolic disorder needs to be ruled to diagnose the condition.

===Laboratory Findings===
[[Cirrhosis laboratory findings|Laboratory tests]] for cryptogenic cirrhosis typically reveal patterns consistent with cirrhosis of other known etiologies. These may include elevated liver enzymes, such as ALT and AST, as well as abnormal bilirubin levels. Additionally, markers of liver function, such as albumin and prothrombin time, may be impaired.

=== Imaging Findings ===
[[Cirrhosis MRI|Imaging studies]] like ultrasound or MRI may show signs of liver damage, such as nodularity or irregularity. CT scans may further corroborate these findings, revealing features like liver atrophy, hypertrophy of the caudate lobe, and evidence of portal hypertension.
[[File:Screenshot (245).jpg|none|thumb|The images are sourced from an article published in Radiology Case Reports (Volume 19; Authors: Wajeeh Ur Rehman, Eeman Ahmad, Arsalan Nadeem, Shahzaib Ahmed, Imam Ali Shah; Title: 'Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights'; Pages: 2735-2740; Copyright Elsevier, 2024).<ref name="pmid386807433">{{cite journal|author=Rehman WU, Ahmad E, Nadeem A, Ahmed S, Shah IA|title=Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights.|journal=Radiol Case Rep|year=2024|volume=19|issue=7|pages=2735-2740|pmid=38680743|doi=10.1016/j.radcr.2024.03.069|pmc=11047172|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38680743}}</ref>[[File:Pre-contrast CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Pre-contrast CT scan of the abdomen and pelvis depicts an irregular nodular margin of the liver (green arrowhead), hypertrophy of the caudate lobe (orange arrow), and the presence of ascites (red arrow).<ref name="pmid38680743" />]][[File:Arterial phase CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Arterial phase CT scan of the abdomen and pelvis shows no enhancing focal lesions in the liver. However, it reveals irregular nodular margins (green arrowhead) and hypertrophy of the caudate lobe (orange arrow), along with the presence of ascites (red arrow).<ref name="pmid38680743">{{cite journal|author=Rehman WU, Ahmad E, Nadeem A, Ahmed S, Shah IA|title=Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights.|journal=Radiol Case Rep|year=2024|volume=19|issue=7|pages=2735-2740|pmid=38680743|doi=10.1016/j.radcr.2024.03.069|pmc=11047172|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38680743}}</ref>]][[File:Portal-venous phase CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Portal/venous phase CT scan of the abdomen and pelvis illustrates heterogeneous liver parenchyma without evident washout. Signs suggestive of a cirrhotic liver include hypertrophy of the caudate lobe and collateral vessels around the perigastric (green circle) and perisplenic (blue circle) areas, accompanied by the presence of ascites.<ref name="pmid38680743" />]][[File:Portal-venous phase CT scan of the abdomen and pelvis in Liver Cirrhosis.png|thumb|Portal/venous phase CT scan of the abdomen and pelvis, the portal vein (green arrow) and its branches appear patent without any signs of thrombosis or obstruction. Furthermore, there are no enhancing focal lesions detected in the liver.<ref name="pmid38680743" />]]]]

== Treatment ==
=== Pharmacotherapy ===

==== Acute Pharmacotherapies ====

==== Chronic Pharmacotherapies ====
While transplantation is the definitive treatment for the disease, medical management prior to transplant is beneficial given the close association between cryptogenic cirrhosis and NASH. Lifestyle modifications and targeted treatments for disease-associated conditions and complications of decompensated cirrhosis are also recommended.

=== Surgery and Device Based Therapy ===

==== Indications for Surgery ====

==== Pre-Operative Assessment ====

==== Post-Operative Management ====

==== Transplantation ====
Liver transplantation is the definitive treatment for cryptogenic cirrhosis.

=== Primary Prevention ===

=== Secondary Prevention ===

=== Cost-Effectiveness of Therapy ===
The estimated cost of a liver transplant in the US was 878,400 USD in 2019, with around 8,000 trqansplanted during the year. {{cite journal|vauthors=Fallowfield JA, Jimenez-Ramos M, Robertson A|title=Emerging synthetic drugs for the treatment of liver cirrhosis|journal=Expert Opin Emerg Drugs|volume=26|issue=2|pages=149–163|date=June 2021|pmid=33856246|doi=10.1080/14728214.2021.1918099|url=}} Outcomes are excellent, with 1-year and 5-year post–elective deceased-donor transplant survival rates of 94% and 83%, respectively.

=== Future or Investigational Therapies ===

==References==
{{Reflist|2}}
<references />
[[Category:Disease]]

Cryptogenic cirrhosis

2025-10-09T18:57:04Z

Imam Ali Shah: /* Chronic Pharmacotherapies */

__NOTOC__
{{SI}}
'''For patient information, click Cryptogenic Cirrhosis'''

{{CMG}} {{AE}} {{IAS}}

{{SK}} Idiopathic Cirrhosis

== Overview ==
Cryptogenic cirrhosis (CC) is defined as [[cirrhosis]] of unknown origin. It is a [[diagnosis of exclusion]] and is only made after extensive investigative workup when the underlying cause of cirrhosis remains elusive. The cause of this condition is, by definition, unknown; however, there are correlations suggesting that [[metabolic dysfunction-associated steatohepatitis (MASH)]] plays a significant role . Advances in investigative methods, understanding of liver disease, and acknowledgment of [[metabolic dysfunction-associated steatohepatitis]] (MASH) as a plausible cause have led to a significant decrease in the use of this term.

==Historical Perspective==

==Pathophysiology==

=== Genetics ===
Genetic factors are increasingly being implicated in the occurrence of CC. Studies have found that thrombophilic and fibrogenic genetic factors and alterations in genes encoding hepatic lipid metabolism regulatory proteins are of particular importance in development and progression of CC.<ref name="pmid291223912">{{cite journal|author=Eslam M, Valenti L, Romeo S|title=Genetics and epigenetics of NAFLD and NASH: Clinical impact.|journal=J Hepatol|year=2018|volume=68|issue=2|pages=268-279|pmid=29122391|doi=10.1016/j.jhep.2017.09.003|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29122391}}</ref> <ref name="pmid31041033">{{cite journal|author=Mercado-Irizarry A, Torres EA|title=Cryptogenic cirrhosis: Current knowledge and future directions.|journal=Clin Liver Dis (Hoboken)|year=2016|volume=7|issue=4|pages=69-72|pmid=31041033|doi=10.1002/cld.539|pmc=6490261|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31041033}}</ref> Genome-wide association studies have uncovered loss-of-function genetic variants that offer protection against liver diseases including CC. Of note is the loss-of-function mutation in one copy of the CIDEB gene, which was identified in a large exome sequencing study to be associated with a lower risk of cirrhosis from any cause.<ref name="pmid35939579">{{cite journal|author=Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P|display-authors=etal|title=Germline Mutations in CIDEB and Protection against Liver Disease.|journal=N Engl J Med|year=2022|volume=387|issue=4|pages=332-344|pmid=35939579|doi=10.1056/NEJMoa2117872|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35939579}}</ref>

=== Associated Conditions===
Cryptogenic cirrhosis has a strong association with metabolic disorders, including [[hypertension]], [[dyslipidemia]], [[diabetes]], and [[hyperuricemia]]. However metabolic-dysfunction associated steatohepatitis must be ruled out to diagnose the condition.

===Gross and Microscopic Pathology===
CC has a similar histopathological findings to non-cryptogenic cirrhosis and is characterized by nodular liver morphology due to fibrous septa formation, dividing the liver into regenerative hepatocyte nodules microscopically. Fibrosis is prominent, disrupting the liver's architecture, with associated hepatocellular changes such as atrophy, hypertrophy, and fatty infiltration. Inflammation and necrosis may be evident, along with features like [[Mallory-Denk bodies]], megamitochondria, and iron deposition, reflecting the chronic liver injury and regenerative processes ongoing within the liver.

== Causes ==
Although the exact cause of cryptogenic cirrhosis remains uncertain, accumulating evidence and research increasingly suggest that metabolic dysfunction-associated steatotic liver disease (MASLD) may be the underlying factor.<ref name="pmid359395792">{{cite journal|author=Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P|display-authors=etal|title=Germline Mutations in CIDEB and Protection against Liver Disease.|journal=N Engl J Med|year=2022|volume=387|issue=4|pages=332-344|pmid=35939579|doi=10.1056/NEJMoa2117872|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35939579}}</ref> Several studies have demonstrated the underlying role of genetic factors in occurrence and progression of CC.<ref name="pmid194186072">{{cite journal|author=Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P|display-authors=etal|title=Hepatocellular carcinoma in patients with cryptogenic cirrhosis.|journal=Clin Gastroenterol Hepatol|year=2009|volume=7|issue=5|pages=580-5|pmid=19418607|doi=10.1016/j.cgh.2009.01.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418607}}</ref> <ref name="pmid264647532">{{cite journal|author=Perumpail RB, Liu A, Wong RJ, Ahmed A, Harrison SA|title=Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways.|journal=World J Hepatol|year=2015|volume=7|issue=22|pages=2384-8|pmid=26464753|doi=10.4254/wjh.v7.i22.2384|pmc=4598608|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26464753}}</ref>

==Differentiating Cryptogenic Cirrhosis from other Diseases==
While there's limited data explicitly differentiating the characteristics of cryptogenic cirrhosis from non-cryptogenic cirrhosis,studies have highlighted the following discernible differences between the two regarding the associations and complications of cirrhosis:

'''Metabolic Syndrome''': Cryptogenic cirrhosis is significantly more prevalent in individuals with underlying metabolic derangements, including hypertension, dyslipidemia, diabetes, and coronary artery disease.

'''Cardiovascular disease''': CC is associated with a higher incidence of cardiovascular disease.

'''Cancer''': Studies have shown higher and earlier occurrence of hepatocellular carcinoma (HCC) and extrahepatic cancer in cryptogenic cirrhosis.<ref name="pmid28293093">{{cite journal|author=Rinaldi L, Nascimbeni F, Giordano M, Masetti C, Guerrera B, Amelia A|display-authors=etal|title=Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis.|journal=World J Gastroenterol|year=2017|volume=23|issue=8|pages=1458-1468|pmid=28293093|doi=10.3748/wjg.v23.i8.1458|pmc=5330831|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28293093}}</ref> HCC also frequently presents at an advanced stage in patients with cryptogenic cirrhosis, likely due to insufficient surveillance measures. Consequently, treatment options are constrained, resulting in shorter survival periods.<ref name="pmid19418607">{{cite journal|author=Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P|display-authors=etal|title=Hepatocellular carcinoma in patients with cryptogenic cirrhosis.|journal=Clin Gastroenterol Hepatol|year=2009|volume=7|issue=5|pages=580-5|pmid=19418607|doi=10.1016/j.cgh.2009.01.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418607}}</ref>

== Epidemiology and Demographics ==
===Age===
Studies indicate that cryptogenic cirrhosis tends to occur more frequently in older individuals compared to non-cryptogenic cirrhosis, with some research suggesting an age difference of approximately ten years <ref name="pmid10051466">{{cite journal|author=Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ|title=Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.|journal=Hepatology|year=1999|volume=29|issue=3|pages=664-9|pmid=10051466|doi=10.1002/hep.510290347|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10051466}}</ref>. Additionally, it is more prevalent among individuals who have obesity, diabetes, and other metabolic comorbidities.

===Gender===
Cryptogenic cirrhosis is more common in females, which can partly be explained by higher prevalence of alcoholic liver disease in men globally.<ref name="pmid100514662">{{cite journal|author=Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ|title=Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.|journal=Hepatology|year=1999|volume=29|issue=3|pages=664-9|pmid=10051466|doi=10.1002/hep.510290347|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10051466}}</ref>

===Race===
No ethnic predilection has been observed in cryptogenic cirrhosis.

===Developed vs. Developing Countries===
Cryptogenic cirrhosis is a more frequent diagnosis in resource-limited and developing economies, probably due to lower availability of more advanced diagnostic modalities.

== Risk Factors ==

== Screening ==

== Natural History, Complications and Prognosis==
Cryptogenic cirrhosis is an irreversible chronic liver disease characterized by chronic liver injury, inflammation, fibrosis, and distortion and nodularity of liver architecture. The natural history of CC characterized by an asymptomatic phase, known as "compensated cirrhosis," followed by a progressive phase known as "decompensated cirrhosis". Decompensated cirrhosis is end-stage liver disease (ESLD) and is marked by the development of complications of portal hypertension and/or liver dysfunction, similar to non-cryptogenic cirrhosis.

=== Complications ===
Patients with cryptogenic cirrhosis are at risk of developing complications associated with advanced liver disease. These include portal hypertension and associated complications, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatocellular carcinoma, and death.

=== Prognosis ===
The prognosis of cryptogenic cirrhosis, like cirrhosis due to other etiologies, depends on various factors including the stage of cirrhosis at diagnosis, the presence of complications, and the response to treatment. An added factor influencing the prognosis of CC is the absence of an underlying cause, adding complexity and uncertainty to the selection and implementation of suitable therapies and interventions. Early diagnosis and intervention may improve outcomes, but cryptogenic cirrhosis still carries a significant risk of morbidity and mortality.

== Diagnosis ==
===Diagnostic Criteria===
There are no standardized diagnostic criteria for CC and it is best defined by exclusion.

=== History and Symptoms ===
Cryptogenic cirrhosis presents with symptoms similar to [[Cirrhosis history and symptoms|cirrhosis]] stemming from other known causes. These may include fatigue, jaundice, abdominal swelling, easy bruising, and confusion. Additionally, individuals might experience weight loss, weakness, and a loss of appetite. It's crucial to note that while the symptoms may resemble those of cirrhosis due to identified causes, the underlying origin in cryptogenic cirrhosis remains unknown.

===Past Medical History===
Diagnosing CC requires a rigorous past medical history evaluations and the presence of any metabolic disorder needs to be ruled to diagnose the condition.

===Laboratory Findings===
[[Cirrhosis laboratory findings|Laboratory tests]] for cryptogenic cirrhosis typically reveal patterns consistent with cirrhosis of other known etiologies. These may include elevated liver enzymes, such as ALT and AST, as well as abnormal bilirubin levels. Additionally, markers of liver function, such as albumin and prothrombin time, may be impaired.

=== Imaging Findings ===
[[Cirrhosis MRI|Imaging studies]] like ultrasound or MRI may show signs of liver damage, such as nodularity or irregularity. CT scans may further corroborate these findings, revealing features like liver atrophy, hypertrophy of the caudate lobe, and evidence of portal hypertension.
[[File:Screenshot (245).jpg|none|thumb|The images are sourced from an article published in Radiology Case Reports (Volume 19; Authors: Wajeeh Ur Rehman, Eeman Ahmad, Arsalan Nadeem, Shahzaib Ahmed, Imam Ali Shah; Title: 'Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights'; Pages: 2735-2740; Copyright Elsevier, 2024).<ref name="pmid386807433">{{cite journal|author=Rehman WU, Ahmad E, Nadeem A, Ahmed S, Shah IA|title=Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights.|journal=Radiol Case Rep|year=2024|volume=19|issue=7|pages=2735-2740|pmid=38680743|doi=10.1016/j.radcr.2024.03.069|pmc=11047172|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38680743}}</ref>[[File:Pre-contrast CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Pre-contrast CT scan of the abdomen and pelvis depicts an irregular nodular margin of the liver (green arrowhead), hypertrophy of the caudate lobe (orange arrow), and the presence of ascites (red arrow).<ref name="pmid38680743" />]][[File:Arterial phase CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Arterial phase CT scan of the abdomen and pelvis shows no enhancing focal lesions in the liver. However, it reveals irregular nodular margins (green arrowhead) and hypertrophy of the caudate lobe (orange arrow), along with the presence of ascites (red arrow).<ref name="pmid38680743">{{cite journal|author=Rehman WU, Ahmad E, Nadeem A, Ahmed S, Shah IA|title=Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights.|journal=Radiol Case Rep|year=2024|volume=19|issue=7|pages=2735-2740|pmid=38680743|doi=10.1016/j.radcr.2024.03.069|pmc=11047172|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38680743}}</ref>]][[File:Portal-venous phase CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Portal/venous phase CT scan of the abdomen and pelvis illustrates heterogeneous liver parenchyma without evident washout. Signs suggestive of a cirrhotic liver include hypertrophy of the caudate lobe and collateral vessels around the perigastric (green circle) and perisplenic (blue circle) areas, accompanied by the presence of ascites.<ref name="pmid38680743" />]][[File:Portal-venous phase CT scan of the abdomen and pelvis in Liver Cirrhosis.png|thumb|Portal/venous phase CT scan of the abdomen and pelvis, the portal vein (green arrow) and its branches appear patent without any signs of thrombosis or obstruction. Furthermore, there are no enhancing focal lesions detected in the liver.<ref name="pmid38680743" />]]]]

== Treatment ==
=== Pharmacotherapy ===

==== Acute Pharmacotherapies ====

==== Chronic Pharmacotherapies ====
While transplantation is the definitive treatment for the disease, medical management prior to transplant is beneficial given the close association between cryptogenic cirrhosis and NASH. Lifestyle modifications and targeted treatments for disease-associated conditions and complications of decompensated cirrhosis are also recommended.

=== Surgery and Device Based Therapy ===

==== Indications for Surgery ====

==== Pre-Operative Assessment ====

==== Post-Operative Management ====

==== Transplantation ====
Liver transplantation is the definitive treatment for cryptogenic cirrhosis.

=== Primary Prevention ===

=== Secondary Prevention ===

=== Cost-Effectiveness of Therapy ===

=== Future or Investigational Therapies ===

==References==
{{Reflist|2}}
<references />
[[Category:Disease]]

Cryptogenic cirrhosis

2025-10-09T18:55:01Z

Imam Ali Shah: /* Transplantation */

__NOTOC__
{{SI}}
'''For patient information, click Cryptogenic Cirrhosis'''

{{CMG}} {{AE}} {{IAS}}

{{SK}} Idiopathic Cirrhosis

== Overview ==
Cryptogenic cirrhosis (CC) is defined as [[cirrhosis]] of unknown origin. It is a [[diagnosis of exclusion]] and is only made after extensive investigative workup when the underlying cause of cirrhosis remains elusive. The cause of this condition is, by definition, unknown; however, there are correlations suggesting that [[metabolic dysfunction-associated steatohepatitis (MASH)]] plays a significant role . Advances in investigative methods, understanding of liver disease, and acknowledgment of [[metabolic dysfunction-associated steatohepatitis]] (MASH) as a plausible cause have led to a significant decrease in the use of this term.

==Historical Perspective==

==Pathophysiology==

=== Genetics ===
Genetic factors are increasingly being implicated in the occurrence of CC. Studies have found that thrombophilic and fibrogenic genetic factors and alterations in genes encoding hepatic lipid metabolism regulatory proteins are of particular importance in development and progression of CC.<ref name="pmid291223912">{{cite journal|author=Eslam M, Valenti L, Romeo S|title=Genetics and epigenetics of NAFLD and NASH: Clinical impact.|journal=J Hepatol|year=2018|volume=68|issue=2|pages=268-279|pmid=29122391|doi=10.1016/j.jhep.2017.09.003|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29122391}}</ref> <ref name="pmid31041033">{{cite journal|author=Mercado-Irizarry A, Torres EA|title=Cryptogenic cirrhosis: Current knowledge and future directions.|journal=Clin Liver Dis (Hoboken)|year=2016|volume=7|issue=4|pages=69-72|pmid=31041033|doi=10.1002/cld.539|pmc=6490261|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31041033}}</ref> Genome-wide association studies have uncovered loss-of-function genetic variants that offer protection against liver diseases including CC. Of note is the loss-of-function mutation in one copy of the CIDEB gene, which was identified in a large exome sequencing study to be associated with a lower risk of cirrhosis from any cause.<ref name="pmid35939579">{{cite journal|author=Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P|display-authors=etal|title=Germline Mutations in CIDEB and Protection against Liver Disease.|journal=N Engl J Med|year=2022|volume=387|issue=4|pages=332-344|pmid=35939579|doi=10.1056/NEJMoa2117872|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35939579}}</ref>

=== Associated Conditions===
Cryptogenic cirrhosis has a strong association with metabolic disorders, including [[hypertension]], [[dyslipidemia]], [[diabetes]], and [[hyperuricemia]]. However metabolic-dysfunction associated steatohepatitis must be ruled out to diagnose the condition.

===Gross and Microscopic Pathology===
CC has a similar histopathological findings to non-cryptogenic cirrhosis and is characterized by nodular liver morphology due to fibrous septa formation, dividing the liver into regenerative hepatocyte nodules microscopically. Fibrosis is prominent, disrupting the liver's architecture, with associated hepatocellular changes such as atrophy, hypertrophy, and fatty infiltration. Inflammation and necrosis may be evident, along with features like [[Mallory-Denk bodies]], megamitochondria, and iron deposition, reflecting the chronic liver injury and regenerative processes ongoing within the liver.

== Causes ==
Although the exact cause of cryptogenic cirrhosis remains uncertain, accumulating evidence and research increasingly suggest that metabolic dysfunction-associated steatotic liver disease (MASLD) may be the underlying factor.<ref name="pmid359395792">{{cite journal|author=Verweij N, Haas ME, Nielsen JB, Sosina OA, Kim M, Akbari P|display-authors=etal|title=Germline Mutations in CIDEB and Protection against Liver Disease.|journal=N Engl J Med|year=2022|volume=387|issue=4|pages=332-344|pmid=35939579|doi=10.1056/NEJMoa2117872|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=35939579}}</ref> Several studies have demonstrated the underlying role of genetic factors in occurrence and progression of CC.<ref name="pmid194186072">{{cite journal|author=Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P|display-authors=etal|title=Hepatocellular carcinoma in patients with cryptogenic cirrhosis.|journal=Clin Gastroenterol Hepatol|year=2009|volume=7|issue=5|pages=580-5|pmid=19418607|doi=10.1016/j.cgh.2009.01.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418607}}</ref> <ref name="pmid264647532">{{cite journal|author=Perumpail RB, Liu A, Wong RJ, Ahmed A, Harrison SA|title=Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways.|journal=World J Hepatol|year=2015|volume=7|issue=22|pages=2384-8|pmid=26464753|doi=10.4254/wjh.v7.i22.2384|pmc=4598608|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26464753}}</ref>

==Differentiating Cryptogenic Cirrhosis from other Diseases==
While there's limited data explicitly differentiating the characteristics of cryptogenic cirrhosis from non-cryptogenic cirrhosis,studies have highlighted the following discernible differences between the two regarding the associations and complications of cirrhosis:

'''Metabolic Syndrome''': Cryptogenic cirrhosis is significantly more prevalent in individuals with underlying metabolic derangements, including hypertension, dyslipidemia, diabetes, and coronary artery disease.

'''Cardiovascular disease''': CC is associated with a higher incidence of cardiovascular disease.

'''Cancer''': Studies have shown higher and earlier occurrence of hepatocellular carcinoma (HCC) and extrahepatic cancer in cryptogenic cirrhosis.<ref name="pmid28293093">{{cite journal|author=Rinaldi L, Nascimbeni F, Giordano M, Masetti C, Guerrera B, Amelia A|display-authors=etal|title=Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis.|journal=World J Gastroenterol|year=2017|volume=23|issue=8|pages=1458-1468|pmid=28293093|doi=10.3748/wjg.v23.i8.1458|pmc=5330831|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28293093}}</ref> HCC also frequently presents at an advanced stage in patients with cryptogenic cirrhosis, likely due to insufficient surveillance measures. Consequently, treatment options are constrained, resulting in shorter survival periods.<ref name="pmid19418607">{{cite journal|author=Giannini EG, Marabotto E, Savarino V, Trevisani F, di Nolfo MA, Del Poggio P|display-authors=etal|title=Hepatocellular carcinoma in patients with cryptogenic cirrhosis.|journal=Clin Gastroenterol Hepatol|year=2009|volume=7|issue=5|pages=580-5|pmid=19418607|doi=10.1016/j.cgh.2009.01.001|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19418607}}</ref>

== Epidemiology and Demographics ==
===Age===
Studies indicate that cryptogenic cirrhosis tends to occur more frequently in older individuals compared to non-cryptogenic cirrhosis, with some research suggesting an age difference of approximately ten years <ref name="pmid10051466">{{cite journal|author=Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ|title=Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.|journal=Hepatology|year=1999|volume=29|issue=3|pages=664-9|pmid=10051466|doi=10.1002/hep.510290347|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10051466}}</ref>. Additionally, it is more prevalent among individuals who have obesity, diabetes, and other metabolic comorbidities.

===Gender===
Cryptogenic cirrhosis is more common in females, which can partly be explained by higher prevalence of alcoholic liver disease in men globally.<ref name="pmid100514662">{{cite journal|author=Caldwell SH, Oelsner DH, Iezzoni JC, Hespenheide EE, Battle EH, Driscoll CJ|title=Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease.|journal=Hepatology|year=1999|volume=29|issue=3|pages=664-9|pmid=10051466|doi=10.1002/hep.510290347|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10051466}}</ref>

===Race===
No ethnic predilection has been observed in cryptogenic cirrhosis.

===Developed vs. Developing Countries===
Cryptogenic cirrhosis is a more frequent diagnosis in resource-limited and developing economies, probably due to lower availability of more advanced diagnostic modalities.

== Risk Factors ==

== Screening ==

== Natural History, Complications and Prognosis==
Cryptogenic cirrhosis is an irreversible chronic liver disease characterized by chronic liver injury, inflammation, fibrosis, and distortion and nodularity of liver architecture. The natural history of CC characterized by an asymptomatic phase, known as "compensated cirrhosis," followed by a progressive phase known as "decompensated cirrhosis". Decompensated cirrhosis is end-stage liver disease (ESLD) and is marked by the development of complications of portal hypertension and/or liver dysfunction, similar to non-cryptogenic cirrhosis.

=== Complications ===
Patients with cryptogenic cirrhosis are at risk of developing complications associated with advanced liver disease. These include portal hypertension and associated complications, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatocellular carcinoma, and death.

=== Prognosis ===
The prognosis of cryptogenic cirrhosis, like cirrhosis due to other etiologies, depends on various factors including the stage of cirrhosis at diagnosis, the presence of complications, and the response to treatment. An added factor influencing the prognosis of CC is the absence of an underlying cause, adding complexity and uncertainty to the selection and implementation of suitable therapies and interventions. Early diagnosis and intervention may improve outcomes, but cryptogenic cirrhosis still carries a significant risk of morbidity and mortality.

== Diagnosis ==
===Diagnostic Criteria===
There are no standardized diagnostic criteria for CC and it is best defined by exclusion.

=== History and Symptoms ===
Cryptogenic cirrhosis presents with symptoms similar to [[Cirrhosis history and symptoms|cirrhosis]] stemming from other known causes. These may include fatigue, jaundice, abdominal swelling, easy bruising, and confusion. Additionally, individuals might experience weight loss, weakness, and a loss of appetite. It's crucial to note that while the symptoms may resemble those of cirrhosis due to identified causes, the underlying origin in cryptogenic cirrhosis remains unknown.

===Past Medical History===
Diagnosing CC requires a rigorous past medical history evaluations and the presence of any metabolic disorder needs to be ruled to diagnose the condition.

===Laboratory Findings===
[[Cirrhosis laboratory findings|Laboratory tests]] for cryptogenic cirrhosis typically reveal patterns consistent with cirrhosis of other known etiologies. These may include elevated liver enzymes, such as ALT and AST, as well as abnormal bilirubin levels. Additionally, markers of liver function, such as albumin and prothrombin time, may be impaired.

=== Imaging Findings ===
[[Cirrhosis MRI|Imaging studies]] like ultrasound or MRI may show signs of liver damage, such as nodularity or irregularity. CT scans may further corroborate these findings, revealing features like liver atrophy, hypertrophy of the caudate lobe, and evidence of portal hypertension.
[[File:Screenshot (245).jpg|none|thumb|The images are sourced from an article published in Radiology Case Reports (Volume 19; Authors: Wajeeh Ur Rehman, Eeman Ahmad, Arsalan Nadeem, Shahzaib Ahmed, Imam Ali Shah; Title: 'Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights'; Pages: 2735-2740; Copyright Elsevier, 2024).<ref name="pmid386807433">{{cite journal|author=Rehman WU, Ahmad E, Nadeem A, Ahmed S, Shah IA|title=Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights.|journal=Radiol Case Rep|year=2024|volume=19|issue=7|pages=2735-2740|pmid=38680743|doi=10.1016/j.radcr.2024.03.069|pmc=11047172|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38680743}}</ref>[[File:Pre-contrast CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Pre-contrast CT scan of the abdomen and pelvis depicts an irregular nodular margin of the liver (green arrowhead), hypertrophy of the caudate lobe (orange arrow), and the presence of ascites (red arrow).<ref name="pmid38680743" />]][[File:Arterial phase CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Arterial phase CT scan of the abdomen and pelvis shows no enhancing focal lesions in the liver. However, it reveals irregular nodular margins (green arrowhead) and hypertrophy of the caudate lobe (orange arrow), along with the presence of ascites (red arrow).<ref name="pmid38680743">{{cite journal|author=Rehman WU, Ahmad E, Nadeem A, Ahmed S, Shah IA|title=Cryptogenic cirrhosis: Decoding diagnostic challenges through radiological insights.|journal=Radiol Case Rep|year=2024|volume=19|issue=7|pages=2735-2740|pmid=38680743|doi=10.1016/j.radcr.2024.03.069|pmc=11047172|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=38680743}}</ref>]][[File:Portal-venous phase CT scan of the abdomen and pelvis in Cryptogenic Cirrhosis.jpg|thumb|Portal/venous phase CT scan of the abdomen and pelvis illustrates heterogeneous liver parenchyma without evident washout. Signs suggestive of a cirrhotic liver include hypertrophy of the caudate lobe and collateral vessels around the perigastric (green circle) and perisplenic (blue circle) areas, accompanied by the presence of ascites.<ref name="pmid38680743" />]][[File:Portal-venous phase CT scan of the abdomen and pelvis in Liver Cirrhosis.png|thumb|Portal/venous phase CT scan of the abdomen and pelvis, the portal vein (green arrow) and its branches appear patent without any signs of thrombosis or obstruction. Furthermore, there are no enhancing focal lesions detected in the liver.<ref name="pmid38680743" />]]]]

== Treatment ==
=== Pharmacotherapy ===

==== Acute Pharmacotherapies ====

==== Chronic Pharmacotherapies ====
While transplantation is the definitive treatment for the disease, medical management until transplant is beneficial given the close association between crytogenic cirrhosis and NASH. Lifestyle changes and specific treatments direct towards disease-associated conditions is also recommended.

=== Surgery and Device Based Therapy ===

==== Indications for Surgery ====

==== Pre-Operative Assessment ====

==== Post-Operative Management ====

==== Transplantation ====
Liver transplantation is the definitive treatment for cryptogenic cirrhosis.

=== Primary Prevention ===

=== Secondary Prevention ===

=== Cost-Effectiveness of Therapy ===

=== Future or Investigational Therapies ===

==References==
{{Reflist|2}}
<references />
[[Category:Disease]]

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

2025-09-14T07:46:23Z

Imam Ali Shah: Author List Edited

Bismuth subnitrate

2025-09-14T07:45:27Z

Imam Ali Shah: Author List Created

'''''{{CMG}} {{AE}} {{IAS}}'''''

== Disclaimer ==
'''''WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer [[wikidoc:General disclaimer|here]].'''''

'''''NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.'''''

== Overview ==
Bismuth subnitrate is used as an [[Over-the-counter drug|over-the-counter (OTC)]] antacid and anti-diarrheic agent.<ref name="pmid14530870">{{cite journal|author=Kondo Y, Himeno S, Satoh M, Naganuma A, Nishimura T, Imura N|title=Citrate enhances the protective effect of orally administered bismuth subnitrate against the nephrotoxicity of cis-diamminedichloroplatinum.|journal=Cancer Chemother Pharmacol|year=2004|volume=53|issue=1|pages=33-8|pmid=14530870|doi=10.1007/s00280-003-0706-9|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14530870}}</ref> Bismuth subnitrate is a [https://www.wikidoc.org/index.php/Homeopathy homeopathic medication] and lacks evaluation from the Food and Drug Administration (FDA) regarding its safety or efficacy. However, the use of bismuth substrate as an active ingredient in OTC antacids is approved by the FDA. Common adverse effects include [[headache]], [[loss of appetite]], and blue-gray skin discoloration.

== Adult Indications and Dosage ==
Indications for Bismuth subnitrate use:

# '''Palliative Cancer Treatment''':
#* Used to prevent renal damage resulting from anti-cancer chemotherapy.
#* Aids in preventing bone marrow damage caused by radiation therapy.
# '''Gastrointestinal Disorders''':
#* Effective for treating duodenal [[ulcers]], as part of triple-therapy for [[Helicobacter pylori|H. pylori]] infection.
#* Alleviates symptoms of diarrhea and vomiting.
# '''Topical Use''':
#* Acts as an astringent agent in the treatment of:
#** [[Wounds]]
#** [[Burns]]
#** [[Hemorrhoids]]
#** Other anorectal disorders.

=== Off-Label Use and Dosage (Adult) ===
'''Guideline-Supported Use'''

There is limited information regarding Off-Label Guideline-Supported Use of Sodium selenite in adult patients.

'''Non–Guideline-Supported Use'''

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium selenite in adult patients.

== Pediatric Indications and Dosage ==

=== Off-Label Use and Dosage (Adult) ===
'''Guideline-Supported Use'''

There is limited information regarding Off-Label Guideline-Supported Use of Sodium selenite in adult patients.

'''Non–Guideline-Supported Use'''

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium selenite in adult patients.

Safety and effectiveness in pediatric patients have not been established.

== Contraindications ==
Bismuth subnitrate is relatively contraindicated in patients with renal impairment and pregnant patients.

== Warnings ==

== Adverse Reactions ==
[[Loss of appetite]], headache, blue-gray discoloration of skin, or renal damage. It can also cause black spots on the tongue and a thin blue-black line along the gum margin.

== Drug Interactions ==
There is limited information regarding drug interactions of Bismuth subnitrate.

== Use in Specific Populations ==
Use of Bismuth subnitrate in pregnant population is relatively contraindicated, particularly in the third trimester.

== Administration and Monitoring ==

== Overdosage ==
Reported oral doses associated with moderate to potentially lethal toxicity in humans range from 0.5 to 5 grams per kilogram. Symptoms of bismuth toxicity include [[osteoarthropathy]], [[nephropathy]], [[colitis]], [[gingivitis]], [[stomatitis]], and [[encephalopathy]].

== Pharmacology ==

== Clinical Studies ==

== Package and Label Display Panel ==
[[File:Bismuth Subnitrate Package and Label Display Panel.jpg|none|thumb|'''Bismuth Subnitrate Package and Label Display Panel''']]

== Brand Names ==
Bismithum Subnitriticum

Antimonite Belladona powder

== Look-Alike Drug Names ==
There is limited information regarding Look-Alike Drug Names.

Category:CS1 maint: Multiple names: authors list

2025-09-14T07:43:58Z

Imam Ali Shah: Edited something out

Category:CS1 maint: Multiple names: authors list

2025-09-14T07:43:09Z

Imam Ali Shah: Contributinh Author

2024-05-08T16:18:18Z

Cryptogenic cirrhosis

2024-04-20T23:22:55Z

Imam Ali Shah:

Cryptogenic cirrhosis

2024-04-20T23:22:06Z