Tom Swift and His Big Tunnel, or, the Hidden City of the Andes, is Volume 19 in the original Tom Swift novel series published by Grosset & Dunlap.

Plot summary
The Titus Brothers Contractors company have won a government contract in Peru to blast a tunnel through a mountain and connect two isolated railroad lines. The deadline is approaching, and the contractors have hit a literal wall: excessively hard rock which defies conventional blasting techniques. The company is under pressure to finish, or else the contract will default to their rivals, Blakeson & Grinder. Mr. Job Titus has heard of Tom Swift and Tom's giant cannon, which is used in protecting the Panama Canal, and wants to hire Tom to develop a special blasting powder to help them finish the excavation.

Mr. Damon, Tom's very good friend, arrives in the middle of this conversation, and is unaware of the situation. By coincidence, Mr. Damon is invested in a business which procures cinchona bark from Peru, but production has all but ceased, prompting Mr. Damon to invite Tom to accompany him to Peru and discover the source of the problem.

Tom, Mr. Damon and Mr. Titus (along with Koku, Tom's giant) embark for Peru. On the way, they encounter Professor Swyington Bumper, who is on a lifelong quest to locate the lost city of Pelone. Professor Bumper returns to Peru each season, and has thus far been unsuccessful. When Professor Bumper discovers that Tom is headed to the same general area, Rimac, Professor Bumper decides to join the company.

Inventions and innovations
Early in the book, Tom is working a new gyroscope, but events soon overtake that project, and Tom puts that aside for the time being.

In Tom Swift and His Giant Cannon, Tom has developed a new propellant to launch the projectiles from his giant cannon, and when Mr. Titus requests Tom's help, Tom begins to develop a new blasting powder. Ultimately Tom finds a suitable solution which can blast through heavy rock with ease. While on the job site, several blasts into the mountain, the rock changes into an even harder substance. Tom needs to modify his formula from a "quick burn" into a "slow burn" blast; rather than blasting the rock via concussion alone, the new formula first builds high pressure in the fissures of the rock, before the concussion splits the rock.

References in modern culture
In the 1990s TV series The Young Indiana Jones Chronicles, Indiana Jones is dating Tom Swift's author's daughter, and in one scene assists Mr. Stratemeyer in forwarding the plot of Tom Swift and His Big Tunnel.

External links
Tom Swift and His Big Tunnel e-text at Project Gutenberg

1916 American novels
Tom Swift
American young adult novels
Novels set in Peru

Tom Swift and His Big Tunnel


The siege of Fort Morgan occurred during the American Civil War, as part of the battle for Mobile Bay, in the Confederate state of Alabama during August 1864.  Union ground forces led by General Gordon Granger conducted a short siege of the Confederate garrison at the mouth of Mobile Bay under the command of General Richard L. Page. The Confederate surrender helped shut down Mobile, Alabama, as an effective Confederate port city.

Background
Admiral David Farragut had defeated the Confederate navy in Mobile Bay on August 5, and Fort Gaines, guarding the western approach to the bay, had surrendered to the cooperating Union land forces under Maj. Gen. Gordon Granger. Granger and Farragut next turned their full attention to Fort Morgan on Mobile Point, east across from Fort Gaines. The fort was a powerful but outdated fortification garrisoned by 600 men under the command of Robert E. Lee's cousin, Brig. Gen. Richard L. Page.

Siege

Granger's soldiers landed at Pilot Town on August 9 and began moving siege artillery within range. The Union fleet also turned their guns on the fort. For the next two weeks Union forces kept up a heavy and consistent artillery fire.  On August 16 the Confederates abandoned two batteries of the outer defenses and Granger moved his siege mortars within 500 yards of the fort and his 30-pounder rifled guns to within 1,200 yards.

On August 23, General Page unconditionally surrendered the fort. Indignant, he broke his sword over his knee instead of surrendering it to the Federals. Page's situation was further worsened when he was suspected of destroying munitions and works within the fort after the surrender agreement. For this he was arrested by the Federal authorities and imprisoned.

Aftermath
The fall of Fort Morgan to the Union forces sealed the mouth of Mobile Bay. The city of Mobile, Alabama would fall on April 12, at the end of the Civil War, after the Battle of Fort Blakeley on April 9, 1865.

General Page remained imprisoned until July. A court of inquiry was convened in New Orleans to investigate the charges against Page for violating the laws of war. The court, however, found him "Not Guilty". The court found that much of the destruction of ammunition resulted from a fire in the Citadel and that Confederates had spiked the artillery pieces before they had raised a white flag of surrender.

References
 Silkenat, David. Raising the White Flag: How Surrender Defined the American Civil War. Chapel Hill: University of North Carolina Press, 2019. .

Fort Morgan
Fort Morgan, Siege of
Fort Morgan
Fort Morgan
Military operations of the American Civil War in Alabama
Fort Morgan
1864 in Alabama
August 1864 events

Siege of Fort Morgan


In abstract algebra, a branch of mathematics, a simple ring is a non-zero ring that has no two-sided ideal besides the zero ideal and itself. In particular, a commutative ring is a simple ring if and only if it is a field.

The center of a simple ring is necessarily a field. It follows that a simple ring is an associative algebra over this field. It is then called a simple algebra over this field.

Several references (e.g., Lang (2002) or Bourbaki (2012)) require in addition that a simple ring be left or right Artinian (or equivalently semi-simple). Under such terminology a non-zero ring with no non-trivial two-sided ideals is called quasi-simple.

Rings which are simple as rings but are not a simple module over themselves do exist: a full matrix ring over a field does not have any nontrivial two-sided ideals (since any ideal of  is of the form  with  an ideal of ), but it has nontrivial left ideals (for example, the sets of matrices which have some fixed zero columns).

An immediate example of a simple ring is a division ring, where every nonzero element has a multiplicative inverse, for instance, the quaternions. Also, for any , the algebra of  matrices with entries in a division ring is simple.

Joseph Wedderburn proved that if a ring  is a finite-dimensional simple algebra over a field , it is isomorphic to a matrix algebra over some division algebra over .   In particular, the only simple rings that are finite-dimensional algebras over the real numbers are rings of matrices over either the real numbers, the complex numbers, or the quaternions.

Wedderburn proved these results in 1907 in his doctoral thesis, On hypercomplex numbers, which appeared in the Proceedings of the London Mathematical Society. His thesis classified finite-dimensional simple and also semisimple algebras over fields. Simple algebras are building blocks of semisimple algebras: any finite-dimensional semisimple algebra is a Cartesian product, in the sense of algebras, of finite-dimensional simple algebras.

One must be careful of the terminology: not every simple ring is a semisimple ring, and not every simple algebra is a semisimple algebra!   However, every finite-dimensional simple algebra is a semisimple algebra, and every simple ring that is left or right artinian is a semisimple ring.

An example of a simple ring that is not semisimple is the Weyl algebra.   The Weyl algebra also gives an example of a simple algebra that is not a matrix algebra over a division algebra over its center: the Weyl algebra is infinite-dimensional, so Wedderburn's theorem does not apply.

Wedderburn's result was later generalized to semisimple rings in the Wedderburn-Artin theorem: this says that every semisimple ring is a finite product of matrix rings over division rings.   As a consequence of this generalization, every simple ring that is left or right artinian is a matrix ring over a division ring.

Examples
Let  be the field of real numbers,  be the field of complex numbers, and  the quaternions.
 A central simple algebra (sometimes called a Brauer algebra) is a simple finite-dimensional algebra over a field  whose center is .
 Every finite-dimensional simple algebra over  is isomorphic to an algebra of  matrices with entries in , , or .  Every central simple algebra over  is isomorphic to an algebra of  matrices with entries  or .  These results follow from the Frobenius theorem.
 Every finite-dimensional simple algebra over  is a central simple algebra, and is isomorphic to a matrix ring over .
 Every finite-dimensional central simple algebra over a finite field is isomorphic to a matrix ring over that field.
 The algebra of all linear transformations of an infinite-dimensional vector space over a field  is a simple ring that is not a semisimple ring.  It is also a simple algebra over  that is not a semisimple algebra.

See also
 Simple (algebra)
 Simple universal algebra

References
 A. A. Albert, Structure of Algebras, Colloquium publications 24, American Mathematical Society, 2003, .  P.37.

Ring theory

Simple ring


Michele Zarrillo (born 13 June 1957) is an Italian singer-songwriter. He is mainly known for hits such as "Una rosa blu" (A blue rose), "Cinque giorni" (Five days), L'elefante e la farfalla (The elephant and the butterfly) and "La notte dei pensieri" (The night of thoughts). In 1987 he won the Sanremo Music Festival, competing in the newcomers' section. Zarrillo took part in the competition several other times, the last time in 2020 with the song "Nell'estasi o nel fango".
He took part in Sanremo's competition 13 times, but only won once, as stated above.

As a songwriter, he penned songs for several artists, including Ornella Vanoni and Renato Zero.

Biography
Zarrillo debuted as a musician in the 1970s, when he started playing guitar in the band Semiramis. In 1973, the band released the album Dedicato a Frazz. Meanwhile, he wrote songs for popular Italian artists, including Ornella Vanoni and Renato Zero.

In 1982 Zarrillo competed as a soloist at the Sanremo Music Festival performing the song "Su quel pianeta libero". The following year he competed for the second time singing "Una rosa blu", but was eliminated on the first night of the show. The song was re-released in 1997 and become a hit in Italy. "Una rosa blu" was also included in Zarrillo's debut album, Sarabanda, released in 1982.

In 1987, Zarrillo competed for the third time at the Sanremo Music Festival, finishing first in the newcomers' section with the song, "La notte dei pensieri". His second studio album, Soltanto amici, was released in 1988. Adesso followed in 1992. Most of the songs included in the album were co-written by Vincenzo Incenzo, who collaborated with Zarrillo on most of his following albums. Once again, the album was launched after competing in the Sanremo Music Festival of the same year, with the song "Strade di Roma".

In 1994, Zarrillo released the single "Cinque giorni", which placed fifth in the 44th Sanremo Music Festival and became one of his best-known songs, receiving strong airplay in the weeks following its release. The song was also included in Zarrillo's third studio album, Come uomo tra gli uomini. Two years later, Zarrillo released the album "L'elefante e la farfalla", including the song with the same title, performed during the Sanremo Music Festival, 1996.

In 1997, Zarrillo released his first compilation album, L'amore vuole amore, which was a commercial success, being certified platinum five times by the Federation of the Italian Music Industry for domestic sales exceeding 500,000 units. A Spanish-language version of the album was also released in Spain, where "Cinco Dias" was released as a single.

In 2001 and 2002, Zarrillo entered the Sanremo Music Festival again with the song "L'acrobata", which finished fourth in 2001 and was included in the albums Il vincitore non-c'è and Gli angeli, respectively.

In 2003, Zarrillo released the album Liberosentire, followed by L'alfabeto degli amanti in 2006, preceded by the single with the same title, which competed once again in the Sanremo Music Festival. Zarrillo's eleventh participation in the Sanremo Music Festival was in 2008, when he performed the song "L'ultimo film insieme", featured on the compilation album Nel tempo e nell'amore.

On 20 September 2011, Zarrillo released the album Unici al mondo, preceded by the single "La prima cosa che farò" and promoted through a concert tour in Italy.

In February 2017, Zarrillo participated at the Sanremo Music Festival, where he sang "Mani nelle mani". (Mani nelle mani means "Hands in the hands"). His final position in the competition is 11th.
During Sanremo's competition, his new album of unprecedented songs "Vivere e rinascere" (that means "To Live and to be Reborn") was released. A tour followed and promoted the album.

He participated at the Sanremo Music Festival 2020 with the song "Nell'estasi o nel fango".

Discography

Studio albums
 Sarabanda (1982)
 Soltanto amici (1988)
 Adesso (1992)
 Come uomo tra gli uomini (1994)
 L'elefante e la farfalla (1996)
 Il vincitore non-c'è (2001)
 Liberosentire (2003)
 L'alfabeto degli amanti (2006)
 Unici al mondo (2011)
 Vivere e Rinascere (2017)

Compilation albums
 L'amore vuole amore (1997)
 Nel tempo e nell'amore (2008)
 Le mie canzoni (2011)

Live albums
 Le occasioni dell'amore (2002)
 Michele Zarrillo Live – Roma (2009)

References

External links
 Michele Zarrillo at Allmusic

1957 births
Italian male singers
Italian pop singers
Living people
Singers from Rome
Italian male singer-songwriters
Italian singer-songwriters
Sanremo Music Festival winners of the newcomers section

Michele Zarrillo


Konangi () (born 1 November 1956) is the pen name of the Tamil writer Ilangovan. He is the maternal grandson of the Tamil playwright, lyricist, writer and Freedom fighter Madurakavi Baskaradoss. His father is the Tamil writer Shanmugam and his mother is Saraswathi. His elder brother is the Tamil short-story writer Tamilselvan and his younger brother is Murugaboopathy a contemporary Tamil playwright.  He grew up in Naagalapuram, bodinayakanur and Nenmeni Mettupatti and he currently lives in Kovilpatti, Tamil Nadu.

Described as the most important Tamil voice since Pudumaipithan, Konangi has published six short story collections and three novels. His works belongs to the less popular serious literature genre in Tamil which is mostly published in literary magazines and only occasionally in magazines and newspapers with wider circulation.

Konangi's first short story veechu (வீச்சு) was published in Thaamarai a Tamil magazine in 1980 and from then on he went to create some of the most original short stories in the Tamil language. His stories are characterised by very dense images, a tight narrative style with a vocabulary like no other bringing a ritualistic shade to the use of the Tamil language. His works often pushes and breaks the limits of fiction in Tamil literature by abandonment of the conventions of plot and character construction.

Konangi quit his job in March 1988 and started his own little magazine Kal Kudhirai in October 1988 in the Kalrayan Hills which continues to publish serious contemporary Tamil fiction, poetry, reviews and translations. Konangi's earlier short stories dealt with the issues of Alienation, effects of Urbanisation in villages leading to farmer suicides, Childhood memories, Rural tales and other metaphysical themes. He later experimented in fiction writing a wide range of genres including Surrealistic and Magical stories of dreamscapes. His previous novels Paazhi dealt with Jainism and Pidhiraa dealt with a wide range of subjects using the reference of the five ancient Sangam landscapes. His latest novel Tha was published in January 2013.

Despite receiving enormous acknowledgements for his literary outputs, Konangi stays away from the media .

Bibliography

தொகுக்கப்படாத கதைகள்

வீச்சு – தாமரை  – 1980.
விளக்குச்சரம் – சிகரம் சிற்றிதழ் – 1980.
தர்ம சக்கரம்

முதல் சில சிறுகதைகள்

இருட்டு – சிகரம் – October 1980.
கருப்பு ரயில் – தேடல் – October 1981.
மதினிமார்கள் கதை – மீட்சி – 1982.

Short story collections

மதினிமார்கள் கதை – அன்னம் வெளியீடு
கொல்லனின் ஆறு பெண்மக்கள்.
பொம்மைகள் உடைபடும் நகரம்.
பட்டுப்பூச்சிகள் உறங்கும் மூன்றாம் ஜாமம்
உப்புக்கத்தியில் மறையும் சிறுத்தை.
இருள்வ மௌத்திகம் .
சலூன் நாற்காலியில் சுழன்றபடி.
வெள்ளரிப் பெண்(Anthology).

Novellas

கைத்தடி கேட்ட நூறு கேள்விகள் – A novella that won the prize in Kanaiyaazhi.
அப்பாவின் குகையில் இருக்கிறேன் – ( I am in my fathers cave)
தழும்புகள் சிவந்த அணங்கு நிலம்.

Novels

பாழி – 2000
பிதிரா – 2004
த – 2013
நீர் வளரி - 2020

பிதிரா

Pidhira was released in 2004 and is largely a novel that was less denser and more accessible than the earlier work paazhi. It had its sections based on the five Tamil sangam landscapes . The first part 'mullai' was written as a fiction based on the travels in Andhra Pradesh.

Tha (த)

Tha published in January 2013 (released in Dhanushkodi) is an enormous piece of imaginary work of lyrical prose which deals with the displacement of the north east Indians, Samaritans, Veenai Dhanammal,Tales from the Silappatikaram, The Music of His Master's Voice, Ancient Tamil music, Saraswathi Mahal Library, the Alipore Jail, the mythology of the Samaritans, the works of Socrates, the landscape of Nagapattinam, the mythological stories of Ravana, HMS Blake, Zen, Kalamkari paintings and other elements in a fictional universe called Tha.

The novel also contains allegories, folk tales, oral histories, ritual details, archetypes, fables, anecdotes, parables, tall tales, legends and ghost stories making it a diverse work.

Non fiction

காவேரியின் பூர்வ காதை
பாட்டியின் குரல் வளையை காப்பாற்றி வைத்திருக்கிறேன்(நேர்காணல்).

On novels

Opposed to other novels in literature, Konangi has his own conventions in all aspects of the building of a novel. His works are usually made up of fragments and it distorts the experience of its main characters, presenting events outside of chronological order and attempts to disrupt the idea of characters with unified and stable personalities. It also has the characteristics of lack of an obvious plot, minimal development of character, variations in time sequence, experiments with vocabulary and syntax, and alternative endings and beginnings. Due to these aspects his works are often thought to be incomprehensible and chaotic despite being implied the other way.

Trivia

 Took his pen name from a poetry line by Subramanya Bharathi.
 Wrote the introduction to பாழி at Sanchi, Vidisha, Ajanta and Ellora caves.
 Fictionalized Mozart's funeral,  the works of Paul Gauguin and Rembrandt  in short stories.
 Cites Mouni, Na.Muthusamy (the short story called Vandi), poomani, Rajendra Chozhan and Vannanilavan as early influences.
 Calls Nakulan as a major influence in the craft of novels. Has written an inventive short story about nakulan which was later translated into English.
An orator par excellence (mostly on Ex tempore) but rarely attends any public literary meetings.
 Have acted in plays. Known plays include Japthi.
 Can Paint. Was in earlier days a painter.
Never Married.

Comments on works include

Criticism on the overtly Baroque style.
A stylist with high sense of the visual.
Difficulties in plot summary.
Deliberately obscuring the plot using language.
Total abandonment of reason for imagination.
Like poetry, uses words and images which can mean several, often contradictory, things at once.
Dense weave of a language designed as much to shield the plot summary than to reveal them.
Usage of a lexicon of old and obscure Tamil words.
New readers who enter the Tamil literary landscape have often been made to believe about the works of Konangi as unapproachable, chaotic and incomprehensible by the general opinions of the media. Due to this some of Konangi's works (novels) often remain as a vast verbal labyrinth of extraordinary images waiting to be deciphered.

Quotes

Sayings quoted below appeared in magazines and from his own works and interviews.

You have to become a bird in order to understand a tree.
Art has no relation with conscious intelligence. It is inherently a fragile thing. Its origins are unknown and at its center are clouds of cold blackness. The aesthetic experience at its summit becomes invisible and disrupts the readers perseverance in understanding it. [See: The imminence of a revelation that does not occur.]
While my characters are highly instinctive, my stories take birth from the sub-conscious and often oscillate into the world of unconscious.
My stories are born out of blindness and not seeing too far ahead.
Sculpting has a direct relation with the evolution of the language of my later stories.
The traditional idea of Plot essentially limits the possibilities of all fiction.
Art is like the process of weaving.
In travel, like music the land of dreams appear out of nowhere and follows us.
Art has nothing to do with either wisdom or understanding. It doesn't have purpose nor intention. Its on its own.
Fictional landscapes resembles waterscapes in general and fiction is born at the moment, the fusion of two unknown creatures that lives inside it occurs.
Stories are living things and they have souls residing inside them.
Beauty when found is often accompanied with a feeling of sense of terror.
I've inherited a tradition where butterflies want to sing, elephants want to dance, alchemists, sorcerers and witches want to overwork, and the storyteller creates landscapes which have no association to any town, city or country, and is yet not alien.

Further reading

Baroque
 Mr Difficult
Antinovel
Stream of consciousness (narrative mode)
Nonlinear narrative
Magic realism
Automatic writing
Postmodern literature
Reader-response criticism
Fiction-writing modes

References

Living people
Tamil-language writers
Postmodern writers
Tamil writers
Writers from Tamil Nadu
Tamil-language literature
1956 births

Konangi


A koff is a historical type of sailing vessel that was used for coastal shipping off Belgium, the Netherlands, and Germany in the 18th and 19th centuries. A typical koff had one and a half masts with a gaff rigged main sail and spanker  and one or two square sails in the main top. The hull was plump with a flat bottom and a heavily rounded, raised bow and stern. Smaller koffs could be equipped with leeboards. Due to the shallow draught, koffs were especially suited for inshore shipping in shallow waters.

The koff had been developed in the late 17th century in the Netherlands. Smaller than the fluyt, its rounded bow and stern provided however for more storage on board. This made it a popular type that saw increasing service.

Koffs were often counted among the galiots by contemporary sources because the differences are very subtle: the galiot was considered more slender and therefore more elegant. On the koff, a deckhouse could be installed between the two masts which would provide shelter for up to twelve crew men. The typical dimensions have been reported as "80 feet long, 21 feet wide and 11 feet deep". Later versions could have a schooner or galeas rig.

References
Notes

General references

Merchant sailing ship types

Koff (ship type)


The Lagos Accord was a peace agreement signed on August 21, 1979, by representatives of eleven warring factions of  the Chadian Civil War, after a conference in Lagos, Nigeria. The accord established the procedures for setting up the Transitional Government of National Unity (GUNT), which was sworn into office in November, 1979. By mutual agreement, Goukouni Oueddei was named president, Wadel Abdelkader Kamougué was appointed vice-president, and Hissène Habré was named minister of national defense, veterans, and war victims. The distribution of cabinet positions was balanced between south (eleven portfolios), north, center, and east (thirteen), and among protégés of neighboring states.

A peacekeeping mission of the Organisation of African Unity (OAU), to be drawn from troops from Republic of the Congo, Guinea, and Benin, was to replace the French. This force never materialized in any effective sense.

The participants of  GUNT deeply mistrusted each other, and they never achieved a sense of coherence. As a result, the various factional militias remained armed. By January 1980, a unit of Habré's army was attacking the forces of one of the constituent groups of GUNT in Ouaddaï Prefecture, and the Chadian conflict soon reached new heights of intensity with widespread destruction of life and property.

See also
Kano Accord
FROLINAT
History of Chad

Sources
Library of Congress Country Study

External links
Frustrations of Regional Peacekeeping: The OAU in Chad, 1977-1982
Full texts of Peace Agreements for Chad

1979 in Chad
Peace treaties of Chad
Treaties concluded in 1979
1979 in Nigeria
20th century in Lagos

Lagos Accord


H. Craig Moody was the speaker of the Utah House of Representatives from 1991–1993.

Moody served as a member of the Utah House of Representative from 1983–1993. He decided not to run for re-election in 1992. In the late 1980s Moody was tapped by Republican Party leaders to counteract the hard hitting campaign strategies of Democratic Party State Chairman Randy Horiuchi.

In 1995, Moody became a director of Security National Financial Corporation. He also formed Moody and Associates, a firm that is involved in political consulting and real estate.

Moody has a bachelor's degree in political science from the University of Utah.

Sources
Deseret News, Nov. 23, 1991
Forbes profile

University of Utah alumni
Speakers of the Utah House of Representatives

Craig Moody


Klitgaarden (lit. "The Dune House") is a former summer residence of the Danish royal family situated just south of Skagen on the northern tip of Jutland. The house was designed by Ulrik Plesner for King Christian X and Queen Alexandrine and completed in 1914. It is now owned and run by a trust and serves as a retreat for artists and scientists.

History

When Prince Christian married Alexandrine of Mecklenburg-Schwerin at a low-key ceremony in Cannes in 1898, the couple was given Marselisborg Palace just south of Aarhus as a summer residence  by Aarhus Municipality. However, the princess fell in love with the scenic and exotic area around Skagen. For the last couple of decades the town had played host to a thriving artists colony of Skagen painters and since 1890, when it was connected by train to Frederikshavn, it had developed into a mondain summer destination. Prince Christian became crown prince of Denmark in January 1906 and when the couple attended the inauguration of the new Skagen harbour the following year, they discreetly visited a number of possible building sites, yet nothing happened until after their ascent to the throne in 1912. Queen Alexandrine missed a retreat from the official life in Copenhagen of more private and intimate proportions than that of  Marselisborg. Word was therefore passed to the mayor of Skagen and soon after the city council presented the royal couple with a 4.5 ha piece of land situated directly on the East Coast a few kilometres south of town.

The architect Ulrik Plesner was charged with the task of designing a suitable house. He was an active member of the artist community in the town, and had already designed a number of prominent buildings there, including the railway station and the church. At the same time he was very active in Copenhagen where, as a result of his spacious, light-filled rooms and clean, aesthetic facades, he had become one of the main proponents of the reaction against the excess of the Historicist style which had dominated Danish architecture for some time.

Construction started in 1913 and the house was inaugurated in the spring of 1914. Over the following decades, Christian X and Queen Alexandrine spent many holidays at the house, especially Easter. Michael Ancher, one of the leading Skagen painters, became a close personal friend of the king. The house was originally located some 50 metres from the sea but the entire beach was washed away during a storm in the autumn of 1919. After the king's death in 1947 the dowager queen took up residency there for extended periods until her own death five years later.

Klitgaarden was then inherited by Hereditary Prince Knud while his elder brother, King Frederik IX, received the more representative Marselisborg Palace. Prince Knud and his family were also frequent users of the property but in 1995 it was put up for sale by his heirs.

With inspiration from San Cataldo in Amalfi in Italy, which had served as a retreat for Danish artists and scientists since 1924, consideration was given to turning Klitgaarden into a similar venue. The town of Skagen and a circle of prominent cultural figures including the  writer Klaus Rifbjerg and art collector and founder of the Louisiana Museum of Modern Art Knud W. Jensen, collaborated to raise the funds needed to realize the plans. After a thorough renovation the refuge opened its doors in the summer of 2000.

Architecture and furnishings
The house is a compact, three-winged building in two storeys. It is built in red bricks, but with yellow whitewashed walls typical of the area and has a steep roof topped by whitewashed chimneys.

Plesner also designed all the furniture. For the living room, the artist Harald Slott-Møller was commissioned to design 55 ornamental plates decorated with the signs of the  zodiac, traditional costumes and coats of arms from Danish market towns.

Klitgaarden today
The purpose of Klitgaarden is to provide Danish artists and researchers with a quiet, inspirational workplace for short periods and to create an environment where the residents can inspire each other. The house has 13 single rooms and one double room. It also provides meeting rooms and studios.

References

External links

 Official website

Royal residences in Denmark
Listed buildings and structures in Frederikshavn Municipality
Buildings and structures in Skagen
Houses completed in 1914

Klitgaarden


The Maverick Party, formerly known as Wexit Canada, is a Canadian federal political party. It advocates for constitutional changes to benefit, or the independence of, Western Canada, which includes British Columbia, Alberta, Saskatchewan, Manitoba, Yukon, Northwest Territories and Nunavut. The party has its roots in Alberta separatism and advocates the use of grassroots politics.

The party ran candidates across the aforementioned provinces and three territories in the 2021 Canadian federal election, but did not run candidates in ridings where there was a strong possibility of electing a Liberal or New Democratic candidate.

The party was led by former Conservative Party of Canada House leader Jay Hill since the resignation of the party's first leader, Peter Downing. Hill came out of retirement to act as interim leader of the Maverick Party until the election of a new leader. Hill has said that he wants the party to serve a purpose in Western Canada similar to what the Bloc Québécois has done for Quebec.

On May 14, 2022, Maverick party members elected Colin Krieger as the new leader of the party. Krieger won the leadership race with 52 percent of the vote against the only other candidate who was running, Tariq Elnaga.

History

The Wexit movement gained traction in October 2019, shortly after the 2019 Canadian federal election, when the Liberal Party under Prime Minister Justin Trudeau was re-elected to form government. In August 2019, Wexit Alberta held several meetings including a small summer meeting in Calgary's beltline. A few months later another meeting in Calgary drew about 1700 attendees.

On January 10, 2020, the party became "eligible for registration" under section 387 of the Canada Elections Act. At the time, it recorded with Elections Canada under the name "Wexit Canada". The following day, the party conducted a protest in Edmonton, involving approximately 100 supporters.

In early 2020, Wexit Alberta started purchasing billboards in Alberta criticizing Prime Minister Trudeau for various things such as "ISIS terrorist reintegration", "tax theft", "economic sabotage", "foreign interference" and "ethics violations". This sparked public discussion over the lack of representation in western Canada for some, and criticism of the billboards themselves for others. Signpatico, an advertising agency based in Regina, that installed the billboards, promised to vet ads more carefully in the future stating that while the company "fundamentally stand[s] by freedom of expression, as per the Charter", Signpatico is not "intending on inciting perceptions of hate speech or offensive ads."

In September 2020, Hill announced that the party had changed its name to the "Maverick Party". When the party changed its name, its records with Elections Canada were updated.  It remains eligible for registration when an election is called.

On September 20, 2021, the party ran in the 2021 Canadian federal election for the first time since its founding in 2020. They lost the election with only 1 to 4 percent of the vote going towards the party.

On May 14, 2022 Colin Krieger was elected party leader, succeeding Jay Hill.

Provincial Wexit parties
While the Wexit movement organized provincial parties to run candidates, the Maverick Party is not directly affiliated with any of these parties. The two main organizers of the #Wexit movement were Peter Downing and Pat King.

Alberta

On January 11, 2020, a Wexit rally was held at the Alberta legislature grounds with the goal of collecting the 8,400 signatures required for official party status.

Wexit reserved the name "Wexit Alberta" with Elections Alberta for use by a provincial party. According to its constitution, its plans included abolishing the provincial branch of the Royal Canadian Mounted Police and the establishment of an "Alberta National Police" and a "Provincial Sheriff Program". It planned to adopt a currency to replace the Canadian dollar as well.

On April 27, 2020, Wexit Alberta and the Freedom Conservative Party of Alberta announced plans to merge into a new party called the Wildrose Independence Party of Alberta. Both parties voted to approve the merger on June 29, 2020. In July 2020, Wildrose Independence Party of Alberta (WIPA) was registered with Elections Alberta, giving effect to the merger. In October 2020, the People's Party of Alberta dissolved and its board members committed support WIPA.

British Columbia
In November 2019, members of a Wexit group held a rally in Prince George. Wexit BC became a registered party with Elections BC on December 27, 2019.

Officially, the party ran two candidates in the 2020 British Columbia general election. At the time the election was called, Lee Smith was the party's leader but he resigned shortly after. After final nominations closed, the party announced that it was retracting its endorsements of both of its candidates. As this occurred after the close of nominations, both candidates still appeared on the ballot identified as Wexit BC candidates.

The party was deregistered on July 4, 2022 after failing to file an annual financial report.

Saskatchewan

The day after the 2019 federal election, Scott Moe, Premier of Saskatchewan, proposed a "New Deal" with the federal government. He called for an end to the federal carbon tax, renegotiation of the equalization formula, and action on oil-pipeline projects. In the weeks after the election, Wexit volunteers began collecting signatures to form a new party. They called on Moe to hold a referendum on separation, saying that if he did not agree they would form a party to do so.

On March 10, 2020, Wexit Saskatchewan became registered as a provincial party with Elections Saskatchewan. Its first interim leader was Jake Wall. Once registered, Wexit Saskatchewan proposed a referendum on independence in its platform.

On June 3, 2020, the party's executive board voted to change the party's name to Buffalo Party of Saskatchewan. That decision ratified by a membership vote. In July 2020, the party changed its name, and named Wade Sira as its new interim leader.

In the 2020 Saskatchewan general election, the Buffalo Party ran in 17 of the 61 ridings and captured 2.56 percent of the vote.

Party leaders

Policies
No politician has ever endorsed Western secession while sitting as a Member of Parliament in the House of Commons. Even at the provincial level it is rare for Western Canadian legislators to openly sympathize with separatism, and no MLA has ever won re-election after doing so. The only Western Canadian candidate to ever win election while openly running for a party with a secessionist platform was Gordon Kesler, who won as a Western Canada Concept MLA in a 1982 by-election; even in that case Kesler, downplayed the separatist aspect of his party's platform.

The party is seeking a presence in the House to advance its goals and ensure the frustrations of Western Canadians are heard.

Following the election of Erin O'Toole as the new Conservative Party of Canada leader, Jay Hill was critical, saying that Western Canada would be on the "back burner" under O'Toole's leadership. In September 2020, Hill criticized O'Toole for statements that the Conservatives would ensure Canada meets the Paris Agreement climate change targets.

On April 26, 2022, the party released their policy platform. The platform includes repealing Trudeau's efforts to block Western economic development such as the 'No More Pipelines bill' (C-69) and the 'Tanker Ban' (C-48), making major revisions to the equalization formula, institute fiscal responsibility, reduce trade barriers within Canada, increase the exploration and mining of minerals, strengthen provincial autonomy, introduce direct democracy, reform firearms legislation, give greater control of immigration to the provinces, and defunding the CBC.

While opposing any form of carbon tax, the Maverick Party takes a different approach to dealing with environmental concerns than the Liberals or Conservatives. It does not ignore climate change altogether, but instead advocates for energy options such as nuclear, thermal, biomass, LNG [liquified natural gas] and carbon capture projects to reduce greenhouse gas emissions in western Canada.

Electoral performance
Popular vote in Canada

See also

 Cascadia (independence movement)
 Reform Party of Canada
 Western alienation
 Western Block Party
 Western Canada Concept

References

External links

2020 establishments in Canada
Conservative parties in Canada
Federal political parties in Canada
Political parties established in 2020
Pro-independence parties
Regionalist parties
Right-wing populism in Canada
Secessionist organizations in Canada

Maverick Party


John Sherlock ( – 25 July 1794) was a Spanish brigadier general in the Ultonia Regiment. He successfully defended Melilla during a 100-day siege by Moroccan troops.

John was the son of Peter Sherlock, who had been made a baronet and knight by titular king, James III, the Old Pretender, in 1716. However, during the Irish Rebellion of 1641, the Sherlock family lost its extensive land holdings in County Waterford. Like many Catholic Irish, John emigrated to Spain with hopes of returning to Ireland once a Catholic was king of England again. And like his father and grandfather he served in the Ultonia Regiment (i.e. Ulster Regiment), part of the Irish Brigade of the Spanish Army.

John Sherlock fought in the Anglo-Spanish War of 1727–1729, a failed Spanish attempt to retake Gibraltar. He was made commander in chief of Melilla by Charles III of Spain. From 9 December 1774 to 19 March 1775, John Sherlock defended Melilla against troops of the sultan of Morocco, Mohammed ben Abdallah. When a Spanish fleet arrived with reinforcements, Sherlock broke the siege and routed the Moroccans. The entrance to the old town at Melilla includes a monument to "Juan Sherlocke." He was later made governor of Sanlúcar de Barrameda, where he died on 25 July 1794, at the age of 89.

References

Year of birth uncertain
1794 deaths
18th-century Irish people
Irish emigrants to Spain
Irish Jacobites
Irish mercenaries
Irish soldiers in the Spanish Army
Spanish generals
Spanish people of Irish descent

John Sherlock


Non-alcoholic fatty liver disease (NAFLD), in 2023 renamed metabolic dysfunction–associated steatotic liver disease (MASLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), with the latter indicating the presence of further liver inflammation. NAFL is less dangerous than NASH and usually does not progress towards it, but this progression may eventually lead to complications such as cirrhosis, liver cancer, liver failure, or cardiovascular disease.

Obesity and type 2 diabetes are strong risk factors for NAFLD. Other risks include being overweight, metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum HDL cholesterol), a diet high in fructose, and older age. NAFLD and alcoholic liver disease are types of fatty liver disease. Obtaining a sample of the liver after excluding other potential causes of fatty liver can confirm the diagnosis.

Treatment for NAFLD is weight loss by dietary changes and exercise; bariatric surgery can improve or resolve severe cases. Although no drugs are approved to treat NAFLD, there is some evidence for GLP-1 agonists, pioglitazone, and vitamin E. Those with NASH have a 2.6% increased risk of dying per year.

NAFLD is the most common liver disorder worldwide and is present in approximately 25% of the world's population. It is very common in developed nations, such as the United States, and affected about 75 to 100 million Americans in 2017. Over 90% of obese, 60% of diabetic, and up to 20% of normal-weight people develop NAFLD. NAFLD is the leading cause of chronic liver disease and the second most common reason for liver transplantation in the US and Europe as of 2017. NAFLD affects about 20 to 25% of people in Europe. In the United States, estimates suggest between 30 and 40% of adults have NAFLD, and about 3 to 12% of adults have NASH. The annual economic burden was approximately US$103 billion in the US in 2016.

Definition
An abnormal accumulation of fat in the liver in the absence of secondary causes of fatty liver, such as significant alcohol use, viral hepatitis, or medications that can induce fatty liver, characterizes non-alcoholic fatty liver disease (NAFLD). The term NAFLD encompasses a continuum of liver abnormalities, from non-alcoholic fatty liver (NAFL, simple steatosis) to non-alcoholic steatohepatitis (NASH). These diseases begin with fatty accumulation in the liver (hepatic steatosis). A liver can remain fatty without disturbing liver function (NAFL), but by various mechanisms and possible insults to the liver, it may also progress into non-alcoholic steatohepatitis (NASH), a state in which steatosis is combined with inflammation and sometimes fibrosis (steatohepatitis). NASH can then lead to complications such as cirrhosis and hepatocellular carcinoma.

A new name, metabolic dysfunction associated steatotic liver disease (MASLD), was proposed after 70% of a panel of experts expressed support for this name.  This new name was adopted in 2023.

Signs and symptoms

People with MASLD (MAFLD or NAFLD) often have no noticeable symptoms, and it is often only detected during routine blood tests or unrelated abdominal imaging or liver biopsy. In some cases, it can cause symptoms related to liver dysfunction such as fatigue, malaise, and dull right-upper-quadrant abdominal discomfort. Mild yellow discoloration of the skin may occur, although this is rare. NASH can severely impair liver function, leading to cirrhosis, liver failure, and liver cancer.

Comorbidities
The condition is strongly associated with or caused by type 2 diabetes, insulin resistance, and metabolic syndrome (defined as at least three of the five following medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein). It is also associated with hormonal disorders (panhypopituitarism, hypothyroidism, hypogonadism, polycystic ovary syndrome), persistently elevated transaminases, increasing age and hypoxia caused by obstructive sleep apnea, with some of these conditions predicting disease progression.

The majority of normal-weight people affected by MAFLD ("lean MAFLD") have impaired insulin sensitivity, are sedentary, and have increased cardiovascular disease risk and increased liver lipid levels. These are the consequences of a decreased capacity for storing fat and reduced mitochondrial function in adipose tissue and increased hepatic de novo lipogenesis. A recent systematic review has reported an increased risk of severe COVID-19 infection in MAFLD patients; however, no difference in mortality was observed between MAFLD and non-MAFLD patients.

Risk factors

Genetics
Two-thirds of families with a history of diabetes type 2 report more than one family member having NAFLD. There is a higher risk of fibrosis for family members where someone was diagnosed with NASH. Asian populations are more susceptible to metabolic syndrome and NAFLD than their western counterparts. Hispanic persons have a higher prevalence of NAFLD than white individuals, whereas the lowest prevalence is observed in black individuals. NAFLD is twice as prevalent in men as in women, which might be explained by lower levels of estrogen in men.

Genetic variations in two genes are associated with NAFLD: non-synonymous single-nucleotide polymorphisms (SNPs) in PNPLA3 and TM6SF2. Both correlate with NAFLD presence and severity, but their roles for diagnosis remain unclear. Although NAFLD has a genetic component, the American Association for the Study of Liver Diseases (AASLD) does not recommend screening family members as there is not enough confirmation of heritability, although there is some evidence from familial aggregation and twin studies.

From diet
According to the Asia-Pacific Working Group (APWG) on NAFLD, overnutrition is a major factor of NAFLD and NASH, particularly for lean MAFLD. Diet composition and quantity, in particular omega-6 fatty acid and fructose, have important roles in disease progression from NAFL to NASH and fibrosis. Choline deficiency can lead to the development of NAFLD.

Higher consumption of processed, red, and organ meats have been associated with higher risk of developing NAFLD. Some research also suggests eggs are also associated with developing NAFLD. On the other hand, studies have found healthful plant foods such as legumes and nuts, to be associated with a lower risk of developing NAFLD. Two different studies have found healthy plant-based diets rich in healthy plant foods and low in animal foods to be associated with a lower risk of developingNAFLD, even after adjusting for BMI.

From lifestyle
Habitual snoring may be a risk factor for MAFLD, even after accounting for established risk factors in individuals. Severe cases of snoring lead to airway blockage or difficulty breathing when sleeping, and usually signals the presence of obstructive sleep apnea (OSAS), a much more serious breathing condition. Blockage or narrowing of the airways, even temporarily, can cause the body to experience lowered oxygen levels in the blood, and these conditions of hypoxia are recurring in those with obstructive sleep apnea (OSAS). Constant hypoxia may cause a variety of changes within the body, such as tissue inflammation, increased insulin resistance, and liver injury. A prospective cohort study found the association between habitual snoring and MAFLD development to be significant, and the trend was noted to be most prominent in lean individuals.

Pathophysiology
The primary characteristic of NAFLD is the accumulation of lipids in the liver, largely in the form of triglycerides. However, the mechanisms by which triglycerides accumulate and the reasons that accumulation can lead to liver dysfunction are complex and incompletely understood.NAFLD can include steatosis along with varied signs of liver injury: either lobular or portal inflammation (a form of liver injury) or ballooning degeneration. Similarly, NASH can include histological features such as portal inflammation, polymorphonuclear cell infiltrates, Mallory bodies, apoptotic bodies, clear vacuolated nuclei, microvesicular steatosis, megamitochondria, and perisinusoidal fibrosis. Hepatocyte death via apoptosis or necroptosis is increased in NASH compared with simple steatosis, and inflammation is a hallmark of NASH.

One debated mechanism proposes that hepatic steatosis progresses to steatosis with inflammation following some further injury, or second hit. Oxidative stress, hormonal imbalances, and mitochondrial abnormalities are potential causes of this "second hit" phenomenon. A further nutrigenomics model named multiple hit extends the second hit model, suggesting that multiple disease biomarkers and factors such as genes and nutrition influence NAFLD and NASH progression. This model attempts to use these factors to predict the impact of lifestyle changes and genetics for the evolution of the NAFLD pathology. Many researchers describe NAFLD as a multisystem disease, as it impacts and is influenced by organs and regulatory pathways other than the liver.

The accumulation of senescent cells in the liver is seen in persons with NAFLD. In mice, liver senescent hepatocytes result in increased liver fat deposition. Treatment of NAFLD mice with senolytic agents has been shown to reduce hepatic steatosis.

Based on gene knockout studies in murine models, it has been suggested that, among many other pathogenic factors, TGF beta signals may be crucially involved in promoting the progression of NASH.

Fructose consumption
Non-alcoholic and alcoholic fatty liver disease share similar histological features, which suggests that they might share common pathogenic pathways. Fructose can cause liver inflammation and addiction similarly to ethanol by using similar metabolic pathways, unlike glucose. Therefore, some researchers argue that non-alcoholic and alcoholic fatty liver diseases are more alike than previously thought. Furthermore, high fructose consumption promotes fat accumulation in the liver by stimulating de novo lipogenesis in the liver and reducing the beta-oxidation of fat. Unlike the sugar glucose, the enzyme fructokinase rapidly metabolizes fructose. This leads to a decreased level of intracellular adenosine triphosphate (ATP). The decrease in ATP increases oxidative stress and impairments in proper protein synthesis and mitochondrial function in the liver.

Insulin resistance
Insulin resistance contributes to the accumulation of toxic fat in the liver in several ways. First, it promotes the release of free fatty acids (FFAs) from adipose tissue into the blood. Typically, adipose tissue stores lipids in the form of triglycerides, slowly releasing them into the bloodstream when insulin is low. In insulin-resistant adipose tissue, such as in people with obesity and type 2 diabetes, more triglycerides are broken down into FFAs and released into the bloodstream, promoting uptake by the liver. Second, insulin promotes the production of new FFAs in the liver via de novo lipogenesis; this production of liver fats continues to be stimulated by insulin, even when other tissues are insulin-resistant. These FFAs are combined back into triglycerides in the liver, forming the major constituent of the accumulated fat in the liver. The three sources of free fatty acids that contribute to liver triglyceride accumulation include FFAs circulating in the bloodstream (59%), FFAs derived from carbohydrates such as fructose and glucose (26%), and diet (14%). Despite the accumulation of triglycerides in the liver, they are not directly toxic to liver tissue. Instead, alteration of the profile of the other lipid subtypes present in the liver, such as diacylglycerols, phospholipids, ceramides, and free cholesterol, have a more significant role in the pathogenesis of MAFLD.

Once NAFLD progresses in severity to the point of NASH, this promotes further insulin resistance in the adipose tissue and liver, which results in a harmful cycle of insulin resistance, liver fat accumulation, and inflammation. Adipose tissue dysfunction also decreases secretion of the insulin-sensitizing adipokine adiponectin in people with NAFLD. Adiponectin has several properties that protect the liver. These properties include improved liver fat metabolism, decreased de novo lipogenesis, decreased glucose production in the liver, anti-inflammatory properties, and anti-fibrotic properties. Skeletal muscle insulin resistance may also play a role in MAFLD. Insulin-resistant skeletal muscle is not as efficient at taking up glucose from the bloodstream after a meal. This inefficient glucose uptake promotes the redistribution of consumed carbohydrates from glucose destined for use in glycogen stores in the skeletal muscles to being used as a substrate for de novo lipogenesis in the liver.

Dysbiosis
Disruptions in the intestinal microbiota seem to influence NAFLD risk in several ways. People with NASH can have elevated levels of blood ethanol and Pseudomonadota (which produce alcohol), with dysbiosis proposed as a mechanism for this elevation. Alterations in the composition of the intestinal microbiota may influence NAFLD risk in several ways. These changes appear to increase the permeability of intestinal tissue, thereby facilitating increased liver exposure to harmful substances (e.g., translocated bacteria, bacterial toxins, and inflammatory chemical signals). The increased transport of these harmful substances to the liver promotes liver inflammation, enhances nutrient and calorie absorption, and alters choline metabolism. Higher levels of intestinal bacteria that produce butyrate may be protective.

Excessive macronutrient intake contributes to gut inflammation and perturbation of homeostasis, and micronutrients may also be involved. In addition to reducing weight and risk factors, lifestyle changes may prompt positive changes in the gut microbiota. In particular, diet diversity may play a role that was overlooked in animal studies, since they often compare a Western high-fat, low-diversity diet against a low-fat but higher-diversity chow. The health benefits after bariatric surgery may also involve changes in the gut microbiota by increasing gut permeability.

Diagnosis

NAFLD is defined by evidence of fatty liver without another factor that could explain the liver fat accumulation, such as excessive alcohol use (>21 standard drinks/week for men and >14 for women in the USA; >30 g daily for men and >20 g for women in UK and EU, >140 g/week for men and >70 g/week for women in Asia-Pacific and most NIH clinical studies), drug-induced steatosis, chronic hepatitis C, heredity or by deficiencies in parenteral nutrition such as choline and endocrine conditions. If any of these factors are observed, an investigation into alternative causes of fatty liver unrelated to NAFLD is recommended. A history of chronic alcohol usage is an important consideration.

NAFLD comprises two histological categories: NAFL, and the more aggressive form NASH. The presence of at least 5% fatty liver is common to both NAFL and NASH, but the features of substantial lobular inflammation and hepatocyte injuries such as ballooning or Mallory hyaline only occur in NASH. The majority of NAFL cases show minimal or no inflammation. Pericentral and perisinusoidal fibrosis occur more often in adult-onset NASH, whereas portal fibrosis is more common in children with the disorder. NASH represents a more advanced stage of NAFL and is associated with poor outcomes such as cardiovascular events, cirrhosis, or hepatocellular carcinoma. ICD-11 does not use the term NAFL as it was deemed confusing with the family of disorders NAFLD. The preferred descriptions are instead: MAFLD without NASH or simple steatosis and "NASH". Also, the modifier with or without fibrosis or cirrhosis completes the diagnostic description.

Blood tests
Elevated liver enzymes are common. According to National Institute for Health and Care Excellence (NICE) guidelines, it is disadvised to test enzyme levels to rule out NAFLD, as they are often within the normal range even in advanced disease.

Blood tests that are useful to confirm diagnosis or rule out others include erythrocyte sedimentation rate, glucose, albumin, and kidney function. Because the liver is important for making proteins used in blood clotting, coagulation-related studies are often carried out, especially the INR (international normalized ratio). In people with fatty liver with associated inflammatory injury (steatohepatitis) blood tests are usually used to rule out viral hepatitis (hepatitis A, B, C and herpesviruses such as Epstein–Barr virus or cytomegalovirus), rubella, and autoimmune diseases. Low thyroid activity is more prevalent in people with NASH, which would be detected by determining the thyroid-stimulating hormone. Some biomarker-based blood tests have been developed and may be useful for diagnosis.

Although blood tests cannot diagnose MAFLD, circulating serum biomarkers of liver fibrosis can give moderate estimates in the diagnosis of liver fibrosis and cirrhosis. The ratio of the transaminase liver enzyme aspartate aminotransferase (AST) to platelets in the blood, known as the AST/platelet ratio index (APRI score), and Fibrotest are recommended as the preferred noninvasive tests for cirrhosis by the Asian-Pacific Association for Study of the Liver (APASL). Several other scores such as FIB-4 score and NAFLD fibrosis score can also reflect the burden of the fibrosis in the liver, and previous studies have confirmed that these scores can predict future development of mortality and liver cancer.

Imaging

A liver ultrasound scan or magnetic resonance imaging (MRI) can diagnose steatosis, but not fibrosis and confirmation of early cirrhosis detection by ultrasound by other diagnostic methods is recommended. The European Association for the Study of the Liver (EASL) recommends screening for steatosis whenever NAFLD is suspected as this is a strong predictor of the disease evolution and predicts future type 2 diabetes, cardiovascular events, and hypertension. These non-invasive methods can be used for NAFLD screening but are not accepted as a substitute for liver biopsy in NAFLD nor NASH clinical trials, as only a liver biopsy can define liver pathology.

Ultrasound presented average sensitivity and specificity for diagnosing the disease in children, while in the adult population, sensitivity and specificity were significantly higher. Proton density fat fraction magnetic resonance imaging has been increasingly used for the diagnosis of steatosis in pediatric patients. Elastography is an effective tool for staging liver fibrosis and discriminating NASH from MAFLD in children.

CT scans and MRIs are more accurate in detecting cirrhosis than conventional ultrasound. Transient elastography is recommended for the initial assessment of liver fibrosis and cirrhosis and helps to predict complications and prognosis, but the interpretation of results is carefully weighed in the presence of limiting factors, such as steatosis, high BMI, lower degrees of hepatic fibrosis and narrow spaces between the ribs (intercostal spaces). However, transient elastography can fail for people with pre-hepatic portal hypertension. Transient elastography is not considered to be a replacement for liver biopsy.

Magnetic resonance elastography (MRE) is an established method that can accurately assess hepatic fibrosis and is recommended by the APASL, AGA, ACR and AASLD. MRE possesses excellent accuracy to detect fibrosis in NAFLD regardless of BMI and inflammation, and is suggested as a more reliable alternative to diagnose NAFLD and its progression to NASH compared to ultrasound and blood tests.

Liver biopsy

A liver biopsy (tissue examination) is the only test widely accepted (gold standard) as definitively diagnosing and distinguishing NAFLD (including NAFL and NASH) from other forms of liver disease and can be used to assess the severity of the inflammation and resultant fibrosis. However, since most people affected by NAFLD are likely to be asymptomatic, liver biopsy presents too high a risk for routine diagnosis, so other methods are preferred, such as liver ultrasonography or liver MRI. For young people, guidelines recommend liver ultrasonography, but biopsy remains the best evidence. Liver biopsy is also the gold standard to detect hepatic fibrosis and assess its progression. Routine liver function blood tests are not sensitive enough to detect MAFLD, and biopsy is the only procedure that can reliably differentiate NAFL from NASH.

There are several liver biopsy techniques available to obtain liver tissue. Percutaneous liver biopsy remains the most common practice. Biopsies can also be performed via the transvenous route, either during surgery or by laparoscopy, especially for people with contraindications to a percutaneous approach. The liver biopsy can also be image-guided, in real-time or not, which is recommended for some clinical situations such as people with known intra-hepatic lesions, previous intra-abdominal surgery who may have adhesions, a small liver that is difficult to percuss, obese people and people with evident ascites. Vital signs must be monitored frequently afterward (at least every 15 minutes in the hour following the biopsy).

According to AASLD guidelines, a liver biopsy may be considered in people with NAFLD who are at increased risk of having steatohepatitis with or without advanced fibrosis, but only when all other competing chronic liver diseases are excluded (such as alcoholic liver disease). The presence of metabolic syndrome, NAFLD Fibrosis Score (FIB-4), or liver stiffness (as measured by Vibration-controlled transient elastography or MRE) can identify the individuals who are at higher risk of steatohepatitis or advanced fibrosis.

The AASLD and ICD-11 consider that clinically useful pathology reporting distinguishes "between NAFL (steatosis), NAFL with inflammation and NASH (steatosis with lobular and portal inflammation and hepatocellular ballooning)" with the presence or absence of fibrosis being described and optionally comment on severity. The EASL recommends the Fatty Liver Inhibition of Progression (FLIP) algorithm to grade the ballooning and classify MAFLD-associated liver injury, and the use of the NAFLD Activity Score (NAS) to grade the severity of NASH rather than for its diagnosis. They also consider the steatosis, activity, and fibrosis (SAF) score to be an accurate and reproducible scoring system. The AASLD recommends the use of the NAS scoring system with or without the SAF score if deemed appropriate. The Asia-Pacific Working Group on MAFLD disadvises the use of NAS, as it is considered uninformative for NAFLD and inappropriate to diagnose NASH.

For liver fibrosis assessment, percutaneous liver biopsy, with or without image guidance, is contraindicated in uncooperative people. Transjugular liver biopsy is indicated for any person with diffuse liver disease who needs a biopsy but has a contraindication to percutaneous biopsy or needs a hemodynamic evaluation for diagnostic purposes. A transvenous liver biopsy is recommended instead of a percutaneous approach in people with clinically evident ascites, although percutaneous biopsy is an acceptable alternative approach after the removal of ascites.

Management
NAFLD warrants treatment regardless of whether the affected person is overweight or not. MAFLD is a preventable cause of death. Guidelines are available from the American Association for the Study of Liver Diseases (AASLD), American Association of Clinical Endocrinologists (AACE) National Institute for Health and Care Excellence (NICE), the European Association for the Study of the Liver (EASL), and the Asia-Pacific Working Party on NAFLD.

Lifestyle
Weight loss is the most effective treatment for NAFLD. A loss of 4% to 10% body weight is recommended, with 10% to 40% weight loss completely reversing NASH without cirrhosis. A structured weight loss program helps people with MAFLD lose more weight compared with advice alone. This type of program also leads to improvements in NAFLD measured using blood tests, ultrasound, imaging, or liver biopsies. Although fibrosis improves with lifestyle interventions and weight loss, there is limited evidence for cirrhosis improvement.

A combination of improved diet and exercise, rather than either alone, appears to best help manage NAFLD and reduce insulin resistance. Motivational support, such as with cognitive behavioral therapy, is helpful, as most people with MAFLD do not perceive their condition as a disease, and thus have a low motivation to change.

Higher-intensity behavioral weight loss therapies (diet and exercise combined) may produce more weight loss than lower-intensity ones. A 2019 systematic review suggested a change of guidelines to recommend these therapies for MAFLD management. Weight loss is associated with improvements in biomarkers, MAFLD grade, and reduced chances of NASH, but its effect on long-term health was not known.

2021 meta-analyses of trials over periods of 1 to 28 months found limited evidence to indicate that lifestyle modifications and nutritional supplementation have an effect on mortality, liver cirrhosis, liver decompensation, liver transplantation, and hepatocellular carcinoma in people with non-alcohol-related fatty liver disease; authors said that it was unlikely that differences in clinical outcomes would become apparent in trials with less than 5 years to 10 years of follow‐up, and that sample sizes needed to be much larger than had been used.

Diet
Treatment of NAFLD typically involves counseling to improve nutrition and calorie restriction. People with NAFLD can benefit from a moderate to low-carbohydrate diet and a low-fat diet. The Mediterranean diet also showed promising results in a 6-week study with a reduction of NASH induced inflammation and fibrosis, independently from weight loss. Tentative evidence supports dietary interventions in individuals with fatty liver who are not overweight.

The EASL recommends energy restriction of 500–1000 kcal per week less than the normal daily diet, a target of 7–10% weight loss for obese/overweight MAFLD, a low- to moderate-fat, and moderate- to high-carbohydrate diet, or a low-carbohydrate ketogenic or high-protein diet such as the Mediterranean diet, and avoiding all beverages and food containing fructose.

Alcohol is an aggravating factor, and the AASLD recommends that people with NAFLD or NASH avoid alcohol consumption. The EASL allows alcohol consumption below 30g/day for men and 20g/day for women. The role of coffee consumption for NAFLD treatment is unclear though some studies indicate that regular coffee consumption may have protective effects.

Herbal compounds such as silymarin (a milk thistle seed extract), curcumin, a turmeric extract, and green tea appear to improve NAFLD biomarkers and reduce the grade of NAFLD. Studies suggest an association between microscopic organisms that inhabit the gut (microbiota) and MAFLD. Reviews reported the use of probiotics and synbiotics (combinations of probiotics and prebiotics) were associated with improvement in liver-specific markers of hepatic inflammation, measurements of liver stiffness, and steatosis in persons with MAFLD.

Vitamin E does not improve established liver fibrosis in those with MAFLD but seems to improve certain markers of liver function and reduces inflammation and fattiness of the liver in some people with MAFLD. The Asia-Pacific Work Group advises that Vitamin E may improve liver condition and aminotransferase levels, but only in adults without diabetes or cirrhosis who have NASH. The NICE guidelines recommend Vitamin E as an option for children and adults with NAFLD with advanced liver fibrosis, regardless of whether the person has diabetes mellitus.

Physical activity
Weight loss may improve MAFLD and is recommended particularly for obese or overweight people; similar physical activities and diets are advisable for overweight people with MAFLD as for other obese and overweight people. Although physical activity is less important for weight loss than dietary adaptations (to reduce caloric intake), the NICE advises physical activity to reduce liver fat even if there is no overall bodyweight reduction. Weight loss, through exercise or diet, is the most effective way to reduce liver fat and help NASH and fibrosis remission. Exercise alone can prevent or reduce hepatic steatosis, but it remains unknown whether it can improve all other aspects of the liver; hence a combined approach with diet and exercise is advised. Aerobic exercise may be more effective than resistance training, although there are contradictory results. Vigorous training is preferable to moderate training, as only the high-intensity exercise reduced the chances of MAFLD developing into NASH or advanced fibrosis. The EASL recommends between 150 and 200 min/week in 3 to 5 sessions of moderate-intensity aerobic physical activity or resistance training. Since both effectively reduce liver fat, a pragmatic approach to the choice of physical activity that accounts for the individual's preferences for what they can maintain in the long-term is preferred. Any engagement in physical activity or increase over previous levels is better than remaining sedentary.

Medication

No medicines specifically for MAFLD or NASH had received approval, . While many treatments appear to improve biochemical markers such as alanine transaminase levels, most do not reverse histological abnormalities or improve outcomes. Treatment with medications is primarily aimed at improving liver disease and is generally limited to those with biopsy-proven NASH and fibrosis.

Insulin sensitizers (metformin and thiazolidinediones, such as pioglitazone) are not specifically recommended for MAFLD as they do not directly improve the liver condition. They can be indicated for diabetic individuals, after a careful assessment of risks, to reduce insulin resistance and risks of complications. Indeed, the side effects associated with thiazolidinedione medications, which include osteopenia, increased fracture risk, fluid retention, congestive heart failure, bladder cancer, and long-term weight gain, have limited their adoption. Due to these side effects, the AASLD recommends the use of pioglitazone only for individuals with biopsy-proven NASH, and the Asia-Pacific Work Group recommends them only for individuals with MAFLD with known diabetic issues. However, the AASLD advises against the use of metformin as studies were inconclusive about the improvement of the liver's histological condition. Although there was an improvement in insulin resistance and serum aminotransferases, this did not translate into NASH improvements. The NICE provides similar guidelines to the AASLD regarding pioglitazone and recommends it be administered in secondary care to adults with advanced liver fibrosis irrespective of whether or not they have diabetes.

Glucagon-like peptide-1 receptor agonists are at least as effective as pioglitazone and Vitamin E and significantly reduce steatosis, ballooning necrosis, lobular inflammation, and fibrosis according to a 2023 systematic review.

Statin medications appear to improve liver histology and markers of liver biochemistry in people with MAFLD. Since people with NAFLD are at a higher risk of cardiovascular disease, statin treatment is indicated. People with NAFLD are not at higher risk for serious liver injury from statins, according to AASLD and EASL. However, even if statins are safe to use in people with NASH cirrhosis, the AASLD suggests avoiding them in people with decompensated cirrhosis. Guidelines recommend statins to treat dyslipidemia for people with MAFLD. According to NICE guidelines, statins can continue unless liver enzyme levels double within three months of starting statins. Treatment with pentoxifylline is not recommended.

Omega-3 fatty acids may reduce liver fat and improve blood lipid profile but do not seem to improve liver histology (fibrosis, cirrhosis, cancer). The NICE does not recommend omega-3 fatty acid supplementation since randomized trials were inconclusive. Previous systematic reviews found that omega-3 fatty acid supplementation in those with MAFLD/NASH using doses of one gram daily or more (median dose four grams/day with median treatment duration six months) has been associated with improvements in liver fat. According to AASLD guidelines, "omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH, but they may be considered to treat hypertriglyceridemia for patients with NAFLD".

Surgery

Bariatric surgery is an effective method for obese and diabetic individuals with MAFLD to induce weight loss and reduce or resolve NASH inflammation, including fibrosis, and improve longevity. For the AASLD, bariatric surgery can be considered only for NASH on a case-by-case basis by an experienced bariatric surgery program. Indeed, some individuals might develop new or worsened features of MAFLD.

About 92% of people with MAFLD saw an improvement in steatosis and 70% a complete resolution after bariatric surgery.

A preoperative diet such as a low-calorie diet or a very-low-calorie diet is usually recommended to reduce liver volume by 16–20%. Preoperative weight loss is the only factor associated with postoperative weight loss. Preoperative weight loss can reduce operative time and hospital stay, although there is insufficient evidence whether preoperative weight loss reduces long-term morbidity or complications. Weight loss and decreases in liver size may be independent of the amount of calorie restriction.

The APWG on MAFLD recommends bariatric surgery as a treatment option for those with class II obesity (BMI >32.5 kg/m2 for Asians, 35 kg/m2 for Caucasians). They consider its effects on improving liver-related complications as unproven yet, but it effectively increases longevity by improving cardiovascular factors.

Surgery carries more risks for individuals with NASH cirrhosis, with a review estimating overall morbidity to be 21%. For people with MAFLD who have undifferentiated cirrhosis, the APWG recommends an investigation to determine the cause of the cirrhosis as well as the person's liver function and whether they have portal hypertension.

Screening
Cardiovascular system screening is considered mandatory by the EASL, as MAFLD outcomes often result in cardiovascular complications, which can manifest as subclinical atherosclerosis, the cause of the majority of MAFLD-related deaths. People with MAFLD are at high risk for cardiovascular morbidity and mortality, and "aggressive modification of cardiovascular disease risk factors is warranted in all patients with NAFLD," according to AASLD.

The AASLD further recommends for people with a cirrhotic NASH to be systematically screened for gastric and esophageal varices and liver cancer. They do not recommend routine liver biopsies and screening for liver cancer for non-cirrhotic people with NASH, but such screening sometimes occurs on a case-by-case basis.

Also, people with MAFLD may be considered for screening for hepatocellular carcinoma (liver cancer) and gastroesophageal varices. The NICE advises regular screening of NAFLD for advanced liver fibrosis every three years to adults and every two years for children using the enhanced liver fibrosis (ELF) blood test. Follow-up is recommended for people with obesity and insulin resistance using the homeostasis model assessment of insulin resistance (HOMA-IR). People with NASH with fibrosis and hypertension merit closer monitoring as there is a higher risk of disease progression.

Transplantation
MAFLD is the second most common indication for liver transplantation in the US and Europe as of 2017. MAFLD/NASH is expected to become the leading cause of liver transplantation by 2020.

For people with NASH and end-stage liver disease, liver failure, or liver cancer, liver transplantation is an accepted procedure according to the EASL. People with NASH cirrhosis NASH who are being considered for a liver transplant warrant systematic evaluation for cardiovascular diseases (whether the symptoms are apparent or not).

The overall survival is comparable to transplantation following other diseases. People with NASH cirrhosis who undergo liver transplantation are more likely to die post-transplant because of cardiovascular disease or chronic kidney disease. These people with NASH are often older and are thus more prone to these complications. For these reasons and others, individuals with morbid obesity (BMI ≥ 40 kg/m2) and NASH with cirrhosis may be considered unfit for liver transplantation until they follow lifestyle modifications to reduce bodyweight. Diabetic people with poor glycemic control are at similar risks, and optimal glycemic control is essential before attempting transplantation.

The Asia Pacific Working Group guidelines recommend healthcare providers discuss lifestyle modifications before and after transplantation to reduce potential surgery risks and to assist with MAFLD management after the transplant.

Simultaneous bariatric surgery and liver transplantation were performed in exceptional circumstances.

After transplantation, liver biopsy is the best method to monitor the evolution of post-transplant fibrosis, with significant fibrosis or portal hypertension one year after transplantation predicting rapid progression and graft loss and indicating the need for urgent intervention.

Related complications
There is no special treatment for liver cancer associated with MAFLD/NASH and are treated according to general guidelines on liver cancers.

Prognosis
The average progression rate from one stage of liver fibrosis to the next in humans with NASH is estimated to be seven years, compared to 14 years with MAFLD. The course of progression varies with different clinical manifestations among individuals. Fibrosis in humans with NASH progressed more rapidly than in humans with MAFLD. Obesity predicts a worse long-term outcome than for lean individuals. In the Asia-Pacific region, about 25% of MAFLD cases progress to NASH under three years, but only a low proportion (3.7%) develop advanced liver fibrosis. An international study showed that people with MAFLD had a 10-year survival rate of 81.5%.

MAFLD is a risk factor for fibrosis, hypertension, chronic kidney disease, atrial fibrillation, myocardial infarction, ischemic stroke, and death from cardiovascular causes based on very-low to low-quality evidence from observational studies. Although MAFLD can cause cirrhosis and liver failure and liver cancer, most deaths among people with NAFLD are attributable to cardiovascular disease. According to a meta-analysis of 34,000 people with MAFLD over seven years, these individuals have a 65% increased risk of developing fatal or nonfatal cardiovascular events when compared to those without MAFLD.

MAFLD and NASH increase the risk of liver cancer. Cirrhosis and liver cancer induced by NAFLD were the second cause of liver transplantation in the US in 2017. Liver cancer develops in NASH in the absence of cirrhosis in 45% in the cases, and people with NASH cirrhosis have an increased risk of liver cancer. The rate of liver cancer associated with NASH increased fourfold between 2002 and 2012 in the US, which is more than any other cause of liver cancer. MAFLD constitutes the third most common risk factor for liver cancer. NAFLD and NASH were found to worsen with cirrhosis in respectively 2–3% and 15–20% of the people over a 10–20 year period. Cirrhosis is found in only about 50% of people with MAFLD and with liver cancer, so that liver cancer and cirrhosis are not always linked.

MAFLD may be a precursor of metabolic syndrome, although a bidirectional influence is possible. The presence and stage of fibrosis are the strongest prognostic factors for liver-related events and mortality, in particular for MAFLD.

Epidemiology

MAFLD incidence is rapidly rising, along with obesity and diabetes, and has become the most common cause of liver disease in developed countries, for adults, teenagers, and children. The percentage of people with MAFLD ranges from 9 to 36.9% in different parts of the world. Approximately 20% of the United States and 25% of the Asia-Pacific populations have non-alcoholic fatty liver. Similar prevalence can be found in Europe, although less data is available. MAFLD is the most common in the Middle East (32%) and South America (30%), while Africa has the lowest rates (13%). Compared to the 2000s, NAFL and NASH respectively increased 2-fold and 2.5-fold in the 2010s in the USA.

MAFLD and NASH are more prevalent in Hispanics - which can be attributed to high rates of obesity and type 2 diabetes in Hispanic populations, intermediate in Whites, and lowest in Blacks. NAFLD was observed to be twice as prevalent in men as women. For severely obese individuals, the prevalence of MAFLD rises over 90%, and for those with diabetes, over 60%, and up to 20% for normal-weight people. MAFLD is present in 65% to 90% of people that had bariatric surgery, and up to 75% of them have NASH. Ultrasonography and proton NMR spectroscopy studies suggest about 25% of the population seems to be affected by MAFLD or NASH.

Although the disease is commonly associated with obesity, a significant proportion of those affected are normal weight or lean. Lean MAFLD affects between 10 and 20% of Americans and Europeans, and approximately 25% of the Asians, although some countries have a higher incidence (e.g., India has a very high proportion of lean MAFLD and almost no obese MAFLD). PNPLA3 may be relevant for the progression of MAFLD in lean people. Thus, people with MAFLD deserve consideration for treatment regardless of the presence or absence of obesity.

In children ages 1 to 19, the prevalence was found to be approximately 8% in the general population up to 34% in studies with data from child obesity clinics.

The majority of cryptogenic cirrhosis is believed to be due to NASH. NAFLD prevalence is expected to increase steadily, from 25% in 2018 to a projected 33.5% of people with MAFLD globally in 2030, and from 20% to a projected 27% of those with MAFLD will progress to NASH.

History
The first acknowledged case of obesity-related non-alcoholic fatty liver was observed in 1952 by Samuel Zelman. Zelman started investigating after observing a fatty liver in a hospital employee who drank more than twenty bottles of Coca-Cola a day. He then went on to design a trial for a year and a half on 20 obese people who were not alcoholic, finding that about half of them had substantially fatty livers. Fatty liver was, however, linked to diabetes since at least 1784 — an observation picked up again in the 1930s. Studies in experimental animals implicated choline inadequacy in the 1920s and excess sugar consumption in 1949.

The name "non-alcoholic steatohepatitis" (NASH) was later defined in 1980 by Jurgen Ludwig and his colleagues from the Mayo Clinic to raise awareness of the existence of this pathology, as similar reports previously were dismissed as "patients' lies". This paper was mostly ignored at the time but eventually came to be seen as a landmark paper, and starting in the mid-1990s, the condition began to be intensively studied, with a series of international meetings being held on the topic since 1998. The broader NAFLD term started to be used around 2002. Diagnostic criteria began to be worked out, and in 2005 the Pathology Committee of the NIH NASH Clinical Research Network proposed the NAS scoring system.

Society and culture

Political recommendations
EASL recommends Europe's public health authorities to "restrict advertising and marketing of sugar-sweetened beverages and industrially processed foods high in saturated fat, sugar, and salt", as well as "fiscal measures to discourage the consumption of sugar-sweetened beverages and legislation to ensure that the food industry improves labeling and the composition of processed foods", as well as "public awareness campaigns on liver disease, highlighting that it is not only linked to excessive consumption of alcohol".

Lobbying
In France, the French syndicate of non-alcoholic beverages "Boissons Rafraîchissantes de France" (that included soft drink producers such as Coca-Cola France, Orangina, PepsiCo France) was denounced by the French journal :fr:Canard Enchainé for misleading consumers using a communication on their website titled "Better understanding the NASH pathology", explaining that "NASH pathology is sometimes called the soda illness by language abuse or an unfortunate semantic shortcut, as it is not directly linked to the consumption of non-alcoholic beverages". This page and others on the same website, such as one titled "Say no to disinformation," were since then removed.

Children
Pediatric MAFLD was first reported in 1983. It is the most common chronic liver disease among children and adolescents since at least 2007, affecting 10 to 20% of them in the US in 2016. MAFLD is associated with metabolic syndrome, which is a cluster of risk factors that contribute to the development of cardiovascular disease and type 2 diabetes mellitus. Studies have demonstrated that abdominal obesity and insulin resistance, in particular, are significant contributors to the development of NAFLD. Coexisting liver diseases, such as hepatitis C and cardiovascular diseases such as atherosclerosis, are also associated with an increased risk of NAFLD. Some children were diagnosed as early as two years old, with a mean age of diagnosis between 11 and 13 years old. The mean age is usually above 10 years, as children can also report non-specific symptoms and are thus difficult to diagnose for MAFLD.

Boys are more likely to be diagnosed with MAFLD than girls. Overweight, or even weight gain, in childhood and adolescence, is associated with an increased risk of MAFLD later in life, with adult NAFLD predicted in a 31-year follow-up study by risk factors during childhood including BMI, plasma insulin levels, male sex, genetic background (PNPLA3 and TM6SF2 variants) and low birth weight, an emerging risk factor for adulthood MAFLD. In a study, simple steatosis was present in up to 45% in children with a clinical suspicion of MAFLD. Children with simple steatosis have a worse prognosis than adults, with significantly more of them progressing from NAFLD to NASH compared to adults. Indeed, 17-25% of children with MAFLD develop a NASH in general, and up to 83% for children with severe obesity (versus 29% for adults), further suggesting that hepatic fibrosis seems to follow a more aggressive clinical course in children compared to adults.

Early diagnosis of MAFLD in children may help prevent the development of liver disease during adulthood. This is challenging as most children with MAFLD are asymptomatic, with only 42-59% showing abdominal pain. Other symptoms might be present, such as right upper quadrant pain or acanthosis nigricans, the latter of which is often present in children with NASH. An enlarged liver occurs in 30–40% of children with NAFLD.

The AASLD recommends a diagnostic liver biopsy in children when the diagnosis is unclear or before starting a potentially hepatotoxic medical therapy. The EASL suggests using fibrosis tests such as elastography, acoustic radiation force impulse imaging, and serum biomarkers to reduce the number of biopsies. In follow up, NICE guidelines recommend that healthcare providers offer children regular MAFLD screening for advanced liver fibrosis every two years using the enhanced liver fibrosis (ELF) blood test. Several studies also suggest magnetic resonance elastography as an alternative to the less reliable ultrasonography.

Intensive lifestyle modifications, including physical activity and dietary changes, are the first line of treatment according to AASLD and EASL as it improves the liver histology and aminotransferase levels. In terms of pharmacological treatment, the AASLD and EASL do not recommend metformin, but vitamin E may improve liver health for some children. The NICE advises the use of vitamin E for children with advanced liver fibrosis, whether they have diabetes or not. The only treatment shown to be effective in childhood MAFLD is weight loss.

Some evidence indicates that maternal undernutrition or overnutrition increases a child's susceptibility to NASH and hastens its progression.

Research

Diagnosis and biomarkers
Since a MAFLD diagnosis based on a liver biopsy is invasive and makes it difficult to estimate epidemiology, it is a high research priority to find accurate, inexpensive, and noninvasive methods of diagnosing and monitoring MAFLD disease and its progression. The search for these biomarkers of MAFLD, NAFL, and NASH involves lipidomics, medical imaging, proteomics, blood tests, and scoring systems.

According to a review, proton density fat fraction estimation by magnetic resonance imaging (MRI-PDFF) may be considered the most accurate and even gold standard test to quantify hepatic steatosis. They recommend ultrasound-based transient elastography to accurately diagnose both fibrosis and cirrhosis in a routine clinical setting, with more objectivity than ultrasonography but with lower accuracy than magnetic resonance elastography; and plasma cytokeratin 18 (CK18) fragment levels to be a moderately accurate biomarker of steatohepatitis. However, transient elastography can fail for people with pre-hepatic portal hypertension.

Medication development
Although no drugs are approved to treat NAFLD or NASH, a variety of medications with different mechanisms of action have been tested in clinical trials. These include glucagon-like peptide-1 receptor agonists (GLP-1 agonists), GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) or glucagon co-agonists, thyromimetics, and lipogenesis inhibitors. Some of these drugs may treat NAFLD by significantly reducing body weight. Other classes of drugs such as  chemokine antagonists, anti-apoptotics, vascular adhesion protein-1 inhibitors, and  c-Jun N-terminal kinase inhibitors aim to directly reduce liver damage, but these drugs have not shown benefit. Anti-fibrotic drugs such as fibroblast growth factor analogues have also largely not met their endpoints. Other treatments such as farnesoid X receptor (FXR) agonists, peroxisome proliferator-activated receptor (PPAR) agonists, and ASK1 (apoptosis signal-regulating kinase 1) inhibitors may improve NAFLD by multiple mechanisms simultaneously. Drugs in phase III trials as of 2023 are obeticholic acid (a FXR agonist), the thyromimetic resmetirom, lanifibranor (a pan-PPAR agonist), and the GLP-1 agonist semaglutide.

See also
 Foie gras, fatty liver induced in poultry, with pathophysiology homologous to that of MAFLD in humans

Notes

References

External links
 NIH page on non-alcoholic steatohepatitis
 Mayo Clinic page on NAFLD

Diseases of liver
Hepatitis

Non-alcoholic fatty liver disease


Karl-Heinz Smuda (born 24 January 1961 in Eschweiler) is a German radio journalist, media-expert, ghostwriter and major in the German Air Force.
He was speaker of the NATO detachment in Siauliai and the German detachment of EUFOR RD Congo in Kinshasa/ DR Congo.

Radio career
Smuda was a correspondent for Deutschlandradio, Germany's national radio public broadcast system, and head of a radio station in the former East German country of Brandenburg. After the fall of the Berlin Wall, he worked as a reporter in Leipzig, and became known for his reports on the lives of the citizens of East Germany. For the past 30 years, Smuda has worked for various radio stations in Germany, as well as making a series of broadcasts from the United States concerning politics and culture in the Oregon, New York, Massachusetts, California and North Carolina. He worked as an editor in the German department of Radio Vatican in 1980 and 1981. Smuda has made 12000 reports from Germany and all over the world. He is a lecturer at the University of Wuppertal and Cottbus, trainer in the academy for communication and information of German Air Force in Strauberg, near Berlin.

Background
Smuda received a scholarship for his work in children's television in Manila. He worked as a reporter in the crisis areas of East Timor and Kosovo. He has studied social science. He currently resides in Wilmersdorf area of West-Berlin. Smuda has also worked as a speaker for the German detachment of NATO Baltic Air Policing in Šiauliai in Lithuania. Afterwards, he worked in the Operation Headquarter of EU in Potsdam for preparation Europe's engagement during the election in the Democratic Republic Congo (PR) and was Press Information Officer (PIO/ Major OF3) in Kinshasa. He was chief-editor of the newspaper "ECHO" during the multinational exercise ELITE 2006 for 16 countries.

References

External links

1961 births
Living people
People from Eschweiler
German journalists
German male journalists
Academic staff of the University of Wuppertal
German male writers

Karl-Heinz Smuda