Cleaning the Liver and Gallbladder

Gallstones can form anywhere in the body, mainly in the liver and gallbladder. Gallstones in the gallbladder are often detected via abdominal ultrasound. However, intrahepatic stones or gallstones in the hepatic biliary duct (liver stones) are often undetected and undiagnosed. They are the culprit of many modern day diseases that we see today. The liver function tests (LFT) may appear normal even though the failing liver is heavily congested with fats and gallstones. Fatty liver is a manifestation of a congested liver and needs cleansing if the liver is to continue to serve as a detox organ. Othwerwise, we die faster due to liver failure.

Weight loss and not eating for long periods are a leading cause for liver stones (intrahepatic gallstones).

There are many ways to clean the liver and gallbladder naturally. Dr Eden offers the Pulverexx Protocol. Andreas Moritz offers a book on how to DIY flush (cleanse) the liver and gallbladder of toxins, based on Ayyurveda. Both procedures will revitalise the liver and give a better quality of life (QOL).


External links
http://www.doctoreden.com/
http://www.doctoreden.com/gallbladder-liver-detox
http://www.ener-chi.com/books/the-amazing-liver-gallbladder-flush/
http://www.healthline.com/human-body-maps/gallbladder

Moritz A.. The Amazing Liver And Gallbladder Flush, Ener-Chi.com (2005), p. 20

Laparoscopic Cholecystectomy (gallbladder removal)

Introduction

Cholecystectomy is the surgical removal of the gallbladder. It is a common treatment of symptomatic gallstones and other gallbladder conditions. Surgical options include the standard procedure, called laparoscopic cholecystectomy, and an older more invasive procedure, called open cholecystectomy.

Indications

Indications for cholecystectomy include inflammation of the gallbladder (cholecystitis), biliary colic, risk factors for gallbladder cancer, and pancreatitis caused by gallstones.

Cholecystectomy is the recommended treatment the first time a person is admitted to hospital for cholecystitis.

Cholecystitis may be acute or chronic, and may or may not involve the presence of gallstones.

Risk factors for gallbladder cancer include a "porcelain gallbladder," or calcium deposits in the wall of the gallbladder, and an abnormal pancreatic duct.

Cholecystectomy can prevent the relapse of pancreatitis that is caused by gallstones that block the common bile duct.

Laparoscopic surgery

Laparoscopic cholecystectomy has now replaced open cholecystectomy as the first-choice of treatment for gallstones and inflammation of the gallbladder unless there are contraindications to the laparoscopic approach. This is because open surgery leaves the patient more prone to infection. Sometimes, a laparoscopic cholecystectomy will be converted to an open cholecystectomy for technical reasons or safety.

Laparoscopic cholecystectomy requires 4 small incisions in the abdomen to allow the insertion of operating ports, small cylindrical tubes approximately 5 to 10 mm in diameter, through which surgical instruments and a video camera are placed into the abdominal cavity. The camera illuminates the surgical field and sends a magnified image from inside the body to a video monitor, giving the surgeon a close-up view of the organs and tissues. The surgeon watches the monitor and performs the operation by manipulating the surgical instruments through the operating ports.

To begin the operation, the patient is placed in the supine position on the operating table and anesthetized. A scalpel is used to make a small incision at the umbilicus. Using either a Veress needle or Hasson technique, the abdominal cavity is entered. The surgeon inflates the abdominal cavity with carbon dioxide (CO2 gas) to create a working space. The camera is placed through the umbilical port and the abdominal cavity is inspected. Additional ports are opened inferior to the ribs at the epigastric, midclavicular, and anterior axillary positions. The gallbladder fundus is identified, grasped, and retracted superiorly. With a second grasper, the gallbladder infundibulum is retracted laterally to expose and open Calot's Triangle (cystic artery, cystic duct, and common hepatic duct). The triangle is gently dissected to clear the peritoneal covering and obtain a view of the underlying structures. The cystic duct and the cystic artery are identified, clipped with tiny titanium clips and cut. Then the gallbladder is dissected away from the liver bed and removed through one of the ports. This type of surgery requires meticulous surgical skill, but in straightforward cases, it can be done in about an hour.

Recently, this procedure is performed through a single incision in the patient's umbilicus. This advanced technique is called Laparoendoscopic Single Site Surgery or "LESS" or Single Incision Laparoscopic Surgery or "SILS". In this procedure, instead of making 3-4 four small different cuts (incisions), a single cut (incision) is made through the navel (umbilicus). Through this cut, specialized rotaculating instruments (straight instruments which can be bent once inside the tummy) are inserted to do the operation. The advantage of LESS / SILS operation is that the number of cuts are further reduced to one and this cut is also not visible after the operation is done as it is hidden inside the navel. A meta-analysis published by Pankaj Garg et al comparing conventional laparoscopic cholecystecomy to SILS Cholecystectomy demonstrated that SILS does have a cosmetic benefit over convention four-hole laparoscopic cholecystectomy while having no advantage in postoperative pain and hospital stay.

Procedural risks and complications

Laparoscopic cholecystectomy does not require the abdominal muscles to be cut, resulting in less pain, quicker healing, improved cosmetic results, and fewer complications such as infection and adhesions. Most patients can be discharged on the same or following day as the surgery, and can return to any type of occupation in about a week. Furthermore, flexible instruments are being used in laparoscopic surgery by some surgeons. Using the SPIDER surgical system, they can perform the cholecystectomy through a single incision through the navel. These patients often recover faster than traditional methods, and have an almost invisible scar.

Abdominal peritoneal adhesions, gangrenous gallbladders, and other problems that obscure vision are discovered during about 5% of laparoscopic surgeries, forcing surgeons to switch to the standard cholecystectomy for safe removal of the gallbladder. Adhesions and gangrene can be serious, but converting to open surgery does not equate to a complication.

A Consensus Development Conference panel, convened by the National Institutes of Health in September 1992, endorsed laparoscopic cholecystectomy as a safe and effective surgical treatment for gallbladder removal, equal in efficacy to the traditional open surgery. The panel noted, however, that laparoscopic cholecystectomy should be performed only by experienced surgeons and only on patients who have symptoms of gallstones.

In addition, the panel noted that the outcome of laparoscopic cholecystectomy is greatly influenced by the training, experience, skill, and judgment of the surgeon performing the procedure. Therefore, the panel recommended that strict guidelines be developed for training and granting credentials in laparoscopic surgery, determining competence, and monitoring quality. According to the panel, efforts should continue toward developing a noninvasive approach to gallstone treatment that will not only eliminate existing stones, but also prevent their formation or recurrence.

Injury of common bile duct

An uncommon but potentially serious complication is injury to the common bile duct, which connects the cystic and common hepatic ducts to the duodenum. An injured bile duct can leak bile and cause a painful and potentially dangerous infection. Many cases of minor injury to the common bile duct can be managed non-surgically. Major injury to the bile duct, however, is a very serious problem and may require corrective surgery. This surgery should be performed by an experienced biliary surgeon.

Post-op biliary leak

One common complication of cholecystectomy is inadvertent injury to analogous bile ducts known as Ducts of Luschka, occurring in 33% of the population. It is non-problematic until the gallbladder is removed, and the tiny supravesicular ducts may be incompletely cauterized or remain unobserved, leading to biliary leak post-operatively. The patient will develop biliary peritonitis within 5 to 7 days following surgery, and will require a temporary biliary stent. It is important that the clinician recognize the possibility of bile peritonitis early and confirm diagnosis via HIDA scan to lower morbidity rate. Aggressive pain management and antibiotic therapy should be initiated as soon as diagnosed.

Gallbladder perforation

During laparoscopic cholecystectomy, gallbladder perforation can occur due to excessive traction during retraction or during dissection from the liver bed. It can also occur during extraction from the abdomen. Infected bile, pigment gallstones, male gender, advanced age, perihepatic location of spilled gallstones, more than 15 gallstones and an average size greater than 1.5 cm have been identified as risk factors for complications. Spilled gallstones can be a diagnostic challenge and can cause significant morbidity to the patient. Clear documentation of spillage and explanation to the patient is of utmost importance, as this will enable prompt recognition and treatment of any complications. Prevention of spillage is the best policy.

Biopsy

After removal, the gallbladder should be sent for pathological examination to confirm the diagnosis and look for an incidental cancer. If cancer is present, a reoperation to remove part of the liver and lymph nodes will be required in most cases.

Long-term prognosis

A minority of the population, from 5% to 40%, develop a condition called postcholecystectomy syndrome, or PCS. Symptoms can include gastrointestinal distress and persistent pain in the upper right abdomen.
As many as 20% of patients develop chronic diarrhea. The cause is unclear, but is presumed to involve the disturbance to the bile system. Most cases clear up within weeks or a few months, though in rare cases the condition may last for many years. It can be controlled with medication such as cholestyramine.

Complications

The most serious complication of cholecystectomy is damage to the common bile duct. This occurs in about 0.25% of cases. Damage to the duct that causes leakage typically manifests as fever, jaundice, and abdominal pain several days following cholecystectomy. A lacerated, leaky bile duct may be repaired through a procedure called ERCP, or endoscopic retrograde cholangiopancreatography.

Another complication is when the gallstone is too large to be removed through the large 2-cm incision below the navel. The gallstone needs to be crushed a bit before removal. When this is done, there is tendency for bile leakage. Leaked bile can be an irritant.

Epidemiology

About 600,000 people receive a cholecystectomy in the United States each year.


External links
Wikipedia: "Cholecystectomy."
USC Surgery: "Laparoscopic cholecystectomy."
USC Surgery: "GALLSTONES."
WebMD: "Laparoscopic gallbladder surgery for gallstones."
WebMD: Types of surgery to remove the gallbladder."

Anatomyguy: "Laparoscopic cholecystectomy."
Dr Gamagami: "Laparoscopic Cholescystectomy".
Carolina Surgical: "Gallbladder removal".

Pressreleasepoint: "Do you suffer gallstone - Learn-about-natural-treatment."
Gallbladderdetox.com" Gallbladder-symptoms."
http://www.gallbladderdetox.com/
http://www.doctoreden.com
Healthline.com: gallstones

Gallstones - A guide for pateints, Part 1 - recommendations for surgery
Gallstones - A guide for patients, Part 2 - tells about ERCP, care of wounds and how to bathe after surgery

Laparoscopic cholescystectomy
https://youtu.be/ecQCvZb9qUA - animation

Gallbladder removal - Patient education
https://youtu.be/iD-5Rp6xdzM

Biochemistry Textbooks

I have always been a biochemistry student, facilitator and lecturer. I have taught medical biochemistry since June 1982; this is my 31st year teaching my favourite subject. There is a big difference between what is needed in pure biochemistry and medical biochemistry. Pure biochemistry requires a good knowledge of basic and applied chemistry. Medical biochemistry requires a good knowledge of applications of biochemical and chemical pathology knowledge in clinical cases.

The way biochemistry is heading, students will need to know quite a lot of biochemistry methods and basic & applied knowledge to be able to appreciate the complexity of depth of knowledge we have today about our own bodies and what goes on inside us. That's makes it very interesting when we have access to good books.

I would always suggest students to read up whenever they come across a case that they know little about. It is very gratifying to be able to understand a case at hand fully when they is sufficient material to read, comprehend and explore more. Nothing is ever complete and studying a case is like that.

Textbooks only fill a part of basic reading we need to know. Higher reading materials are those produced by specialised research groups and institutes. These are published as articles in scientific journals and monographs. It will be good to always be on the lookout for developments in any research area and try to understand issues and challenges as and when they are published.

Even though we don't read textbooks once we enter into the workforce, I still think they are necessary once in a while. They are needed to see what the new developments are. We should be reminded that what goes into textbooks have been out there for at least 10 years. So textbooks are backward in this regard. Nevertheless, we need them to teach our students. They will in turn need to turn to journals and more recent research book publications to find out more about recent development and updates.

The language used in the textbooks sometimes confuse students. Here in Malaysia we use British English or UK English spellings and measures. US textbooks use US spellings and measures. I often tell the students the differences so that they are aware.

I noticed that it is easier to read textbooks written in US English as the sentence structure is straight forward. I noticed that textbooks written in UK English are harder to read and comprehend as the sentence structure is not so straight forward. I have seen Stryer written in Korean script. I have seen Biochemistry written in Malaysian Malay. The diagrams matter most when I don't understand the text when it is written in languages other than English.

The following are some of the books I have used and/or evaluated for teaching medical biochemistry to our first year medical and dental students at our medical school. I evaluate books for class use and suggest to students in class or here at my blog. Some are new books. I will add more when they come to my desk and attention.


Title: Basic Medical Biochemistry: A clinical approach.
Author: Dawn B. Marks, Allan D. Marks, Colleen M. Smith
Publisher: Williams & Wilkins, Philadelphia
Textbook: International Edition, 1996
ISBN: 0-683-05595-X
Web: www.wwilkins.com
Email: custserv@wwilkins.com
Language: US English
Purchase date: May 1997 (softcover)
Review:

1. 2-tone texts, diagrams, titles and highlights (black and green). 
2. Two-part layout with a bigger column for text and a side column for additional texts, diagrams, reaction pathways, definitions, or cases. 
3. Well-drawn, clear simplified, annotated diagrams with bold and light texts.
4. The cases are laid out differently; they are introduced in one chapter and completed in other chapters; it is easy to lose track of the cases. To put an entire case together means flipping through several pages.
5. Each chapter opens with the scope that will be covered.
6. Easy to read for first year students.

Title: Essential Biochemistry
Author: Pratt
Publisher: John Wiley & Sons
Year: 2014
ISBN: 1118083504
Complimentary copy was sent from Singapore office for evaluation (hardcover; 27 Oct 2013)
WILEY
BOOK DISTRIBUTION
1 FUSIONOPOLIS WALK
#07-01 SOLARIS SOUTH TOWER
SINGAPORE 138628
TEL. 65 66438000 (MAIN)
TEL. 65 66438333 (CSD HOTLINE)
FAX. 65 66438397
EMAIL. csd_ord@wiley.com

Review:

1. This is a good book if you need more recent structures on many biochemical compounds. 
2. Many of the diagrams feature 3D structures which were obtained from research labs
3. Colourful iStock photos appear at the start of each chapter
4. Colourful diagrams in most chapters
5. Very detailed mechanisms in some parts especially on nucleic acids and cell signalling
6. Detailed calculations for many reactions
7. Clinical correlates appear at the end of each chapter or section
8. More updated clinical information compared to many textbooks

Hypertension

Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is a chronic medical condition in which the blood pressure in the arteries is elevated. This requires the heart to work harder than normal to circulate blood through the blood vessels.

Blood pressure is summarised by two measurements, systolic and diastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole) and equate to a maximum and minimum pressure, respectively. Normal blood pressure at rest is within the range of 100-140mmHg systolic (top reading) and 60-90mmHg diastolic (bottom reading). High blood pressure is said to be present if it is persistently at or above 140/90 mmHg.

Hypertension is classified as either primary (essential) hypertension or secondary hypertension; about 90–95% of cases are categorized as "primary hypertension" which means high blood pressure with no obvious underlying medical cause. The remaining 5–10% of cases (secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart or endocrine system.

Hypertension is a major risk factor for stroke, myocardial infarction (heart attacks), heart failure, aneurysms of the arteries (e.g. aortic aneurysm), peripheral arterial disease and is a cause of chronic kidney disease. Even moderate elevation of arterial blood pressure is associated with a shortened life expectancy.

Dietary and lifestyle changes can improve blood pressure control and decrease the risk of associated health complications, although drug treatment is often necessary in people for whom lifestyle changes are not enough or not effective.

Case 1

Age: 55 years

Gender: Female

Weight: 75kg

Height: 153cm

BMI: 32kg/m2 (obese)
BP: 153/104 mmHg
Pulse: 102 bpm

BP: 153/104mmHg and Pulse 102/min

Anti-hypertensive drug: Twynsta 80mg/10mg Telmisartan/Amlodipine

Case 2 (after 2 weeks)

Age: 55 years

Gender: Female

Weight: 73.0kg

Height: 153cm

BMI: 31kg/m2 (obese)
BP: 123/80 mmHg
Pulse: 79 bpm

External links
http://en.wikipedia.org/wiki/Hypertension
http://healthintotality.blogspot.com/2013/03/hypertension-in-young-adults.html

Hepatitis A

Synonym: infectious hepatitis
Hepatitis A virus (HAV)
HAV is a picornavirus

Review (original in German)

The virus responsible for hepatitis A--hepatitis A virus (HAV)--is a small, spherical, and exceptionally resistant RNA-virus. It is transmitted preferentially by the faecal-oral route and apparently replicates exclusively in the liver. The damage of the liver ensuing from HAV infection most likely does not stem directly from virus replication but is the result of an interaction of cell mediated virus-specific immunity with infected hepatocytes. Infection is usually self limiting, yet, in individual cases may also take a protracted and even relapsing course. True chronic infections, however, are not observed. HAV has a world-wide distribution. In countries where inadequate sanitary conditions prevail, the virus persists in the environment and almost 100% of the population acquires infection in childhood. At that age, infection causes no or only minimal clinical symptoms. Infected individuals nevertheless develop protective, long lasting immunity, probably persisting for entire life. In developed, industrialized countries HAV has ceased to circulate in the environment and the general population. Here, infections predominantly occur in adults travelling to endemic areas or exposed at home to thus infected individuals or members of high risk groups (e.g. children in day care centres, i.v. drug users). With increasing age infections become more and more clinically manifest and at and beyond of adolescence more than 80% of patients develop icteric, in some cases even fulminant and fatal hepatitis. Acute hepatitis A infection can be diagnosed by demonstrating the presence of anti-HAV-IgM antibodies. Immunity following either infection or successful vaccination is assessed by measuring anti-HAV-IgG. Preventive measures rely on strict personal and alimentary hygiene as well as on vaccination with inactivated (killed) hepatitis A vaccines. These vaccines are safe, highly immunogenetic and induce long lasting (> 20 years) protection against hepatitis A. Specific antiviral therapy is not yet available.

Introduction

Hepatitis A (formerly known as infectious hepatitis) is an acute infectious disease of the liver. It is caused by the hepatitis A virus (HAV). The HAV is an RNA virus. It is usually spread by the fecal-oral route. It can be transmitted person-to-person by ingestion of contaminated food or water. It can be contracted through direct contact with an infectious person.

Tens of millions of individuals worldwide are estimated to become infected with HAV each year. The time between infection and the appearance of the symptoms (the incubation period) is between two and six weeks and the average incubation period is 28 days.

In developing countries, and in regions with poor standards of hygiene, the incidence of infection with HAV is high. The illness is usually contracted in early childhood. As incomes rise and access to clean water increases, the incidence of HAV decreases. Hepatitis A infection causes no clinical signs and symptoms in over 90% of infected children. The infection confers lifelong immunity. The disease is of no special significance to those infected early in life.

In more developed countries, in Europe, the USA and other industrialized countries, the infection is contracted primarily by susceptible young adults. Most of whom are infected with the virus during trips to countries with a high incidence of the disease. They can also contract HAV through contact with infectious persons.

HAV infection produces a self-limited disease that does not result in chronic infection or chronic liver disease. However, 10–15% of patients might experience a relapse of symptoms during the 6 months after acute illness.

Acute liver failure from Hepatitis A is rare (overall case-fatality rate: 0.5%). The risk for symptomatic infection is directly related to age, with more than 80% of adults having symptoms compatible with acute viral hepatitis and the majority of children having either asymptomatic or unrecognized infection. Antibody produced in response to HAV infection persists for life and confers protection against reinfection. The disease can be prevented by vaccination. Hepatitis A vaccines have been proven effective in controlling outbreaks worldwide.

Signs and symptoms

Early symptoms of hepatitis A infection can be mistaken for influenza. Some sufferers, especially children, exhibit no symptoms at all. Symptoms typically appear 2 to 6 weeks (the incubation period) after the initial infection.

Symptoms usually last less than 2 months, although some people can be ill for as long as 6 months:

• Fatigue
• Fever
• Nausea
• Loss of appetite (LOA)
• Jaundice, a yellowing of the skin or whites of the eyes (sclarae) due to hyperbilirubinemia
• Bile is removed from blood stream and excreted in urine, giving it a dark amber colour
• Diarrhea
• Clay-coloured faeces (lacking the usual brown pigment)

Virology

Following ingestion, HAV enters the bloodstream through the epithelium of the oropharynx or intestine. The blood carries the virus to its target, the liver, where it multiplies within hepatocytes (liver cells) and Kupffer cells (liver macrophages).

Virions are secreted into the bile (hempedu) and released in stool. HAV is excreted in large quantities approximately 11 days prior to appearance of symptoms or anti-HAV IgM antibodies in the blood.

The incubation period is 15–50 days and mortality is less than 0.5%. Within the liver hepatocytes the RNA genome is released from the protein coat and is translated by the cell's own ribosomes.

Unlike other members of the Picornaviruses this virus requires an intact eukaryote initiating factor 4G (eIF4G) for the initiation of translation. The requirement for this factor results in an inability to shut down host protein synthesis unlike other picornaviruses.

The virus must then inefficiently compete for the cellular translational machinery which may explain its poor growth in cell culture. Presumably for this reason the virus has strategically adopted a naturally highly deoptimized codon usage with respect to that of its cellular host. Precisely how this strategy works is not quite clear yet.

There is no apparent virus-mediated cytotoxicity presumably because of the virus' own requirement for an intact eIF4G and liver pathology is likely immune-mediated.

Structure

The Hepatitis A virus (HAV) is a Picornavirus; it is non-enveloped and contains a single-stranded RNA packaged in a protein shell. There is only one serotype of the virus, but multiple genotypes exist. Codon use within the genome is biased and unusually distinct from its host. It also has a poor internal ribosome entry site. In the region that codes for the HAV capsid, there are highly conserved clusters of rare codons that restrict antigenic variability.

Transmission

The virus spreads by the fecal-oral route. Infections often occur in conditions of poor sanitation and overcrowding. Hepatitis A can be transmitted by the parenteral route but very rarely by blood and blood products.

Food-borne outbreaks are not uncommon. Ingestion of shellfish cultivated in polluted water is associated with a high risk of infection. Approximately 40% of all acute viral hepatitis is caused by HAV.

Infected individuals are infectious prior to onset of symptoms, roughly 10 days following infection.

The virus is resistant to detergent, acid (pH 1), solvents (e.g., ether, chloroform), drying, and temperatures up to 60 °C. It can survive for months in fresh and salt water.

Common-source (e.g., water, restaurant) outbreaks are typical.

Infection is common in children in developing countries, reaching 100% incidence, but following infection there is lifelong immunity.

HAV can be inactivated by: chlorine treatment (drinking water), formalin (0.35%, 37 °C, 72 hours), peracetic acid (2%, 4 hours), beta-propiolactone (0.25%, 1-hour), and UV radiation (2 μW/cm2/min).

Diagnosis

(i) Serum IgG and IgM

Two antibodies are used to detect HAV infection, HAV-specific IgM and HAV-specific IgG. Antibodies to HAV (anti-HAV) in the blood are a marker of past or current infection.

• HAV-specific IgM are used to detect present HAV infection.
• HAV-specific IgG are used to detect past HAV infection.

Although HAV is excreted in the faeces towards the end of the incubation period, specific diagnosis is made by the detection of HAV-specific IgM antibodies in the blood. IgM antibody is only present in the blood following an acute hepatitis A infection. It is detectable from one to two weeks after the initial infection and persists for up to 14 weeks.

The presence of IgG antibody in the blood means that the acute stage of the illness is past and the person is immune to further infection. IgG antibody to HAV is also found in the blood following vaccination and tests for immunity to the virus are based on the detection of this antibody.

(ii) Hepatitis serological panel

Serological markers of acute hepatitis: HBsAg, HBcIgM, anti-HCV, HEV-IgM, and HAV-IgM.
Serological markers of chronic hepatitis: HBsAg, HBcIgG, HBeAg, and anti-HCV.

(iii) Serum ALT

During the acute stage of the infection, the liver enzyme alanine transferase (ALT) is present in the blood at levels much higher than is normal. The enzyme comes from the liver cells (hepatocytes) that have been damaged by the virus.

(iv) EM: Presence of HAV particles in blood and faeces

HAV is present in blood and faeces. It can be detected by electron microscopy (EM).

Hepatitis A virus is present in the blood (viremia) and faeces of infected people up to two weeks before clinical illness develops.

Prevention

Hepatitis A can be prevented by vaccination, good hygiene and sanitation.

For information about the vaccine, its properties, and its application, see Hepatitis A vaccine.

There are two types of vaccines: one containing inactivated hepatitis A virus, and another containing a live but attenuated virus.

Both provide active immunity against a future infection.

The vaccine protects against HAV in more than 95% of cases for longer than 25 years.

In the USA the vaccine was first phased in 1996 for children in high-risk areas, and in 1999 it was spread to areas with elevating levels of infection.

The vaccine is given by injection.

An initial dose provides protection starting two to four weeks after vaccination; the second booster dose, given six to twelve months later, provides protection for over twenty years.

Vaccination programmes

The vaccine was introduced in 1992 and was initially recommended for persons at high risk.

Since then Bahrain and Israel have embarked on eradication programmes.

Australia, China, Belarus, Italy, Spain and the USA have started similar programmes.

The incidence of hepatitis A where widespread vaccination has been practised has decreased dramatically.

In China and the USA the incidence of hepatitis A has decreased by 90% since 1990.

Treatment

There is no specific treatment for hepatitis A.

(i) The normal doctors' advice

Sufferers are advised to rest, avoid fatty foods and alcohol (these may be poorly tolerated for some additional months during the recovery phase and cause minor relapses), eat a well-balanced diet, and stay hydrated.

(ii) Traditional Malay advice

In the Malay World, the elderly will advise to take fresh goat's milk with infusion of the dukung anak plant. These are taken twice a day. This clears HAV infection within 2 weeks (as opposed to 1 month in the usual course of HAV clearance). The dukung anak plant is a common garden weed.

Prognosis

The United States Centers for Disease Control and Prevention (CDC) in 1991 reported a low mortality rate for hepatitis A of 4 deaths per 1000 cases for the general population but a higher rate of 17.5 per 1000 in those aged 50 and over.

The risk of death from acute liver failure following HAV infection increases with age and when the person has underlying chronic liver disease.

Young children that are infected with hepatitis A typically have a milder form of the disease, usually lasting from 1–3 weeks, whereas adults tend to experience a much more severe form of the disease.

Epidemiology

High-income regions (Western Europe, Australia, New Zealand, Canada, the United States, Japan, the Republic of Korea, and Singapore) have very low HAV endemicity levels and a high proportion of susceptible adults.

Low-income regions (sub-Saharan Africa and parts of South Asia) have high endemicity levels and almost no susceptible adolescents and adults.

Most middle-income regions have a mix of intermediate and low endemicity levels.

Anti-HAV prevalence suggest that middle-income regions in Asia, Latin America, Eastern Europe, and the Middle East currently had an intermediate or low level of endemicity in 2005. The countries in these regions may have an increasing burden of disease from hepatitis A.

Globally, in 2010, acute hepatitis A resulted in 102,000 deaths which is slightly up from 99,000 in 1990.

There were 30,000 cases of Hepatitis A reported to the CDC in the U.S. in 1997. There were as many as 270,000 cases each year from 1980 through 2000.

Approximately one third of the US population has been infected by hepatitis A, most of whom go undiagnosed.

Genotypes

Only one serotype and seven different genetic groups (four humans and three simian) have been described.

The human genotypes are numbered I-III. Six subtypes have been described (IA, IB, IIA, IIB, IIIA, IIIB).

The simian (monkey) genotypes have been numbered IV-VI.

A single isolate of genotype VII isolated from a human has also been described.

Genotype III has been isolated from both humans and owl monkeys.

Most human isolates are of genotype I. Of the type I isolates subtype IA accounts for the majority. The mutation rate in the genome has been estimated to be 1.73 - 9.76 x 10−4 nucleotide substitution per site per year.

Cases

(i) USA - tainted green onions

The most widespread hepatitis A outbreak in the 2003 United States hepatitis outbreak afflicted at least 640 people (killing four) in north-eastern Ohio and south-western Pennsylvania in late 2003. The outbreak was blamed on tainted green onions at a restaurant in Monaca, Pennsylvania.

(ii) USA - recall of frozen berries

In June 2013, frozen berries sold by US retailer Costco and purchased by around 240,000 people were the subject of a recall, after at least 158 people were infected with HAV, 69 of whom were hospitalized.

(iii) China - contaminated river clams

In 1988, more than 300,000 people in Shanghai, China were infected with HAV after eating clams (Anadara subcrenata) from a contaminated river.

(iv) Italy

During the period 1985-1994, 25553 viral hepatitis cases were reported. Of these, 6408 (25%) were due to hepatitis A (HAV).

(v) Brazil

The prevalence of hepatitis A varies greatly in different Brazilian regions, from 56% in South and Southeast to 93% in North region (Manaus, Amazon). Such differences are also found in different socioeconomic levels among age groups.

(vi) India

Hepatitis A (HAV) is endemic in India and most of the population is infected asymptomatically in early childhood with lifelong immunity. Because of altered epidemiology and decreasing endemicity, the pattern of acute HAV infection is changing from asymptomatic childhood infection to an increased incidence of symptomatic disease in the 18-40 age group. Sera collected from 3495 patients with acute (1932) and chronic (1563) liver disease attending the Medical Outpatient Department of Lok Nayak Hospital during the previous five years (1999-2003) were tested for various serological markers of acute (HBsAg, HBcIgM, anti-HCV, HEV-IgM, and HAV-IgM) and chronic (HBsAg, HBcIgG, HBeAg, and anti-HCV) hepatitis. In addition, 500 normal healthy attendants of the patients above the age of 15 years were tested for IgG anti-HAV as controls. Of 1932 patients with acute viral hepatitis, 221 (11.4%) were positive for immunoglobulin M (IgM) anti-HAV. The patients who were IgM anti-HAV negative included hepatitis B (321 patients), C (39 patients), E (507 patients) and unclassified (844 patients). Although the frequency of HAV infection among children had increased (10.6% to 22.0%) in the 5-year period, the frequency of HAV infection among adults had also increased (3.4% to 12.3%) during the same period. A total of 300 patients with chronic liver diseases that were etiologically related to hepatitis B (169), C (73) or dual infection (10) and alcoholic liver injury (48) were tested for the presence of IgG anti-HAV antibody; 98% (294/300) were positive for the antibody. Although universal vaccination against HAV is not currently indicated, selective vaccination of the high-risk population, based on their serological evidence of HAV antibody, would be a rational and cost-effective approach.

(vii) Argentina

Hepatitis A virus (HAV) has shown intermediate endemicity in Argentina. Its incidence has decreased since the HAV vaccine was introduced in 2005. Environmental surveillance was conducted in 5 rivers from Argentina from 2005 to 2012. HAV detection decreased since 2005. It is being circulated, maintaining viral diversity but not undergoing antigenic drift. Most sequences belonged to subgenotype IA, closely related to Argentinean clinical sequences. However, one belonged to proposed subgenotype IC, previously undetected in the country. Environmental surveillance might contribute to monitoring the single-dose vaccination schedule.

Implications of HAV infection to Malaysian food imports

Malaysia imports its beef or beef cattles from Argentina and India. It is important that the Malaysian authorities are strict with hepatitis A infection in frozen beef (daging beku) coming from overseas. Malaysia's high beef consumption hovers around the two festive seasons that are celebrated nationwide - Aidilfitri and Aidiladha.

Malaysians have started consuming milk and milk products from overseas since the 1980s. They include fresh and flavoured milk, ice-creams, yoghurts and yoghurt drinks. Food poisoning has been reported from primary schools but there are no reports of HAV infection from dairy produce.


External links
http://en.wikipedia.org/wiki/Hepatitis_A
Southscience.pbworks.com: "Hepatitis A."
Health-advisors.org: "Hepatitis-a-symptoms."
Abcnews.go.com: "Frozen-berries-recalled-over-hepatitis-fears."
Food.com: "Green-onion."
Sciencedirect.com/Clinical course and consequences of hepatitis A infection."
http://www.ncbi.nlm.nih.gov/pubmed/10683554
http://www.ncbi.nlm.nih.gov/pubmed/9126784
http://www.ncbi.nlm.nih.gov/pubmed/15771857
http://www.ncbi.nlm.nih.gov/pubmed/14579471
http://www.ncbi.nlm.nih.gov/pubmed/16677154
http://www.ncbi.nlm.nih.gov/pubmed/23072283
Emedicinehealth.com: "Hepatitis A Symptoms."

Hepatitis B

Synonym: Serum hepatitis
Hepatitis B virus (HBV)
Human immunodeficiency virus (HIV)


Introduction

Hepatitis B is an infectious inflammatory illness of the liver. It is caused by the hepatitis B virus (HBV). Hepatitis B affects humans.

It was originally known as "serum hepatitis". The disease has caused epidemics in parts of Asia and Africa. it is endemic in China. About a third of the world population has been infected at one point in their lives. There are 350 million people who are chronic carriers.

The HBV is transmitted by exposure to infectious blood or body fluids such as semen and vaginal fluids. Viral DNA has been detected in the saliva, tears, and urine of chronic carriers.

Perinatal infection is a major route of infection in endemic (mainly developing) countries.

Other risk factors for developing HBV infection include working in a healthcare setting, transfusions, dialysis, acupuncture, tattooing, sharing razors or toothbrushes with an infected person, travel in countries where it is endemic, and residence in an institution.

HBV cannot be spread by holding hands, sharing eating utensils or drinking glasses, kissing, hugging, coughing, sneezing, or breastfeeding.

The acute illness causes liver inflammation, vomiting, jaundice, and, rarely, death. Chronic hepatitis B may eventually cause cirrhosis and liver cancer—a disease with poor response to all but a few current therapies. The infection is preventable by vaccination.

HBV is a hepadnavirus—hepa from hepatotropic (attracted to the liver) and dna because it is a DNA virus—and it has a circular genome of partially double-stranded DNA (dsDNA). The viruses replicate through an RNA intermediate form by reverse transcription, which in practice relates them to retroviruses. Although replication takes place in the liver, the virus spreads to the blood where viral proteins and antibodies against them are found in infected people. The HBV is 50 to 100 times more infectious than HIV.

Signs and symptoms

(i) Acute HBV infection

Acute infection with HBV is associated with acute viral hepatitis–an illness that begins with general ill-health, loss of appetite, nausea, vomiting, body aches, mild fever, and dark urine, and then progresses to development of jaundice.

It has been noted that itchy skin has been an indication as a possible symptom of all hepatitis virus types. The illness lasts for a few weeks and then gradually improves in most affected people.

A few people may have more severe liver disease (fulminant hepatic failure), and may die as a result. The infection may be entirely asymptomatic and may go unrecognized.

(ii) Chronic HBV infection

Chronic infection with hepatitis B virus either may be asymptomatic or may be associated with a chronic inflammation of the liver (chronic hepatitis), leading to cirrhosis over a period of several years. This type of infection dramatically increases the incidence of hepatocellular carcinoma (liver cancer).

Across Europe Hepatitis B and C cause approximately 50% hepatocellular carcinomas. Chronic carriers are encouraged to avoid consuming alcohol as it increases their risk for cirrhosis and liver cancer.

HBV has been linked to the development of membranous glomerulonephritis (MGN).

Symptoms outside of the liver are present in 1–10% of HBV-infected people and include serum-sickness–like syndrome, acute necrotizing vasculitis (polyarteritis nodosa), membranous glomerulonephritis, and papular acrodermatitis of childhood (Gianotti-Crosti syndrome). The serum-sickness–like syndrome occurs in the setting of acute hepatitis B, often preceding the onset of jaundice. The clinical features are fever, skin rash, and polyarteritis. The symptoms often subside shortly after the onset of jaundice, but can persist throughout the duration of acute hepatitis B. About 30–50% of people with acute necrotizing vasculitis (polyarteritis nodosa) are HBV carriers. HBV-associated nephropathy has been described in adults but is more common in children. Membranous glomerulonephritis is the most common form. Other immune-mediated hematological disorders, such as essential mixed cryoglobulinemia and aplastic anemia.

Virology

HBV Structure

HBV is a member of the Hepadnavirus family. The virus particle (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. These virions are 30-42 nm in diameter. The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity. The outer envelope contains embedded proteins that are involved in viral binding of, and entry into, susceptible cells. The virus is one of the smallest enveloped animal viruses, and the 42 nM virions, which are capable of infecting hepatocytes (liver cells), are referred to as "Dane particles". In addition to the Dane particles, filamentous and spherical bodies lacking a core can be found in the serum of infected individuals. These particles are not infectious and are composed of the lipid and protein that forms part of the surface of the virion, which is called the hepatitis B surface antigen (HBsAg), and is produced in excess during the life cycle of the virus.

HBV Genome

The genome of HBV is made of circular DNA, but it is unusual because the DNA is not fully double-stranded. One end of the full length strand is linked to the viral DNA polymerase. The genome is 3020–3320 nucleotides long (for the full-length strand) and 1700–2800 nucleotides long (for the short length-strand). The negative-sense (non-coding) is complementary to the viral mRNA. The viral DNA is found in the nucleus soon after infection of the cell. The partially double-stranded DNA is rendered fully double-stranded by completion of the (+) sense strand and removal of a protein molecule from the (-) sense strand and a short sequence of RNA from the (+) sense strand. Non-coding bases are removed from the ends of the (-) sense strand and the ends are rejoined. There are four known genes encoded by the genome, called C, X, P, and S. The core protein is coded for by gene C (HBcAg), and its start codon is preceded by an upstream in-frame AUG start codon from which the pre-core protein is produced. HBeAg is produced by proteolytic processing of the pre-core protein. The DNA polymerase is encoded by gene P. Gene S is the gene that codes for the surface antigen (HBsAg). The HBsAg gene is one long open reading frame but contains three in frame "start" (ATG) codons that divide the gene into three sections, pre-S1, pre-S2, and S. Because of the multiple start codons, polypeptides of three different sizes called large, middle, and small (pre-S1 + pre-S2 + S, pre-S2 + S, or S) are produced. The function of the protein coded for by gene X is not fully understood but it is associated with the development of liver cancer. It stimulates genes that promote cell growth and inactivates growth regulating molecules.

HBV Replication

The life cycle of HBV is complex. Hepatitis B is one of a few known pararetroviruses: non-retroviruses that still use reverse transcription in their replication process. The virus gains entry into the cell by binding to NTCP on the surface and being endocytosed. Because the virus multiplies via RNA made by a host enzyme, the viral genomic DNA has to be transferred to the cell nucleus by host proteins called chaperones. The partially double stranded viral DNA is then made fully double stranded and transformed into covalently closed circular DNA (cccDNA) that serves as a template for transcription of four viral mRNAs. The largest mRNA, (which is longer than the viral genome), is used to make the new copies of the genome and to make the capsid core protein and the viral DNA polymerase. These four viral transcripts undergo additional processing and go on to form progeny virions that are released from the cell or returned to the nucleus and re-cycled to produce even more copies. The long mRNA is then transported back to the cytoplasm where the virion P protein (the DNA polymerase) synthesizes DNA via its reverse transcriptase activity.

HBV Serotypes and genotypes

The HBV is divided into four major serotypes (adr, adw, ayr, ayw) based on antigenic epitopes presented on its envelope proteins, and into eight genotypes (A-H) according to overall nucleotide sequence variation of the genome. The genotypes have a distinct geographical distribution and are used in tracing the evolution and transmission of the virus. Differences between genotypes affect the disease severity, course and likelihood of complications, and response to treatment and possibly vaccination.

Genotypes differ by at least 8% of their sequence and were first reported in 1988 when six were initially described (A-F). Two further types have since been described (G and H). Most genotypes are now divided into subgenotypes with distinct properties.

Distribution of genotypes

Genotype A is most commonly found in the Americas, Africa, India and Western Europe. It is divided into subgenotypes. Of these subgenotype A1 is further subdivided into an Asian and an African clade.

Genotype B is most commonly found in Asia and the United States. Genotype B1 dominates in Japan, B2 in China and Vietnam while B3 is confined to Indonesia. B4 is confined to Vietnam. All these strains specify the serotype ayw1. B5 is most common in the Philippines.

Genotype C is most common in Asia and the United States. Subgenotype C1 is common in Japan, Korea and China. C2 is common in China, South-East Asia and Bangladesh and C3 in Oceania. All these strains specify the serotype adr. C4 specifying ayw3 is found in Aborigines from Australia.

Genotype D is most commonly found in Southern Europe, India and the United States and has been divided into 8 subtypes (D1–D8). In Turkey genotype D is also the most common type. A pattern of defined geographical distribution is less evident with D1–D4 where these subgenotypes are widely spread within Europe, Africa and Asia. This may be due to their divergence having occurred before that of genotypes B and C. D4 appears to be the oldest split and is still the dominating subgenotype of D in Oceania.

Type E is most commonly found in West and Southern Africa.

Type F is most commonly found in Central and South America and has been divided into two subgroups (F1 and F2).

Genotype G has an insertion of 36 nucleotides in the core gene and is found in France and the United States.

Type H is most commonly found in Central and South America and California in United States.

Africa has five genotypes (A-E). Of these the predominant genotypes are A in Kenya, B and D in Egypt, D in Tunisia, A-D in South Africa and E in Nigeria. Genotype H is probably split off from genotype F within the New World.

Evolution

A Bayesian analysis of the genotypes suggests that the rate of evolution of the core protein gene is 1.127 (95% credible interval 0.925-1.329) substitutions per site per year.

The most recent common ancestor of genotypes A, B, D evolved in 1895 (95% confidence interval 1819-1959), 1829 (95% confidence interval 1690-1935) and 1880 (95% confidence interval 1783-1948) respectively.

Mechanisms / Pathogenesis

HBV primarily interferes with the functions of the liver by replicating in liver cells (hepatocytes). A functional receptor is NTCP. There is evidence that the receptor in the closely related duck HBV is carboxypeptidase D. The virions bind to the host cell via the preS domain of the viral surface antigen and are subsequently internalized by endocytosis. HBV-preS-specific receptors are expressed primarily on hepatocytes; however, viral DNA and proteins have also been detected in extrahepatic sites, suggesting that cellular receptors for HBV may also exist on extrahepatic cells.

During HBV infection, the host immune response causes both hepatocellular damage and viral clearance. Although the innate immune response does not play a significant role in these processes, the adaptive immune response, in particular virus-specific cytotoxic T lymphocytes(CTLs), contributes to most of the liver injury associated with HBV infection. CTLs eliminate HBV infection by killing infected cells and producing antiviral cytokines, which are then used to purge HBV from viable hepatocytes. Although liver damage is initiated and mediated by the CTLs, antigen-nonspecific inflammatory cells can worsen CTL-induced immunopathology, and platelets activated at the site of infection may facilitate the accumulation of CTLs in the liver.

Transmission

Transmission of HBV results from exposure to infectious blood or body fluids containing blood. Possible forms of transmission include sexual contact, blood transfusions and transfusion with other human blood products, re-use of contaminated needles and syringes, and vertical transmission from mother to child transmission (MTCT) during childbirth. Without intervention, a mother who is positive for HBsAg confers a 20% risk of passing the infection to her offspring at the time of birth. This risk is as high as 90% if the mother is also positive for HBeAg. HBV can be transmitted between family members within households, possibly by contact of nonintact skin or mucous membrane with secretions or saliva containing HBV. However, at least 30% of reported hepatitis B among adults cannot be associated with an identifiable risk factor. Breastfeeding after proper immunoprophylaxis did not contribute to MTCT of HBV.

Diagnosis

Hepatitis B viral antigens and antibodies detectable in the blood following acute infection are:

Hepatitis B surface antigen (HBsAg)
Hepatitis B core antigen (HBcAg)
IgM antibodies to the hepatitis B core antigen (anti-HBc IgM)
IgG antibodies to the hepatitis B core antigen (anti-HBc IgG)
Anti-HBc (both IgM and IgG)
Hepatitis B e antigen (HBeAg)

Hepatitis B viral antigens and antibodies detectable in the blood of a chronically infected person. The tests, called assays, for detection of hepatitis B virus infection involve serum or blood tests that detect either viral antigens (proteins produced by the HBV) or antibodies produced by the host. Interpretation of these assays is complex.

The hepatitis B surface antigen (HBsAg) is most frequently used to screen for the presence of this infection. It is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be present and it may be undetectable later in the infection as it is being cleared by the host. The infectious virion contains an inner "core particle" enclosing viral genome. The icosahedral core particle is made of 180 or 240 copies of core protein, alternatively known as hepatitis B core antigen (HBcAg). During this 'window' in which the host remains infected but is successfully clearing the virus, IgM antibodies to the hepatitis B core antigen (anti-HBc IgM) may be the only serological evidence of disease. Therefore most hepatitis B diagnostic panels contain HBsAg and total anti-HBc (both IgM and IgG).

Shortly after the appearance of the HBsAg, another antigen called hepatitis B e antigen (HBeAg) will appear. Traditionally, the presence of HBeAg in a host's serum is associated with much higher rates of viral replication and enhanced infectivity; however, variants of the hepatitis B virus do not produce the 'e' antigen, so this rule does not always hold true. During the natural course of an infection, the HBeAg may be cleared, and antibodies to the 'e' antigen (anti-HBe) will arise immediately afterwards. This conversion is usually associated with a dramatic decline in viral replication.

Ground glass hepatocytes as seen in a chronic hepatitis B liver biopsy.

H and E stain

If the host is able to clear the infection, eventually the HBsAg will become undetectable and will be followed by IgG antibodies to the hepatitis B surface antigen (anti-HBs IgG) and core antigen (anti HBc IgG). The time between the removal of the HBsAg and the appearance of anti-HBs is called the window period. A person negative for HBsAg but positive for anti-HBs either has cleared an infection or has been vaccinated previously.

Individuals who remain HBsAg positive for at least six months are considered to be hepatitis B carriers. Carriers of the virus may have chronic hepatitis B, which would be reflected by elevated serum alanine aminotransferase (ALT) levels and inflammation of the liver, as revealed by biopsy. Carriers who have seroconverted to HBeAg negative status, in particular those who acquired the infection as adults, have very little viral multiplication and hence may be at little risk of long-term complications or of transmitting infection to others.

PCR tests have been developed to detect and measure the amount of HBV DNA, called the viral load, in clinical specimens. These tests are used to assess a person's infection status and to monitor treatment. Individuals with high viral loads, characteristically have ground glass hepatocytes on biopsy.

Prevention

(i) Hepatitis B vaccine

Vaccines for the prevention of hepatitis B have been routinely used since the early 1980s.

The first vaccines contained inactivated HBsAg that was derived from human plasma of hepatitis B virus carriers.

Modern vaccines contain HBsAg from yeast or mammalian cell cultures using recombinant DNA technology and have no risk of transmitting HBV.

Most vaccines are given in three doses over a course of months.

A protective response to the vaccine is defined as an anti-HBs antibody concentration of at least 10 mIU/ml in the recipient's serum.

The vaccine is more effective in children and 95% of those vaccinated have protective levels of antibody. This drops to around 90% at forty years of age and to around 75% in those over sixty.

The protection afforded by vaccination is long lasting even after antibody levels fall below 10 mIU/ml.

Vaccination at birth is recommended for all infants of HBV infected mothers.

A combination of hepatitis B immunoglobulin (Ig) and an accelerated course of HBV vaccine prevents perinatal HBV transmission in around 90% of cases.

(ii) Sperm washing

In assisted reproductive technology, The Practice Committee of the American Society for Reproductive Medicine advises that sperm washing is not necessary for males with hepatitis B to prevent transmission, unless the female partner has not been effectively vaccinated. In females with hepatitis B, the risk of vertical transmission (mother to child) during in vitro fertilisation (IVF) is no different from the risk in spontaneous conception.

Treatment

The hepatitis B infection does not usually require treatment because most adults clear the infection spontaneously. Early antiviral treatment may be required in fewer than 1% of people, whose infection takes a very aggressive course (fulminant hepatitis) or who are immunocompromised. On the other hand, treatment of chronic infection may be necessary to reduce the risk of cirrhosis and liver cancer. Chronically infected individuals with persistently elevated serum alanine aminotransferase (ALT), a marker of liver damage, and HBV DNA levels are candidates for therapy. Treatment lasts from six months to a year, depending on medication and genotype.

Although none of the available drugs can clear the infection, they can stop the HBV from replicating, thus minimizing liver damage. As of 2008, there are seven medications licensed for treatment of HBV infection in the USA. These include antiviral drugs lamivudine (Epivir), adefovir (Hepsera), tenofovir (Viread), telbivudine (Tyzeka) and entecavir (Baraclude), and the two immune system modulators interferon alpha-2a and PEGylated interferon alpha-2a (Pegasys). The use of interferon, which requires injections daily or thrice weekly, has been supplanted by long-acting PEGylated interferon, which is injected only once weekly. However, some individuals are much more likely to respond than others, and this might be because of the genotype of the infecting HBV or the person's heredity. The treatment reduces viral replication in the liver, thereby reducing the viral load (the amount of HBV particles as measured in the blood). Response to treatment differs between the genotypes.

Seroconversion

Interferon treatment may produce an e antigen seroconversion rate of 37% in genotype A but only a 6% seroconversion in type D. Genotype B has similar seroconversion rates to type A while type C seroconverts only in 15% of cases. Sustained e antigen loss after treatment is ~45% in types A and B but only 25–30% in types C and D.

Prognosis[edit]Hepatitis B virus infection may be either acute (self-limiting) or chronic (long-standing). Persons with self-limiting infection clear the infection spontaneously within weeks to months.

Children are less likely than adults to clear the infection. More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the HBV. However, this drops to 30% for younger children, and only 5% of newborns that acquire the infection from their mother at birth will clear the infection. This population has a 40% lifetime risk of death from cirrhosis or hepatocellular carcinoma. Of those infected between the age of one to six, 70% will clear the infection.

Co-infection

Hepatitis D (HDV) can occur only with a concomitant hepatitis B infection, because HDV uses the HBV surface antigen to form a capsid. Co-infection with hepatitis D increases the risk of liver cirrhosis and liver cancer. Polyarteritis nodosa is more common in people with hepatitis B infecti

Reactivation

HBV DNA persists in the body after infection, and in some people the disease recurs. Although rare, reactivation is seen most often following alcohol or drug use, or in people with impaired immunity. HBV goes through cycles of replication and non-replication. Approximately 50% of overt carriers experience acute reactivation.

Males with baseline ALT of 200 UL/L are three times more likely to develop a reactivation than people with lower levels.

Although reactivation can occur spontaneously, people who undergo chemotherapy have a higher risk. Immunosuppressive drugs favor increased HBV replication while inhibiting cytotoxic T cell function in the liver.

The risk of reactivation varies depending on the serological profile; those with detectable HBsAg in their blood are at the greatest risk, but those with only antibodies to the core antigen are also at risk. The presence of antibodies to the surface antigen, which are considered to be a marker of immunity, does not preclude reactivation.

Treatment with prophylactic antiviral drugs can prevent the serious morbidity associated with HBV disease reactivation.

Epidemiology

Prevalence of HBV as of 2005.

In 2004, an estimated 350 million individuals were infected worldwide. National and regional prevalence ranges from over 10% in Asia to under 0.5% in the USA and northern Europe. Routes of infection include vertical transmission (such as through childbirth), early life horizontal transmission (bites, lesions, and sanitary habits), and adult horizontal transmission (sexual contact, intravenous drug use).

The primary method of transmission reflects the prevalence of chronic HBV infection in a given area. In low prevalence areas such as the continental USA and Western Europe, injection drug abuse and unprotected sex are the primary methods, although other factors may also be important.

In moderate prevalence areas, which include Eastern Europe, Russia, and Japan, where 2–7% of the population is chronically infected, the disease is predominantly spread among children.

In high-prevalence areas such as China and South East Asia (SEA), transmission during childbirth is most common (vertical transmission), although in other areas of high endemicity such as Africa, transmission during childhood is a significant factor.

The prevalence of chronic HBV infection in areas of high endemicity is at least 8% with 10-15% prevalence in Africa/Far East.

As of 2010, China has 120 million infected people, followed by India and Indonesia with 40 million and 12 million, respectively. According to World Health Organization (WHO), an estimated 600,000 people die every year related to the infection.

History

(i) Smallpox in Bremen shipyard 1883; vaccination with lymph; Lurman's paper 1885; hypodermic needles 1909; Salvarsan for treating syphilis

The earliest record of an epidemic caused by hepatitis B virus (HBV) was made by Lurman in 1885. An outbreak of smallpox occurred in Bremen in 1883 and 1,289 shipyard employees were vaccinated with lymph from other people. After several weeks, and up to eight months later, 191 of the vaccinated workers became ill with jaundice and were diagnosed as suffering from serum hepatitis (HBV infection). Other employees who had been inoculated with different batches of lymph remained healthy. Lurman's paper, now regarded as a classical example of an epidemiological study, proved that contaminated lymph was the source of the outbreak. Later, numerous similar outbreaks were reported following the introduction, in 1909, of hypodermic needles that were used, and, more importantly, reused, for administering Salvarsan for the treatment of syphilis.

(ii) Baruch Blumberg at NIH 1966; Australian Ag (HBsAg); Australian aborigines; MacCallum 1947; DS Dane 1970 by EM; HBV genome sequenced and vaccines made 1980s;

The HBV was not discovered until 1966 when Baruch Blumberg, then working at the National Institutes of Health (NIH), discovered the Australia antigen (later known to be hepatitis B surface antigen, or HBsAg) in the blood of Australian aboriginal people. Although a virus had been suspected since the research published by MacCallum in 1947, D.S. Dane and others discovered the HBV particle in 1970 by electron microscopy. By the early 1980s the genome of the virus had been sequenced, and the first vaccines were being tested.

Society and culture

World Hepatitis Day is observed on 28 July. It aims to raise global awareness of hepatitis B and hepatitis C and encourage prevention, diagnosis and treatment. It has been led by the World Hepatitis Alliance since 2007 and in May 2010, it received global endorsement from the World Health Organization (WHO).



Sources and external links:
http://en.wikipedia.org/wiki/Hepatitis_B
http://healthintotality.blogspot.com/2010/07/reducing-risks-of-hepatitis.html

Hepatitis C

Introduction

Hepatitis C is usually spread through contact with blood or contaminated needles, including tattoo needles. Although hepatitis C may cause only mild symptoms or none at all, about 20% to 30% of those infected develop cirrhosis within 20 years to 30 years. The disease can be passed on through blood transfusions, but screening has greatly reduced the number of such cases. Hepatitis C is generally not spread through sex.

Organ

Hepatitis C is an infectious disease affecting primarily the liver, caused by the hepatitis C virus (HCV). The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years. In some cases, those with cirrhosis will go on to develop liver failure, liver cancer or life-threatening esophageal and gastric varices.

Spread

HCV is spread primarily by blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment and transfusions. It can be contracted from eating roadside iced food such as ais tapai cendol, which is a favourite ice-based food in Kelantan during hot days or the hot and dry season.

Infection

An estimated 150–200 million people worldwide are infected with hepatitis C. The existence of hepatitis C (originally "non-A non-B hepatitis") was postulated in the 1970s and proven in 1989. Hepatitis C infects only humans and chimpanzees.

Treatment

The virus persists in the liver in about 85% of those infected. This persistent infection can be treated with medication: the standard therapy is a combination of peginterferon and ribavirin, with either boceprevir or telaprevir added in some cases. Prescribed therapeutic drugs can take longer to cure, up to a month to cure hepatitis, compared to traditional cures.

A traditional cure is to take the boiled infusion of a common weed, pokok dukung anak, with raw goat's milk (should be clean bread goats and the milk should be TB-free) until malaise resolves and the patient gains sufficient energy to move and clean himself properly, i.e., able to take care of his personal hygiene. Cure is expected within 2 weeks of diagnosis of suspected hepatitis (with jaundice), and confirmed hepatitis C.

Cure

Overall, 50–80% of people treated are cured on prescribed drugs.

Traditional cures have a better outcome, and continue to be used by the Malay community in Kelantan.

Liver transplant

Those who develop cirrhosis or liver cancer may require a liver transplant. Hepatitis C is the leading reason for liver transplantation, though the virus usually recurs after transplantation.

Vaccine

No vaccine against hepatitis C is available yet.

Vaccine research will require knowledge of how the virus attaches to the human cell types. Vaccines can then be created against component(s) involved with viral attachment and viral replication.

Acute infection

Hepatitis C infection causes acute symptoms in 15% of cases.

Symptoms are generally mild and vague, including a decreased appetite, fatigue, nausea, muscle or joint pains, and weight loss and rarely does acute liver failure result.

Most cases of acute infection are not associated with jaundice.

The infection resolves spontaneously in 10-50% of cases, which occurs more frequently in individuals who are young and female.

Women can experience sudden weakness, lack of energy and jaundice. These clear up within 2 weeks with consumption of herbal infusion of pokok dukung anak and raw goat's milk.

Chronic infection

About 80% of those exposed to the virus develop a chronic infection. This is defined as the presence of detectable viral replication for at least six months. Most experience minimal or no symptoms during the initial few decades of the infection, although chronic hepatitis C can be associated with fatigue. Chronic infection after several years may cause cirrhosis or liver cancer. The liver enzymes are normal in 7-53%.

As for liver enzymes, ALP levels may remain high long after a hepatitis infection has occurred, but eventually resolves with avoidance of fatty foods and consumption of a mixture of apple cider vinegar (ACV), ginger, lemon and honey in cold water. Mix 1 teaspoon ACV + 1 slice ginger + 1 slice lemon and 2 tablespoons of honey in a cup of cold water. Consume twice daily - once in the morning before breakfast, and once before bedtime at night.

Liver changes

Fatty changes to the liver occur in about half of those infected and are usually present before cirrhosis develops. Usually (80% of the time) this change affects less than a third of the liver.

Worldwide hepatitis C is the cause of 27% of cirrhosis cases and 25% of hepatocellular carcinoma. About 10–30% of those infected develop cirrhosis over 30 years.

In those with hepatitis C, excess alcohol increases the risk of developing cirrhosis 100-fold. Those who develop cirrhosis have a 20-fold greater risk of hepatocellular carcinoma. This transformation occurs at a rate of 1–3% per year.

Liver cirrhosis may lead to portal hypertension, ascites (accumulation of fluid in the abdomen), easy bruising or bleeding, varices (enlarged veins, especially in the stomach and esophagus), jaundice, and a syndrome of cognitive impairment known as hepatic encephalopathy. Ascites occurs at some stage in more than half of those who have a chronic infection. Late relapses after apparent cure have been reported, but these can be difficult to distinguish from reinfection.

Complications

Extrahepatic complications: The most common problem due to hepatitis C but not involving the liver is mixed cryoglobulinemia (usually the type II form) - an inflammation of small and medium-sized blood vessels.

Hepatitis C is also associated with Sjögren's syndrome (an autoimmune disorder); thrombocytopenia; lichen planus; porphyria cutanea tarda; necrolytic acral erythema; insulin resistance; diabetes mellitus; diabetic nephropathy; autoimmune thyroiditis and B-cell lymphoproliferative disorders.

Thrombocytopenia is estimated to occur in 0.16% to 45.4% of people with chronic hepatitis C. 20-30% of people infected have rheumatoid factor - a type of antibody.

Possible associations include Hyde's prurigo nodularis and membranoproliferative glomerulonephritis. Cardiomyopathy with associated arrhythmias has also been reported. A variety of central nervous system disorders have been reported. Chronic infection seems to be associated with an increased risk of pancreatic cancer.

Occult infection

Persons who have been infected with hepatitis C may appear to clear the virus but remain infected. The virus is not detectable with conventional testing but can be found with ultra-sensitive tests.

The original method of detection was by demonstrating the viral genome within liver biopsies, but newer methods include an antibody test for the virus' core protein and the detection of the viral genome after first concentrating the viral particles by ultracentrifugation.

A form of infection with persistently moderately elevated serum liver enzymes but without antibodies to hepatitis C has also been reported. This form is known as cryptogenic occult infection. Several clinical pictures have been associated with this type of infection. It may be found in people with anti-hepatitis-C antibodies but with normal serum levels of liver enzymes; in antibody-negative people with ongoing elevated liver enzymes of unknown cause; in healthy populations without evidence of liver disease; and in groups at risk for HCV infection including those on haemodialysis or family members of people with occult HCV. The clinical relevance of this form of infection is under investigation.

The consequences of occult infection appear to be less severe than with chronic infection but can vary from minimal to hepatocellular carcinoma.

The rate of occult infection in those apparently cured is controversial but appears to be low. 40% of those with hepatitis but with both negative hepatitis C serology and the absence of detectable viral genome in the serum have hepatitis C virus in the liver on biopsy.

Virology

The hepatitis C virus (HCV) is a small, enveloped, single-stranded, positive-sense RNA virus. It is a member of the Hepacivirus genus in the family Flaviviridae. There are seven major genotypes of HCV, which are known as genotypes one to seven. The genotypes are divided into several subtypes with the number of subtypes depending on the genotype.

In the United States, about 70% of cases are caused by genotype 1, 20% by genotype 2 and about 1% by each of the other genotypes. Genotype 1 is also the most common in South America and Europe. The genotype distribution in Malaysia is unknown.

The half life of the virus particles in the serum is around 3 hours and may be as short as 45 minutes. In an infected person, about 1012 virus particles are produced each day. In addition to replicating in the liver the virus can multiply in lymphocytes. The virus can be detected in the blood plasma, lymphocytes, and liver cells (hepatocytes).

Transmission

The routes of transmission are intravenous drug use (IDU), blood transfusions and unsafe medical procedures. The cause of transmission remains unknown in 20% of cases; however, many of these are believed to be accounted for by IDU.

Hospital equipment has also been documented as a method of transmission of hepatitis C, including reuse of needles and syringes; multiple-use medication vials; infusion bags; and improperly sterilized surgical equipment, among others.

Limitations in the implementation and enforcement of stringent standard precautions in public and private medical and dental facilities are known to be the primary cause of the spread of HCV in Egypt, which has the highest rate of infection in the world.

Diagnosis

Serologic profile of Hepatitis C infection

There are a number of diagnostic tests for hepatitis C, including HCV antibody enzyme immunoassay or ELISA, recombinant immunoblot assay, and quantitative HCV RNA polymerase chain reaction (PCR). HCV RNA can be detected by PCR typically one to two weeks after infection, while antibodies can take substantially longer to form and thus be detected.

Chronic hepatitis C infection

Chronic hepatitis C is defined as infection with the hepatitis C virus persisting for more than six months based on the presence of its RNA. Chronic infections are typically asymptomatic during the first few decades, and thus are most commonly discovered following the investigation of elevated liver enzyme levels or during a routine screening of high-risk individuals. Testing is not able to distinguish between acute and chronic infections.

Biopsy

Liver biopsies are used to determine the degree of liver damage present; however, there are risks from the procedure. The typical changes seen are lymphocytes within the parenchyma, lymphoid follicles in portal triad, and changes to the bile ducts. There are a number of blood tests available that try to determine the degree of hepatic fibrosis and alleviate the need for biopsy.

Treatment

HCV induces chronic infection in 50–80% of infected persons. Approximately 40–80% of these clear with treatment. In rare cases, infection can clear without treatment.

Advice

Those with chronic hepatitis C are advised to avoid alcohol and medications toxic to the liver, and to be vaccinated for hepatitis A and hepatitis B.

Ultrasound

Ultrasound surveillance for hepatocellular carcinoma is recommended in those with accompanying cirrhosis.

Medications

In general, treatment is recommended for those with proven HCV infection liver abnormalities. All are combination drugs (combo drugs).

Treatment during the first six months is more effective than once hepatitis C has become chronic.

(i) Pegylated interferon alpha and ribavirin

Since 2010, treatments consist of a combination of pegylated interferon alpha and the antiviral drug ribavirin for a period of 24 or 48 weeks, depending on HCV genotype. This results cure rates of between 70–80% for genotype 2 and 3, and 45 to 70% for other genotypes.

When combined with ribavirin, pegylated interferon-alpha-2a may be superior to pegylated interferon-alpha-2b, though the evidence is not strong.

If someone develops a new infection and it has not cleared after eight to twelve weeks, 24 weeks of pegylated interferon is recommended.

In people with thalassemia, ribavirin appears to be useful but increases the need for transfusions.

(ii) Sofosbuvir and ribavirin

Another agent, sofosbuvir, when combined with ribavirin, shows improved response rates in the 95% range for genotype 2. This benefit is somewhat offset by a greater rate of adverse effects.

(iii) Boceprevir or teleprevir with ribavirin and peginterferon alfa

Combining either boceprevir or telaprevir with ribavirin and peginterferon alfa improves antiviral response for hepatitis C genotype 1.

Adverse effects

Adverse effects with treatment are common, with half of people getting flu like symptoms and a third experiencing emotional problems.

Surgery

Cirrhosis due to hepatitis C is a common reason for liver transplantion though the virus usually (80–90% of cases) recurs afterwards. Infection of the graft leads to 10–30% of people developing cirrhosis within five years. Treatment with pegylated interferon and ribavirin post transplant decreases the risk of recurrence to 70%.

Alternative medicine

Several alternative therapies are claimed by their proponents to be helpful for hepatitis C including milk thistle, ginseng, and colloidal silver. However, no alternative therapy has been shown to improve outcomes in hepatitis C, and no evidence exists that alternative therapies have any effect on the virus at all.

Also refer to previous posts on fatty liver and alternative medicine (Ayurvedic herbs).

Prognosis

The responses to treatment is measured by sustained viral response and vary by HCV C genotype. A sustained response occurs in about 40-50% in people with HCV genotype 1 given 48 weeks of treatment. A sustained response is seen in 70-80% of people with HCV genotypes 2 and 3 with 24 weeks of treatment. A sustained response occurs about 65% in those with genotype 4 after 48 weeks of treatment. The evidence for treatment in genotype 6 disease is sparse and what evidence there is supports 48 weeks of treatment at the same doses used for genotype 1 disease. Successful treatment decreases the future risk of hepatocellular carcinoma by 75%.

Among those chronically infected, the risk of cirrhosis after 20 years varies between studies but has been estimated at ~10%-15% for men and ~1-5% for women. The reason for this difference is not known. Once cirrhosis is established, the rate of developing hepatocellular carcinoma is ~1%-4% per year. Rates of new infections have decreased in the Western world since the 1990s due to improved screening of blood before transfusion.

Research

Since 2011, there are about 100 medications in development for hepatitis C. These include vaccines to treat hepatitis, immunomodulators, and cyclophilin inhibitors. These potential new treatments have come about due to a better understanding of the hepatitis C virus.

External links
http://www.hepatitisc.uw.edu/go/evaluation-staging-monitoring/natural-history/core-concept/all
http://www.herbalprovider.com/liver-enzymes.html
http://www.webmd.com/hepatitis/hepatitis-prevent-10/hepatitis-basics?page=2
http://en.wikipedia.org/wiki/Hepatitis_C
http://www.khatorepharma.com/wellness-1/kamalahar-wellness-1.html
http://en.wikipedia.org/wiki/Peginterferon_alfa-2b
http://www.drugs.com/cdi/peginterferon-alfa-2b.html
http://www.pegintron.com/peg/pegintron/consumer/index.jsp
http://en.wikipedia.org/wiki/Ribavirin
http://en.wikipedia.org/wiki/Sofosbuvir
http://en.wikipedia.org/wiki/Boceprevir
http://www.sahealth.sa.gov.au/

Gluconeogenesis

Questions

1. Does gluconeogenesis continue during starvation and in diabetes?
2. What happens to gluconeogenesis during starvation? Is it reduced or maintained?

Answers

The 2 conditions above are mostly discussed in biochemistry - starvation and diabetes. Pay attention to them.

In trying to answer the questions above, I have stuck only to hepatic glucose production in humans. I have broken up the answers into many parts so you can see what thoughts must go into trying to answer the questions.

I have included that on animals at the end to avoid confusion.

I have excluded the glyoxylate cycle which occurs in plants and nematodes.


1. Means for Producing Glucose

Blood glucose must be maintained within normal range. There are 2 sources of hepatic glucose production when blood glucose becomes low (hypoglycaemia). One is gluconeogenesis, and the other is glycogenolysis (degradation or breakdown of glycogen).

2. How does gluconeogenesis operate?

Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as:

1. pyruvate, 
2. lactate, 
3. glycerol, 
4. glucogenic amino acids (14 of them), and 
5. odd-chain fatty acids.

Lactate is transported back to the liver where it is converted into pyruvate by the Cori cycle using the enzyme lactate dehydrogenase (LD). 

Pyruvate, the first designated substrate of the gluconeogenic pathway, can then be used to generate glucose. 

Transamination or deamination of amino acids facilitates entering of their carbon skeleton into the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle (Kreb's cycle).

Gluconeogenesis is highly exergonic until ATP or GTP are utilized, effectively making the process endergonic. For example, the pathway leading from pyruvate to glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP.

Exergonic reactions release energy as ATP or GTP.
Endergonic reactions consume energy in the form of ATP or GTP.


3. Human Gluconeogenesis

In vertebrates (includes humans), gluconeogenesis takes place mainly in the liver and, to a lesser extent, in the cortex of kidneys.

In humans the main gluconeogenic precursors are lactate, glycerol (which is a part of the triacylglycerol molecule), alanine (Ala) and glutamine (Gln). Altogether, they account for over 90% of the overall gluconeogenesis. 

Other glucogenic amino acid as well as all citric acid cycle intermediates, the latter through conversion to oxaloacetate, can also function as substrates for gluconeogenesis.

Gluconeogenesis is often associated with ketosis; this indicates that gluconeogenesis goes on in starvation and diabetes.

Gluconeogenesis is also a target of therapy for type II diabetes, such as metformin, which inhibits glucose formation and stimulates glucose uptake by cells.

The existence of glyoxylate cycles in humans has not been established. It is widely held that fatty acids cannot be converted to glucose in humans directly. However, carbon-14 has been shown to end up in glucose when it is supplied in fatty acids. Despite these findings, it is considered unlikely that the 2-carbon acetyl-CoA derived from the oxidation of fatty acids would produce a net yield of glucose via the citric acid cycle. Put simply acetic acid (in the form of acetyl-CoA) is used to partially produce glucose; acetyl groups can only form part of the glucose molecules (not the 5th carbon atom) and require extra substrates (such as pyruvate) in order to form the rest of the glucose molecule.

In mammals, gluconeogenesis is restricted to the liver, the kidney (and possibly the intestine). However these organs use somewhat different gluconeogenic precursors. Liver uses primarily lactate and alanine while kidney uses lactate and glutamine.

In humans, PEP carboxykinase that converts oxaloacetate to PEP, can be found dispersed evenly between the mitochondria and the cytosol. 

4. Catabolism of Amino Acids

Amino acids are classified according to the abilities of their downstream products to enter gluconeogenesis or ketogenesis or both:

1. Glucogenic amino acids have the ability to enter gluconeogenesis and produce glucose. They are alanine (Ala), glycine (Gly), threonine (Thr), cysteine (Cys), serine (Ser), asparagine (Asn), aspartate (Asp), arginine (Arg), proline (Pro), histidine (His), glutamine (Gln), glutamate (Glu), valine (Val), and methionine (Met).
2. Ketogenic amino acids do not enter gluconeogenesis and do not produce glucose. Their products are used for ketogenesis or lipid synthesis. They are leucine (Leu) and lysine (Lys).
3. Some amino acids are catabolized into both glucogenic and ketogenic products. They are isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp).

5. Gluconeogenesis Pathway

Gluconeogenesis is a pathway consisting of a series of 11 enzyme-catalyzed reactions. The pathway may begin in the mitochondria or cytoplasm, this being dependent on the substrate being used. Many of the reactions are the reversible steps found in glycolysis (in cytosol).

What are the reactions in gluconeogenesis?

1. Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate (OAA) by the carboxylation of pyruvate. This reaction also requires one molecule of ATP, and is catalyzed by pyruvate carboxylase. This enzyme is stimulated by high levels of acetyl-CoA (produced in β-oxidation in fat breakdown in the liver) and inhibited by high levels of ADP.
2. Oxaloacetate (OAA) is reduced to malate using NADH, a step required for its transportation out of the mitochondria. Refer OAA-malate cycle.
3. Malate is oxidized to oxaloacetate (OAA) using NAD+ in the cytosol, where the remaining steps of gluconeogenesis take place.
4. Oxaloacetate (OAA) is decarboxylated and then phosphorylated to form phosphoenolpyruvate (PEP) using the enzyme phosphoenolpyruvate carboxykinase (PEP carboxykinase). A molecule of GTP is hydrolyzed to GDP during this reaction.
5. The next steps in the reaction are the same as reversed glycolysis. However, fructose-1,6-bisphosphatase converts fructose-1,6-bisphosphate to fructose 6-phosphate, using one water molecule and releasing one phosphate. This is also the rate-limiting step of gluconeogenesis.
6. Glucose-6-phosphate (G6P) is formed from fructose 6-phosphate (F6P) by phosphoglucoisomerase. Glucose-6-phosphate (G6P) can be used in other metabolic pathways or dephosphorylated to free glucose. Whereas free glucose can easily diffuse in and out of the cell, the phosphorylated form (glucose-6-phosphate) is locked in the cell, a mechanism by which intracellular glucose levels are controlled by cells.
7. The final reaction of gluconeogenesis, the formation of glucose, occurs in the lumen of the endoplasmic reticulum, where glucose-6-phosphate (G6P) is hydrolyzed by glucose-6-phosphatase to produce glucose. 
8. Glucose is shuttled into the cytoplasm by glucose transporters located in the endoplasmic reticulum's membrane.

6. How is gluconeogenesis regulated?

1. Reciprocal control by 3 major enzymes

While most steps in gluconeogenesis are the reverse of those found in glycolysis, three regulated and strongly exergonic reactions are replaced with more kinetically favorable reactions. 

Hexokinase/glucokinase, phosphofructokinase, and pyruvate kinase enzymes of glycolysis are replaced with glucose-6-phosphatase, fructose-1,6-bisphosphatase, and PEP carboxykinase. 

This system of reciprocal control allow glycolysis and gluconeogenesis to inhibit each other and prevent the formation of a futile cycle.

The majority of the enzymes responsible for gluconeogenesis are found in the cytoplasm; the exceptions are mitochondrial pyruvate carboxylase and, in animals, phosphoenolpyruvate carboxykinase. The latter exists as an isozyme located in both the mitochondrion and the cytosol.

The rate of gluconeogenesis is ultimately controlled by the action of a key enzyme, fructose-1,6-bisphosphatase, which is also regulated through signal transduction by cAMP and its phosphorylation.

Most factors that regulate the activity of the gluconeogenesis pathway do so by inhibiting the activity or expression of key enzymes. However, both acetyl CoA and citrate activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively). Due to the reciprocal control of the cycle, acetyl-CoA and citrate also have inhibitory roles in the activity of pyruvate kinase.

2. Hormonal control and acid-base imbalance

Global control of gluconeogenesis is mediated by glucagon (released when blood glucose is low); it triggers phosphorylation of enzymes and regulatory proteins by protein kinase A (a cyclic AMP regulated kinase) resulting in inhibition of glycolysis and stimulation of gluconeogenesis. 

Recent studies have shown that the absence of hepatic glucose production has no major effect on the control of fasting plasma glucose (FPG) concentration. 

Compensatory induction of gluconeogenesis occurs in the kidneys and intestine, driven by glucagon, glucocorticoids, and acidosis.

To answer the questions then;

1. Does gluconeogenesis continue during starvation and in diabetes? Yes.

2. What happens to gluconeogenesis during starvation? Is it reduced or maintained?

It is not reduced but it is maintained so that blood glucose remains at a level that is compatible with life (sustains life), and coma is avoided (which happens when hypoglycaemia dips further). All possible sources for gluconeogenesis to proceed will be used, but lipid sources will prevail since lipids are the eventual source of energy in starvation.

Animal Gluconeogenesis

In ruminants (cows, goats, and sheep), gluconeogenesis tends to be a continuous process. In ruminants, because metabolizable dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc.

In ruminants, propionate is the principal gluconeogenic substrate.

In many other animals (that hibernate or hunt for food), gluconeogenesis occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

Whether even-chain fatty acids can be converted into glucose in animals has been a longstanding question in biochemistry. It is known that odd-chain fatty acids can be oxidized to yield propionyl CoA, a precursor for succinyl CoA, which can be converted to pyruvate and enter into gluconeogenesis.

Propionate is the principal substrate for gluconeogenesis in the ruminant liver. The ruminant liver may make increased use of gluconeogenic amino acids, e.g. alanine, when glucose demand is increased. The capacity of liver cells to use lactate for gluconeogenesis declines from the preruminant stage to the ruminant stage in calves and lambs. In sheep kidney tissue, very high rates of gluconeogenesis from propionate have been observed. The intestine uses mostly glutamine and glycerol.

In all species, the formation of oxaloacetate from pyruvate and TCA cycle intermediates is restricted to the mitochondria, and the enzymes that convert phosphoenolpyruvic acid (PEP) to glucose are found in the cytosol. The location of the enzyme that links these two parts of gluconeogenesis by converting oxaloacetate to PEP, PEP carboxykinase, is variable by species: it can be found entirely within the mitochondria, entirely within the cytosol, or dispersed evenly between the two, as it is in humans. Transport of PEP across the mitochondrial membrane is accomplished by dedicated transport proteins; however no such proteins exist for oxaloacetate. Therefore, in species that lack intra-mitochondrial PEP carboxykinase, oxaloacetate must be converted into malate or aspartate, exported from the mitochondria, and converted back into oxaloacetate in order to allow gluconeogenesis to continue.

Source: http://en.wikipedia.org/wiki/Gluconeogenesis